General Information About Breast Cancer

This summary discusses only primary epithelial breast cancers. Rarely, the breast may be involved by other tumors such as lymphomas, sarcomas, or melanomas. (Refer to the PDQ summaries on Adult Hodgkin Lymphoma Treatment , Adult Soft Tissue Sarcoma Treatment , and Melanoma Treatment for more information.)

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2011:[1]

• New cases: 230,480.
• Deaths: 39,520.

Genetic Characteristics and Risk Factors

Several well-established factors have been associated with an increased risk of breast cancer, including family history, nulliparity, early menarche, advanced age, and a personal history of breast cancer (in situ or invasive).

Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.[2,3] Of all women with breast cancer, 5% to 10% may have a germ-line mutation of the genes BRCA1 and BRCA2.[4] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[5] The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as great as 5% per year.[6] Ma le carriers of BRCA2 mutations are also at increased risk for breast cancer.[7]

Mutations in either the BRCA1 or BRCA2 gene also confer an increased risk of ovarian cancer.[7,8,9] In addition, mutation carriers may be at increased risk of other primary cancers.[7,9] Genetic testing is available to detect mutations in members of high-risk families.[10,11,12,13,14] Such individuals should first be referred for counseling.[15] (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer ; Breast Cancer Prevention ; and Breast Cancer Screening for more information.)

Screening

Clinical trials have established that screening with mammography, with or without clinical breast examination, may decrease breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.)

Patient Evaluation

Patient management following initial suspicion of breast cancer generally includes confirmation of the diagnosis, evaluation of stage of disease, and selection of therapy. At the time the tumor tissue is surgically removed, estrogen receptor (ER) and progesterone receptor (PR) status should be determined.

Prognostic and Predictive Factors

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):[16]

• The age and menopausal status of the patient.
• The stage of the disease.
• The histologic and nuclear grade of the primary tumor.
• The ER and PR status of the tumor.
• Human epidermal growth factor type 2 receptor (HER2/neu) overexpression.
• Proliferative capacity of the tumor (e.g., Ki67).

Molecular profiling has led to classification of breast cancer into the following five distinct subtypes:[17,18]

• Basal-like.
• HER2+.
• Normal.
• Luminal A.
• Luminal B.

The use of molecular profiling in breast cancer includes the following:[17,18]

• ER and PR status testing.
• HER2/neureceptor status testing.
• Gene profile testing by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint,Onco type DX).

Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1 /BRCA2 mutation carriers who have developed breast cancer are conflicting; these women are at greater risk of developing contralateral breast cancer. Since criteria for menopausal status vary widely, some studies have substituted age older than 50 years as a surrogate for the postmenopausal state. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. For example, favorable histologic types include mucinous, medullary, and tubular carcinoma.[19,20,21]

Contralateral Disease

Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. Patients who have breast cancer should have bilateral mammography at the time of diagnosis to rule out synchronous disease. The role of magnetic resonance imaging (MRI) in screening and follow-up continues to evolve. Having demonstrated an increased detection rate of mammographically occult disease, the selective use of MRI for additional screening is being used with increased frequency despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation prior to treatment action is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.[22,23,24] When BRCA1 /BRCA2 mutation carriers were diagnosed at a young age, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.[25,26]

Patients should continue to have regular breast physical examinations and mammography to detect either recurrence in the ipsilateral breast in those patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast.[27] The risk of a primary breast cancer in the contralateral breast is approximately 1% per year.[28,29] Patient age younger than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.[30] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[31,32]

Hormone Replacement Therapy

The use of hormone replacement therapy (HRT) poses a dilemma for the rising numbers of breast cancer survivors, many of whom enter menopause prematurely as a result of therapy. HRT has generally not been used for women with a history of breast cancer because estrogen is a growth factor for most breast cancer cells in the laboratory; however, empiric data on the safety of HRT after breast cancer are limited.[33,34]

Two randomized trials (including Regional Oncologic Center-Hormonal Replacement Therapy After Breast Cancer--Is It Safe [ROC-HABITS]) comparing HRT with no hormonal supplementation have been reported.[35,36] The first trial included 345 evaluable breast cancer patients with menopausal symptoms and was terminated early because of an increased incidence of recurrences and new primaries in the HRT group (hazard ratio [HR] = 3.5; 95% confidence interval [CI], 1.5–7.4).[35][Level of evidence: 1iiDii] In total, 26 women in the HRT group and 7 in the non-HRT group developed recurrences or new primaries. This study, however, was not double blinded, and it is possible that patients on HRT were monitored more closely. Because of the results of the first trial, the second trial, which was conducted under a joint steering committee with the first, closed prematurely after the enrollment of 378 patients.[36] With a median follow-up of 4.1 years, there were 11 recurrences in the hormone replacement group and 13 recurrences in the patients assigned to no hormone replacement (HR = 0.82; 95% CI, 0.35–1.9).[36][Level of evidence: 1iiDii] The trials differed in several ways;[37] however, until further data become available, decisions concerning the use of HRT in patients with breast cancer will have to be based on the results of these studies and on inferences from the impact of HRT use on breast cancer risk in other settings.[37] A comprehensive intervention, including education, counseling, and nonhormonal drug therapy, has been shown to reduce menopausal symptoms and to improve sexual functioning in breast cancer survivors.[38][Level of evidence: 1iiC] (For more information, refer to the PDQ summaries on Fever, Sweats, and Hot Flashes and Sexuality and Reproductive Issues.)

Breast Reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[39,40,41,42] Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is replaced by a permanent implant. (Visit the FDA's Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[43]

Follow-up

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared to routine physical examinations.[44,45,46] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[45] Based on these data, some investigators recommend that acceptable follow-up be limited to physical examination and annual mammography for asymptomatic patients who complete treatment for stage I to stage III breast cancer. The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I to stage III breast cancer remain controversial.

Related Summaries

Other PDQ summaries containing information related to breast cancer include the following:

• Breast Cancer Prevention
• Breast Cancer Screening
• Breast Cancer Treatment and Pregnancy
• Genetics of Breast and Ovarian Cancer
• Male Breast Cancer Treatment
• Unusual Cancers of Childhood Treatment(breast cancer in children)

References:

1.	American Cancer Society.: Cancer Facts and Figures 2011. Atlanta, Ga: American Cancer Society, 2011. Also available online. Last accessed December 1, 2011.
2.	Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.
3.	Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.
4.	Blackwood MA, Weber BL: BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 16 (5): 1969-77, 1998.
5.	Offit K, Gilewski T, McGuire P, et al.: Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347 (9016): 1643-5, 1996.
6.	Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.
7.	Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.
8.	Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.
9.	Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.
10.	Biesecker BB, Boehnke M, Calzone K, et al.: Genetic counseling for families with inherited susceptibility to breast and ovarian cancer. JAMA 269 (15): 1970-4, 1993.
11.	Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.
12.	Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.
13.	Berry DA, Parmigiani G, Sanchez J, et al.: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89 (3): 227-38, 1997.
14.	Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995.
15.	Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.
16.	Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000.
17.	Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001.
18.	Perou CM, Sørlie T, Eisen MB, et al.: Molecular portraits of human breast tumours. Nature 406 (6797): 747-52, 2000.
19.	Rosen PP, Groshen S, Kinne DW: Prognosis in T2N0M0 stage I breast carcinoma: a 20-year follow-up study. J Clin Oncol 9 (9): 1650-61, 1991.
20.	Diab SG, Clark GM, Osborne CK, et al.: Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas. J Clin Oncol 17 (5): 1442-8, 1999.
21.	Rakha EA, Lee AH, Evans AJ, et al.: Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol 28 (1): 99-104, 2010.
22.	Lehman CD, Gatsonis C, Kuhl CK, et al.: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 356 (13): 1295-303, 2007.
23.	Solin LJ, Orel SG, Hwang WT, et al.: Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J Clin Oncol 26 (3): 386-91, 2008.
24.	Morrow M: Magnetic resonance imaging in the breast cancer patient: curb your enthusiasm. J Clin Oncol 26 (3): 352-3, 2008.
25.	Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009.
26.	Garber JE, Golshan M: Contralateral breast cancer in BRCA1/BRCA2 mutation carriers: the story of the other side. J Clin Oncol 27 (35): 5862-4, 2009.
27.	Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. Radiology 183 (1): 201-6, 1992.
28.	Rosen PP, Groshen S, Kinne DW, et al.: Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol 11 (11): 2090-100, 1993.
29.	Gustafsson A, Tartter PI, Brower ST, et al.: Prognosis of patients with bilateral carcinoma of the breast. J Am Coll Surg 178 (2): 111-6, 1994.
30.	Broët P, de la Rochefordière A, Scholl SM, et al.: Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol 13 (7): 1578-83, 1995.
31.	Healey EA, Cook EF, Orav EJ, et al.: Contralateral breast cancer: clinical characteristics and impact on prognosis. J Clin Oncol 11 (8): 1545-52, 1993.
32.	Heron DE, Komarnicky LT, Hyslop T, et al.: Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease. Cancer 88 (12): 2739-50, 2000.
33.	Cobleigh MA, Berris RF, Bush T, et al.: Estrogen replacement therapy in breast cancer survivors. A time for change. Breast Cancer Committees of the Eastern Cooperative Oncology Group. JAMA 272 (7): 540-5, 1994.
34.	Roy JA, Sawka CA, Pritchard KI: Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits? J Clin Oncol 14 (3): 997-1006, 1996.
35.	Holmberg L, Anderson H; HABITS steering and data monitoring committees.: HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 363 (9407): 453-5, 2004.
36.	von Schoultz E, Rutqvist LE; Stockholm Breast Cancer Study Group.: Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 97 (7): 533-5, 2005.
37.	Chlebowski RT, Anderson GL: Progestins and recurrence in breast cancer survivors. J Natl Cancer Inst 97 (7): 471-2, 2005.
38.	Ganz PA, Greendale GA, Petersen L, et al.: Managing menopausal symptoms in breast cancer survivors: results of a randomized controlled trial. J Natl Cancer Inst 92 (13): 1054-64, 2000.
39.	Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.
40.	Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, eds.: Advances in Breast and Endocrine Surgery. Chicago, Ill: Year Book Medical Publishers, 1986, pp 213-226.
41.	Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.
42.	Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.
43.	Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991.
44.	Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994.
45.	Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994.
46.	Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006.

Cellular Classification of Breast Cancer

The following is a list of breast cancer histologic classifications.[1] Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

• Carcinoma, NOS (not otherwise specified).
• Ductal.
  • Intraductal (in situ).
  • Invasive with predominant intraductal component.
  • Invasive, NOS.
  • Comedo.
  • Inflammatory.
  • Medullary with lymphocytic infiltrate.
  • Mucinous (colloid).
  • Papillary.
  • Scirrhous.
  • Tubular.
  • Other.
• Lobular.
  • In situ.
  • Invasive with predominantin situ component.
  • Invasive.[2]
• Nipple.
  • Paget disease, NOS.
  • Paget disease with intraductal carcinoma.
  • Paget disease with invasive ductal carcinoma.
• Other.
  • Undifferentiated carcinoma.

The following are tumor subtypes that occur in the breast but are not considered to be typical breast cancers:

• Phyllodes tumor.[3,4]
• Angiosarcoma.
• Primary lymphoma.

References:

1.	Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
2.	Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222 (4): 549-59; discussion 559-61, 1995.
3.	Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000.
4.	Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to tumor size, lymph node status, estrogen-receptor and progesterone-receptor levels in the tumor tissue, human epidermal growth factor receptor 2 (HER2/neu) status, menopausal status, and the general health of the patient.

Definitions of TNM

The AJCC has designated staging by TNM classification to define breast cancer.[1] When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III.[2] As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.[3]

Table 1. Primary Tumor (T)^a,b

DCIS = ductal carcinomain situ; LCIS = lobular carcinomain situ.
a Reprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
b The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.
c Invasion of the dermis alone does not qualify as T4.
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinomain situ.
Tis (DCIS)	DCIS.
Tis (LCIS)	LCIS.
Tis (Paget)	Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinomain situ(DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
T1	Tumor ≤20 mm in greatest dimension.
T1mi	Tumor ≤1 mm in greatest dimension.
T1a	Tumor >1 mm but ≤5 mm in greatest dimension.
T1b	Tumor >5 mm but ≤10 mm in greatest dimension.
T1c	Tumor >10 mm but ≤20 mm in greatest dimension.
T2	Tumor >20 mm but ≤50 mm in greatest dimension.
T3	Tumor >50 mm in greatest dimension.
T4	Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules).c
T4a	Extension to the chest wall, not including only pectoralis muscle adherence/invasion.
T4b	Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma.
T4c	Both T4a and T4b.
T4d	Inflammatory carcinoma.

Table 2. Regional Lymph Nodes (N)^a

Clinical
a Reprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
bClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment.
NX	Regional lymph nodes cannot be assessed (e.g., previously removed).
N0	No regional lymph node metastases.
N1	Metastases to movable ipsilateral level I, II axillary lymph node(s).
N2	Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted.
	OR
	Metastases in clinically detectedb ipsilateral internal mammary nodes in theabsence of clinically evident axillary lymph node metastases.
N2a	Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
N2b	Metastases only in clinically detectedb ipsilateral internal mammary nodes and in theabsence of clinically evident level I, II axillary lymph node metastases.
N3	Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement.
	OR
	Metastases in clinically detectedb ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases.
	OR
	Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.
N3a	Metastases in ipsilateral infraclavicular lymph node(s).
N3b	Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
N3c	Metastases in ipsilateral supraclavicular lymph node(s).

Table 3. Pathologic (pN)^a,b

AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse transcriptase/polymerase chain reaction.
a Reprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
b Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).
c"Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.
d"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination.
pNX	Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study).
pN0	No regional lymph node metastasis identified histologically.
Note: ITCs are defined as small clusters of cells ≤0.2 mm, or single tumor cells, or a cluster of <200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by IHC methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.
pN0(i–)	No regional lymph node metastases histologically, negative IHC.
pN0(i+)	Malignant cells in regional lymph node(s) ≤0.2 mm (detected by H&E or IHC including ITC).
pN0(mol–)	No regional lymph node metastases histologically, negative molecular findings (RT-PCR).
pN0(mol+)	Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC.
pN1	Micrometastases.
	OR
	Metastases in 1–3 axillary lymph nodes.
	AND/OR
	Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected.c
pN1mi	Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm).
pN1a	Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
pN1b	Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c
pN1c	Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
pN2	Metastases in 4–9 axillary lymph nodes.
	OR
	Metastases in clinically detectedd internal mammary lymph nodes in theabsence of axillary lymph node metastases.
pN2a	Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2 mm).
pN2b	Metastases in clinically detectedd internal mammary lymph nodes in theabsence of axillary lymph node metastases.
pN3	Metastases in ≥10 axillary lymph nodes.
	OR
	Metastases in infraclavicular (level III axillary) lymph nodes.
	OR
	Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in thepresence of one or more positive level I, II axillary lymph nodes.
	OR
	Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c
	OR
	Metastases in ipsilateral supraclavicular lymph nodes.
pN3a	Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
	OR
	Metastases to the infraclavicular (level III axillary lymph) nodes.
pN3b	Metastases in clinically detectedd ipsilateral internal mammary lymph nodes in thepresence of one or more positive axillary lymph nodes;
	OR
	Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c
pN3c	Metastases in ipsilateral supraclavicular lymph nodes.
Posttreatment ypN
–Posttreatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above. The modifier "SN" is used only if a sentinel node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND.
–The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed.
–N categories are the same as those used for pN.

Table 4. Distant Metastases (M)^a

a Reprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
M0	No clinical or radiographic evidence of distant metastases.
cM0(i+)	No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of metastases.
M1	Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm.

Posttreatment yp M classification. The M category for patients treated with neoadjuvant therapy is the category assigned in the clinical stage, prior to initiation of neoadjuvant therapy. Identification of distant metastases after the start of therapy in cases where pretherapy evaluation showed no metastases is considered progression of disease. If a patient was designated to have detectable distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout.[1]

Table 5. Anatomic Stage/Prognostic Groups^a,b

Stage	T	N	M
a Reprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
b T1 includes T1mi.
c T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.
–M0 includes M0(i+).
–The designation pM0 is not valid; any M0 should be clinical.
–If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.
–Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.
–Postneoadjuvant therapy is designated with "yc" or "yp" prefix. Of note, no stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, ypT0ypN0cM0.
0	Tis	N0	M0
IA	T1b	N0	M0
IB	T0	N1mi	M0
	T1b	N1mi	M0
IIA	T0	N1c	M0
	T1b	N1c	M0
	T2	N0	M0
IIB	T2	N1	M0
	T3	N0	M0
IIIA	T0	N2	M0
	T1b	N2	M0
	T2	N2	M0
	T3	N1	M0
	T3	N2	M0
IIIB	T4	N0	M0
	T4	N1	M0
	T4	N2	M0
IIIC	Any T	N3	M0
IV	Any T	Any N	M1

References:

1.	Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
2.	Singletary SE, Allred C, Ashley P, et al.: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20 (17): 3628-36, 2002.
3.	Woodward WA, Strom EA, Tucker SL, et al.: Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 21 (17): 3244-8, 2003.

Ductal Carcinoma In Situ

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Introduction

Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.

Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone.[1] DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern: micropapillary, papillary, solid, cribriform, and comedo. Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.[2]

Treatment Option Overview

Until recently, the customary treatment of DCIS was mastectomy.[1] The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy following wide excision alone, and a 25% to 50% incidence of breast recurrence following limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[1,3] The combined local and distant recurrence rate following mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.

In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.[4,5,6,7]

Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[7][Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[7][Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[8] In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.

Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[9,10,11,12]

The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[12] Using this prognostic index, patients with favorable lesions, who received surgical excision alone, had a low recurrence rate (i.e., 2% with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control.[13] Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.[2,4,14,15]

To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24) of 1,804 women.[16] Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years).[16] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured not larger than 1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on a placebo (8.2% vs. 13.4%; P = .009).[16][Level of evidence: 1iDii] With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins.[17] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Treatment Options for Patients With DCIS

1.	Breast-conserving surgery and radiation therapy with or without tamoxifen.
2.	Total mastectomy with or without tamoxifen.
3.	Breast-conserving surgery without radiation therapy. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed due to poor accrual, and results are pending.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997.
2.	Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999.
3.	Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982.
4.	Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998.
5.	Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001.
6.	Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000.
7.	Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006.
8.	Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001.
9.	Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995.
10.	Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75(6): 1223-1227, 1995.
11.	Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994.
12.	Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996.
13.	Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999.
14.	Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009.
15.	Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev (3): CD000563, 2009.
16.	Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.
17.	Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003.

Lobular Carcinoma In Situ

Introduction

The term lobular carcinoma in situ (LCIS) is misleading. This lesion is more appropriately termed lobular neoplasia. Strictly speaking, it is not known to be a premalignant lesion, but rather a marker that identifies women at an increased risk for subsequent development of invasive breast cancer. This risk remains elevated even beyond 2 decades, and most of the subsequent cancers are ductal rather than lobular. LCIS is usually multicentric and is frequently bilateral. In a large prospective series from the National Surgical Adjuvant Breast and Bowel Project with a 5-year follow-up of 182 women with LCIS managed with excisional biopsy alone, only eight women developed ipsilateral breast tumors (four of the tumors were invasive).[1] In addition, three women developed contralateral breast tumors (two of the tumors were invasive).

Treatment Option Overview

Most women with LCIS have disease that can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. The use of tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women.[2] The NSABP-P-1 trial of 13,388 high-risk women comparing tamoxifen to placebo demonstrated an overall 49% decrease in invasive breast cancer, with a mean follow-up of 47.7 months.[2] Risk was reduced by 56% in the subset of 826 women with a history of LCIS, and the average annual hazard rate for invasive cancer fell from 12.99 per 1,000 women to 5.69 per 1,000 women. In women older than 50 years, this benefit was accompanied by an annual incidence of 1 to 2 per 1,000 women of endometrial cancer and thrombotic events. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Bilateral prophylactic mastectomy is sometimes considered an alternative approach for women at high risk for breast cancer. Many breast surgeons, however, now consider this to be an overly aggressive approach. Axillary lymph node dissection is not necessary in the management of LCIS.

Treatment Options for Patients With LCIS

1.	Observation after diagnostic biopsy.
2.	Tamoxifen to decrease the incidence of subsequent breast cancers.
3.	Breast cancer prevention trials, including the National Cancer Institute of Canada's trial (CAN-NCIC-MAP3 [NCT00083174]), for example.
4.	Bilateral prophylactic total mastectomy, without axillary node dissection.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with lobular breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Fisher ER, Redmond C, Fisher B, et al.: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Projects (NSABP). Prognostic discriminants for 8-year survival for node-negative invasive breast cancer patients. Cancer 65 (9 Suppl): 2121-8, 1990.
2.	Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.

Stage I, II, IIIA, and Operable IIIC Breast Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Primary Therapy

Local-regional treatment

Stage I, II, IIIA, and operable IIIC breast cancer often requires a multimodality approach to treatment. Irrespective of the eventual procedure selected, the diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures. In many cases, the diagnosis of breast carcinoma using core needle biopsy or fine-needle aspiration cytology may be sufficient to confirm malignancy. After the presence of a malignancy is confirmed and histology is determined, treatment options should be discussed with the patient before a therapeutic procedure is selected. The surgeon may proceed with a definitive procedure that may include biopsy, frozen section confirmation of carcinoma, and the surgical procedure elected by the patient. Estrogen-receptor (ER) and progesterone-receptor (PR) protein status should be determined for the primary tumor.[1] Additional pathologic characteristics, including grade, proliferative activity, and human epidermal growth factor receptor 2 (HER2/neu) status, may also be of value.[2,3,4,5]

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials (including the European Organization for Research and Treatment of Cancer's trial [EORTC-10801]).[6,7,8,9,10,11,12,13] Selection of a local therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, and the patient's attitude toward preserving the breast. The presence of multifocal disease in the breast or a history of collagen vascular disease are relative contraindications to breast-conserving therapy.[14] A retrospective study of 753 patients who were divided into three groups based on receptor status (ER- or PR-positive; ER- and PR-negative but HER2/neu -positive; and ER-, PR-, and HER2/neu -negative [triple-negative]) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.[15]

All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[16] The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary is debatable.[17,18,19]

Retrospective studies have shown the following examples of tumor characteristics to correlate with a greater likelihood of finding persistent tumor on re-excision:

• Large tumors (T2 lesions).
• Positive axillary nodes.
• Tumors with an extensive intraductal component.[20]
• Palpable tumors.
• Lobular histology.

Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.[21,22]

Radiation therapy (as part of breast-conserving local therapy) consists of postoperative external-beam radiation therapy (EBRT) to the entire breast with doses of 45 Gy to 50 Gy, in 1.8 Gy to 2.0 Gy daily fractions over a 5-week period. Shorter hypofractionation schemes achieve comparable results.[23,24,25] A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[26][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[27][Level of evidence: 1iiDiii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.[28]

The age of the patient should not be a determining factor in the selection of breast-conserving treatment versus mastectomy. A study has shown that treatment with lumpectomy and radiation therapy in women 65 years and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years.[29] Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is not certain. Retrospective studies indicate no difference in local failure rates or overall survival (OS) when women with strong family histories are compared with similarly treated women without such histories.[30,31][Level of evidence: 3iiiDii] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years.[30] This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[32][Level of evidence: 3iiiDii] Because of the available evidence indicating no difference in outcome, women with strong family histories should be considered candidates for breast-conserving treatment. For women with germ-line mutations in BRCA1 and BRCA2, further study of breast-conserving treatment is needed.

Breast-conserving surgery alone without radiation therapy has been compared with breast-conserving surgery followed by radiation therapy in six prospective randomized trials (including the National Surgical Adjuvant Breast and Bowel Project's trial [NSABP-B-06] and the Cancer and Leukemia Group B's trial [CLB-9343]).[6,33,34,35,36,37] In two of these trials, all patients also received adjuvant tamoxifen.[36,37] Every trial demonstrated a lower in-breast recurrence rate with radiation therapy, and this effect was present in all patient subgroups. In some groups, for example, women with receptor-positive small tumors [36] and those older than 70 years,[38] the absolute reduction in the rate of recurrence was small (<5%). The limited impact of radiation therapy in this group of women was also reported in a confirmatory observational study looking at in-breast control rates using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.[39] The impact of radiation therapy on local control was additionally clarified by showing that healthy women aged 70 to 79 years were most likely to benefit from radiation therapy (number needed to treat [NNT] to prevent one event = 21–22 patients) when compared to women aged 80 years or older or to those who have comorbidities (NNT = 61–125 patients).[39] The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.[38]

Axillary lymph node surgery

The axillary lymph nodes should be staged to aid in determining prognosis and therapy. Sentinel lymph node (SLN) biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor, therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[40,41] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection (ALND).[42,43,44,45]

A multicenter randomized phase III trial of 5,611 patients randomly assigned to either SLN plus ALND or to SLN resection alone with ALND only if the SLNs were positive showed no detectable difference in OS, disease-free survival (DFS), and regional control. OS was 91.8% versus 90.3% in the SLN plus ALND and SLN alone, respectively (P = .12).[46][Level of evidence: 1iiA]

Similarly, a single-center randomized trial of 532 patients with T1 carcinomas undergoing either SLN biopsy plus complete axillary dissection or SLN biopsy alone showed, after a median follow-up of 78 months, no difference in 5-year DFS (92.9% in the SLN biopsy without routine axillary dissection group vs. 88.9% in patients having axillary dissection irrespective of SLN findings, P = .1).[47][Level of evidence: 1iiDii]

The reported false-negative rates of SLN biopsy using axillary node dissection as the gold standard range from 0% to 15% with an average of 8.8%.[48] The success rate varies with the surgeon's experience and with the primary tumor characteristics. In general, studies have restricted the use of SLN biopsy to women with T1 and T2 disease, without evidence of multifocal involvement or clinically positive lymph nodes. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy. In a randomized trial of 1,031 women that compared SLN biopsy followed by axillary dissection when the SLN was positive with axillary dissection in all patients, quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. axillary dissection groups, respectively; P = .001).[49][Level of evidence 1iiC] Arm function was also better in the SLN group. The NSABP-B-32 (NCT00003830) trial, a randomized study of 5,611 women, found the same results with respect to accuracy and technical success.[50] Based on this body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer.

A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer.[51] This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1–T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND versus no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast irradiation, and appropriate systemic therapy, and OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms. At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% CI, 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone. The secondary endpoint of 5-year disease-free survival (DFS) was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.[51][Level of evidence: 1iiA] On the basis of the results of this trial, the medical necessity of ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation, radiation, and systemic therapy is called into question.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., 6–10 at least), while reducing morbidity from the procedure. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[52,53] In another series, the incidence of axillary node relapse in patients with T1a tumors treated without ALND was 2%.[54][Level of evidence: 3iiiA] Because the axillary node status remains the most important predictor of outcome in breast cancer patients, insufficient evidence is available to recommend that lymph node staging can be omitted in most patients with invasive breast cancer.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[55,56,57,58] Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the FDA's Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[59]

Adjuvant Radiation Therapy

Radiation therapy is regularly employed after breast-conservation surgery. Radiation therapy also can be indicated for postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[60]

Post-breast conservation surgery

For women who are treated with breast-conserving surgery, the most common site of local recurrence is the conserved breast itself. The risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node-negative women. Thus, whole breast radiation therapy after breast-conserving surgery is recommended.[61]

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, in the 2005 Early Breast Cancer Trialists' Collaborative Group's (EBCTCG) update, when all relevant trials were combined, 15-year breast cancer mortality was reduced from 35.9% to 30.5% in women receiving radiation therapy (absolute difference of 5.4%; 95% CI, 2.1%–8.7%; breast cancer death rate ratio 0.83; 95% CI, 0.75–0.91; P = .002). There was a similar effect on all-cause mortality.[60]

Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. The National Cancer Institute of Canada's study (CAN-NCIC-MA20 [NCT00005957]) has closed, but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure following mastectomy. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy.[62] Patients at highest risk for local recurrence include those with four or more positive axillary nodes, grossly evident extracapsular nodal extension, large primary tumors, and very close or positive deep margins of resection of the primary tumor.[63,64,65]

Patients with one to three involved nodes without any of the previously noted risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting has been unclear. The 2005 EBCTCG update indicates, however, that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[60][Level of evidence: 1iiA] For women with node-positive disease postmastectomy and axillary clearance, radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain = 17%; 95% confidence interval [CI], 15.2%–18.8%). This translated into a significant (P = .002) reduction in breast cancer mortality, 54.7% versus 60.1% with an absolute gain of 5.4% (95% CI, 2.9%–7.9%). In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8.0%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In contrast, for women with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality in these patients (absolute gain = 1.0%; P > .1 95%; CI, -0.8%–2.8%). Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors, when axillary nodes were negative, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.[66]

Late toxic effects of radiation

Late toxic effects of radiation therapy, though uncommon, can include radiation pneumonitis, cardiac events, arm edema, brachial plexopathy, and the risk of second malignancies. Such toxic effects can be minimized with current radiation delivery techniques and with careful delineation of the target volume.

In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.[67] The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[67][Level of evidence: 3iii]

Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, had an association with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.[62,68,69,70] This was probably caused by the radiation received by the left myocardium.

Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.[71,72] At this time, cardiac mortality was also decreasing in the United States.

An analysis of SEER data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[73,74][Level of evidence: 3iB]

Lymphedema consequent to cancer management remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. Axillary radiation therapy can increase the risk of arm edema in patients who received axillary dissection from 2% to 10% with dissection alone to 13% to 18% with adjuvant radiation therapy.[75,76,77] (Refer to the PDQ summary on Lymphedema for more information.)

Radiation injury to the brachial plexus following adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were followed for 5.5 years to assess the rate of brachial plexus injury.[78] The diagnosis of such injury was made clinically with computerized tomography to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0% compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

The rate of second malignancies following adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with the long-term risk at 0.2% at 10 years.[79] One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.[80] No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.[81] Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[82] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.[83]

Adjuvant Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, estrogen and/or progesterone receptor–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression (e.g., triple negative, which is common in the basal-like tumors) nor hormone receptors are present, adjuvant therapy relies on chemotherapeutic regimens, which are often combined with experimental targeted approaches.

Hormone therapy

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[84]

Tamoxifen

The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. The most recent analysis, which included information on 80,273 women in 71 trials of adjuvant tamoxifen, was published in 2005.[85] In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors. In these women, the 15-year absolute reductions in recurrence and mortality associated with 5 years of use were 12% and 9%, respectively.[85][Level of evidence: 1iiA]

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, =70 years), PR status, or other tumor characteristics.[85] This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.[85] Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the latter group (5.3% vs. 12.5% with 5 years of use).[85][Level of evidence: 1iiA] Similar results were found in the IBCSG-13-93 trial.[86] Of 1,246 women with stage II disease, only the women with ER-positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[85,87,88,89] Results from the EBCTCG meta-analysis show a highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction 7.9%; P = .01).[85] Results from the NSABP-B-14 study, which compared 5 years of adjuvant tamoxifen to 10 years of adjuvant tamoxifen for women with early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[87][Level of evidence: 1iA]

Another trial that included both node-positive and node-negative women also demonstrated the equivalence of 5 years and 10 years of therapy.[88][Level of evidence: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment. In one trial EST-5181, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation.[89] In the ER-positive subgroup, a longer time to relapse was associated with continued tamoxifen use, but no improvement in OS was observed. The current recommendation is that adjuvant tamoxifen be discontinued after 5 years in all patients as current standard therapy.[90] Clinical trials such as the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment--Offer More? (CRC-TU-ATTOM) trial have addressed different durations of adjuvant tamoxifen, and results are pending.

(Refer to the Letrozole section in the Aromatase inhibitors section of this summary for more information.)

Tamoxifen and chemotherapy

That chemotherapy should add to the effect of tamoxifen in postmenopausal women has been postulated.[91,92] In a trial (NSABP-B-16) of node-positive women older than 50 years with hormone receptor–positive tumors, 3-year DFS and OS rates were better in those who received doxorubicin, cyclophosphamide, and tamoxifen versus tamoxifen alone (DFS was 84% vs. 67%; P = .004; OS was 93% vs. 85%; P = .04).[93][Level of evidence: 1iiA] The NSABP-B-20 study compared tamoxifen alone with tamoxifen plus chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU] [CMF] or sequential methotrexate and 5-FU) in women with node-negative, ER-positive breast cancer.[94] After 12 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 89% DFS and 87% OS compared with a 79% DFS and 83% OS with tamoxifen alone.[94][Level of evidence: 1iiA]

In another study of postmenopausal women with node-positive disease, tamoxifen alone was compared with tamoxifen plus three different schedules of CMF. A small, DFS advantage was conferred by the addition of early CMF to tamoxifen in women with ER-positive disease.[95][Level of evidence: 1iiDii] However, another study in a similar patient population, in which women were randomly assigned to receive adjuvant tamoxifen with or without CMF, showed no benefit in the chemotherapy arm; in this study, intravenous (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[96][Level of evidence: 1iiA] The overall results of the available evidence suggest that the addition of chemotherapy to tamoxifen in postmenopausal women with ER-positive disease results in a significant, but small, survival advantage.

Tamoxifen toxic effects

The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important effect is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is two times to seven times greater than that observed in untreated women.[97,98,99,100] Women taking tamoxifen should be evaluated by a gynecologist if they experience any abnormal uterine bleeding. Although one retrospective study raised concern that endometrial cancers in women taking tamoxifen (40 mg/day) had a worse outcome and were characterized by higher-grade lesions and a more advanced stage than endometrial cancers in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 mg/day) have not supported this finding.[97,101,102] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer who were randomly assigned to receive tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range, 3 months–75 months; median, 24 months), while no cases occurred on the control arm.[103] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[104,105] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.[106]

Tamoxifen use is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[87,93,107,108,109] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen.[110] The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[109,111,112] In the NSABP Breast Cancer Prevention Trial (NSABP-P-1), this increase was not statistically significant.[111]

Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[113] The relationship between tamoxifen and ovarian tumors requires further study.[114] Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation).[115] (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.) Ophthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[116,117,118] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug.

Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[119,120] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than for women taking it for 2 years.[121] In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone.[120] In the NSABP-B-14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant.[122] To date, three large controlled trials have shown a decrease in heart disease.[120,121,122]

Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[123,124,125] In premenopausal women, decreased bone mineral density is a possibility.[126]

Ovarian ablation, tamoxifen, and chemotherapy

The EBCTCG meta-analysis included almost 8,000 premenopausal women who were randomly assigned to undergo ovarian ablation with surgery or radiation therapy (4,317) or ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists (3,408). Overall, ovarian ablation or suppression reduced the absolute risk of recurrence at 15 years by 4.3% (P < .001) and the risk of death from breast cancer by 3.2% (P = .004).[85] No evidence showed that the relative benefit of suppression differed from that of ablation, but the benefit of either was less in patients who received chemotherapy.[127][Level of evidence: 1iiA]

A single study of more than 300 patients that compared cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP) with the same chemotherapy regimen plus surgical oophorectomy showed no additional survival benefit from oophorectomy.[128][Level of evidence: 1iiA] Three trials (including the International Breast Cancer Study Group's trial [IBCSG-VIII] and the Eastern Cooperative Oncology Group's trial [EST-5188]) involving more than 3,000 patients assessed the impact on DFS and OS from the use of an LHRH analogue (in one trial, 50% of the patients had radiation oophorectomy rather than an LHRH analogue) in addition to chemotherapy.[127,129,130][Level of evidence: 1iiA] None of the trials identified a statistically significant benefit in OS or DFS from ovarian suppression.

As an adjuvant strategy, ovarian ablation has also been compared with chemotherapy in premenopausal women. In a direct comparison of surgical or radiation ablation and CMF, DFS and OS rates were identical in 332 premenopausal women with stage II disease.[131][Level of evidence: 1iiA] A trial of 599 premenopausal node-positive patients found leuprorelin acetate to be similar to CMF with respect to DFS and OS.[132] A Danish trial compared ovarian ablation or suppression to CMF (9 cycles intravenously every 3 weeks) in premenopausal, ER-positive women and found no difference in OS or DFS in the two study groups.[133,134] The study did not have tamoxifen as an adjuvant arm and also did not use taxanes or anthracyclines. Results may have been different with these two contemporary modifications to the study. A trial of CMF versus tamoxifen plus ovarian ablation (e.g., by surgery, radiation therapy, or gonadotropin-releasing hormone [GnRH]) in premenopausal or perimenopausal women with receptor-positive tumors has been reported.[135][Level of evidence: 1iiA] In this small trial, which did not meet its target accrual, the combination of tamoxifen and ovarian ablation provided comparable DFS and OS rates. In three larger trials in which medical ovarian ablation with goserelin was used, the impact of goserelin alone on DFS was found to be comparable to CMF in the subgroup of ER+ patients,[127,136][Level of evidence: 2Dii] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.[137][Level of evidence: 1iiDii] Whether tamoxifen or aromatase inhibitors add to ovarian ablation, and the elucidation of the optimal roles for endocrine manipulation and chemotherapy in receptor-positive premenopausal women, require further evaluation.[138] These issues are the subject of several trials.

Aromatase inhibitors

Based on DFS advantage as described below, aromatase inhibitors have become the first-line adjuvant therapy for postmenopausal women; however, because there is no demonstrated survival advantage to aromatase inhibitors, tamoxifen remains a reasonable alternative.[139,140]

Anastrozole

A large randomized trial of 9,366 patients has compared the use of the aromatase inhibitor anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative and node-positive disease.[141,142] Most (84%) of the patients in the study were hormone-receptor positive. Slightly more than 20% had received chemotherapy. With a median follow-up of 33.3 months, no benefit was observed for the combination arm relative to tamoxifen. Patients on anastrozole, however, had a significantly longer DFS (hazard ratio [HR] = 0.83) than those on tamoxifen. In an analysis conducted when all but 8% of the patients had completed protocol therapy at a follow-up of 68 months,[142] the benefit of anastrozole relative to tamoxifen with respect to DFS was slightly less (HR = 0.87; 95% CI, 0.78–0.96; P = .01). A greater benefit was seen in hormone receptor-positive patients (HR = 0.83; 95% CI, .73–0.94; P = .05). There was an improvement in time to recurrence (HR = 0.79; 95% CI, 0.70–0.90; P = .005), distant DFS (HR = 0.86; 95% CI, 0.74–0.99; P = .04) and contralateral breast cancer (42% reduction; P = .01) in patients who received anastrozole.[142][Level of evidence: 1iDii] No difference was shown in OS (HR = 0.97; 95% CI, 0.85–1.12; P = .7 ). Arthralgia and fractures were reported significantly more often in patients who received anastrozole, whereas hot flushes, vaginal bleeding and discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic and deep venous thromboembolic events were more common in patients who received tamoxifen.[142] An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[143,144]

Three trials examined the effect of switching to anastrozole to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[145,146,147] One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR = 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS.[145][Level of evidence: 1iiA] The other two trials were reported together.[146] A total of 3,224 patients were randomized after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR = 0.61; 95% CI, 0.42–0.88; P = .007) was observed.[147]

A meta-analysis of these three studies showed that patients who switched to anastrozole had significant improvements in DFS (HR = 0.59; 95% CI, 0.48–0.74; P < .001), EFS (HR = 0.55; 95% CI, 0.42–0.71; P < .001), distant DFS (HR = 0.61; 95% CI, 0.45–0.83; P = .002), and OS (HR = 0.71; 95% CI, 0.52–0.98; P = .04) compared with the patients who remained on tamoxifen.[148]

Letrozole

A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole versus tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years.[149] In an updated analysis from the Breast International Group (IBCSG-1-98) including only the 4,922 women who received tamoxifen or letrozole for 5 years, at a median follow-up time of 51 months, DFS was significantly superior in patients treated with letrozole (HR = 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS = 84.0% vs. 81.1%).[150][Level of evidence: 1iDii] OS was not significantly different (HR = 0.91; 95% CI, 0.75–1.11; P = .35). Patients on letrozole had significantly fewer thromboembolic events, endometrial pathology, hot flashes, night sweating, and less vaginal bleeding. Patients on tamoxifen had significantly fewer bone fractures, arthralgia, hypercholesterolemia, and cardiac events other than ischemic heart disease and cardiac failures.[150]

A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years.[151] After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR = 0.57) favoring the letrozole arm.[151][Level of evidence: 1iDii] After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Women on letrozole had significantly more hot flashes, arthritis, arthralgia and myalgia, but less vaginal bleeding. New diagnoses of osteoporosis were more frequent on letrozole (5.8% vs. 4.5%), though the difference was not statistically significant (P = .07). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[152,153] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis.[154] In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR = 0.60; 95% CI, 0.43–0.84; P = .002). Although no significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR = 0.61; 95% CI, 0.38–0.98; P = .04), though the P value was not corrected for multiple comparisons. An ASCO Technology Assessment panel has commented on the implications of these results.[143,144]

Exemestane

A large double-blinded randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[155,156] After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR = 0.68) favoring the exemestane arm.[155][Level of evidence: 1iDii] After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[157] At 2.5 years after randomization, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).[157][Level of evidence: 1iA] Women on exemestane had significantly more arthralgia, diarrhea, hypertension, fractures, arthritis, musculoskeletal pain, carpal tunnel syndrome, insomnia, and osteoporosis, but women on tamoxifen had significantly more gynecologic symptoms, muscle cramps, vaginal bleeding and discharge, thromboembolic disease, endometrial hyperplasia, and uterine polyps. (For information on diarrhea, refer to the PDQ summary on Gastrointestinal Complications; for information on insomnia, refer to the PDQ summary on Sleep Disorders.)

A large randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years.[158] The primary endpoints were DFS at 2.75 years and 5.0 years. Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR = 0.97; 95% CI, 0.88–1.08; P = .60).[158][Level of evidence: 1iDii] The results of this trial support the use of exemestane, either sequentially after tamoxifen or as initial treatment for early-stage hormone receptor–positive breast cancer in postmenopausal women.

Chemotherapy

Overview of chemotherapy

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which meets every 5 years to review data from global breast cancer trials. The year 2000 overview analysis (published in 2005) summarized the results of randomized adjuvant trials initiated by 1995.[85] The analyses of adjuvant chemotherapy involved 28,764 women participating in 60 trials of combination chemotherapy (polychemotherapy) versus no chemotherapy, 14,470 women in 17 trials of anthracycline-containing versus CMF-type chemotherapy, and 6,125 women in 11 trials of longer versus shorter chemotherapy duration.

For women younger than 50 years, polychemotherapy reduced the annual risk of disease relapse and death from breast cancer by 37% and 30%, respectively. This translated into a 10% absolute improvement in 15-year survival (HR = 42% vs. 32%). For women aged 50 to 69 years, the annual risk of relapse or death from breast cancer was decreased by 19% and 12%, respectively. This translated into a 3% absolute gain in 15-year survival (HR = 50% vs. 47%). The absolute gain in survival for polychemotherapy versus no adjuvant therapy in women younger than 50 was twice as great at 15 years as it was at 5 years (10% vs. 4.7%), while the main effect on disease recurrence was seen in the first 5 years.[85] The 15-year cumulative reduction in mortality from 6 months of an anthracycline-based regimen (e.g., fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, epirubicin, cyclophosphamide [FEC]) was 38% in women younger than 50 years, and 20% in those aged 50 to 60 years. The meta-analysis also showed that the reduction in risk of recurrence was similar in the presence or absence of tamoxifen, irrespective of age (<50 years vs. 50 to 69 years), though the result did not attain statistical significance in those randomly assigned women younger than 50 years. This finding, however, is most likely the result of the relatively small number of younger women in trials of combined chemoendocrine therapy. Few women older than 70 years had been studied, and specific conclusions could not be reached in this group. Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to ER status, and they were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[85] As a result, they may not reflect treatment outcomes based on evolving treatment patterns.

Results of individual trials are generally in agreement with the conclusions of the meta-analysis. The NSABP-B-13 study demonstrated a benefit for chemotherapy with sequential methotrexate and 5-FU versus surgery alone in patients with node-negative, ER-negative tumors.[93,94,159,160][Level of evidence: 1iiA]

Duration of CMF-based chemotherapy

The EBCTCG meta-analysis assessed data from five trials comparing durations of at least 6 months with longer durations of 9 to 24 months. No survival benefit was demonstrated for durations greater than 6 months.[161][Level of evidence: 1iiA]

Anthracycline-based regimens

The EBCTCG meta-analysis analyzed 11 trials that began in 1976 through 1989 in which women were randomized to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) versus CMF alone. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of FEC or FAC) with CMF (either oral or IV) in approximately 14,000 women, 64% of whom were under 50 years.[85] Compared to CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[161][Level of evidence: 1iiA]

The largest direct comparison of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) (six cycles) versus CMF (six cycles) occurred in a U.S. Intergroup study (SWOG-8897), which was not included in the meta-analysis.[162] In this study, 2,691 patients were randomized to receive CAF or CMF with a second randomization to 5 years of tamoxifen versus no tamoxifen. Ten-year follow-up estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% vs. 75%; HR = 1.09; 95% CI, 0.94–1.27). CAF had slightly better OS than CMF (85% vs. 82%, HR = 1.19 for CMF vs. CAF; 95% CI, 0.99–1.43), though values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with tamoxifen. Overall, tamoxifen had no benefit (DFS, P = .16; OS, P = .37), but the tamoxifen effect differed by high-risk groups. For high-risk node-positive patients, tamoxifen was beneficial (DFS: HR = 1.32 for no tamoxifen vs. tamoxifen; 95% CI, 1.09–1.61; P = .003; OS: HR = 1.26; 95% CI, 0.99–1.61; P = .03) but not for high-risk node-negative patients (DFS: HR = 0.81 for no tamoxifen vs. tamoxifen; 95% CI, 0.64–1.03; OS: HR = 0.79; 95% CI, 0.60–1.05). The conclusion of this trial was that CAF did not improve DFS compared with CMF; and, there was a slight effect on OS. Given greater toxicity, CAF cannot be concluded to be superior to CMF. Tamoxifen was effective in high-risk node-positive disease but not in high-risk node-negative disease.[162][Level of evidence: 1iiA]

Several investigators have attempted to improve outcomes by combining CMF and anthracycline-containing regimens. Two Italian studies have evaluated these regimens.[163,164] In one study, 490 premenopausal and postmenopausal women with one to three axillary lymph nodes were randomized to receive CMF (12 cycles) or CMF (eight cycles) followed by doxorubicin (four cycles).[163] After a median observation of 17.5 years, no statistically significant difference was documented in the first study (relapse-free survival [RFS], HR = 1.06; total survival, HR = 1.03). In contrast, the delivery of doxorubicin first, followed by CMF significantly reduced the risk of disease relapse (HR = 0.68; 95% CI, 0.54–0.87; P =.0017) and death (HR = 0.74; 95% CI, 0.57–0.95; P = .018) compared with the alternating regimen. In the other study, 403 premenopausal and postmenopausal women with four or more positive axillary lymph nodes were randomized to receive doxorubicin (four cycles) followed by CMF (eight cycles) or CMF (two cycles) alternating with doxorubicin (one cycle) for a total of 12 cycles.[164] Women who received doxorubicin followed by CMF had better RFS (42% vs. 28%; P = .002) and OS (58% vs. 44%; P = .002).[164][Level of evidence: 1iiA]

The NSABP-B-15 trial randomized 2,194 patients with axillary node-positive breast cancer and tumors determined nonresponsive to tamoxifen to doxorubicin and cyclophosphamide (AC) (four cycles), CMF (six cycles), or AC (four cycles) followed after a 6-month delay by CMF (three cycles).[165] No differences were seen in DFS or OS among the three groups.[165][Level of evidence: 1iiA] This study has also shown no difference in survival rates between four cycles of AC and six cycles of CMF.

The results of these various studies comparing and combining CMF and anthracycline-containing regimens suggest a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal patients. Uncertainty remains, however, about whether there is an advantage to combining both regimens.

Evidence suggests that particular tumor characteristics may predict anthracycline-responsiveness. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant CAF,[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA] A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[166][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods. The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in RFS and OS. In patients with HER2/neu amplification, the RFS and OS were increased by CEF. In the absence of HER2/neu amplification, CEF and CMF were similar to RFS (HR for relapse = 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HR for death = 1.06; 95% CI, 0.83–1.44; P = .68). Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with non–anthracycline-containing regimens.[167]

The role of adding taxanes to adjuvant therapy

A number of trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen. A literature-based meta-analysis of 13 such studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR = 0.83; 95% CI, 0.79–0.87; P < .0001; OS: HR = 0.85; 95% CI, 0.79–0.91; P < .0001).[168][Level of evidence: 1iiA] Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens. There were no differences in benefit observed in patient subsets defined by nodal status, hormone receptor status, or age/menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies reviewed involved a direct comparison between paclitaxel and docetaxel.

A European Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) following standard-dose AC chemotherapy given every 3 weeks.[169][Level of evidence: 1iiA] There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR] = 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR = 1.06; 95% CI, 0.94–1.20; P = .33). However, there was a significant interaction between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR = 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR = 1.32; 95% CI, 1.02–1.72; P = .01). Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR = 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR = 1.13; 95% CI, 0.88–1.46; P = .25). Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs. Thus, these results are hypothesis generating and should be confirmed.

Dose-intensity, dose-density, and high-dose chemotherapy

Retrospective and some prospective data support the view that physicians should avoid arbitrary reductions in dose intensity.[170,171] The data for the benefit of dose escalation in breast cancer, however, are more controversial. The CLB-8541 trial compared three dose intensities of CAF in 1,550 patients with node-positive breast cancer. Patients received either CAF (300/30/300 mg/m² every 4 weeks for four cycles; low-dose arm), CAF (400/40/400 mg/m² every 4 weeks for six cycles; moderate-dose arm), or CAF (600/60/600 mg/m² every 4 weeks for four cycles; high-dose arm). The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had 66% of the dose intensity as the high-dose arm but the same total drug dose. At a median follow-up of 9 years, DFS and OS on the high-dose and intermediate-dose arms were superior to the corresponding survival measures on the low-dose arm (P = .001) with no difference in these measures between the high-dose and intermediate-dose arms.[170][Level of evidence: 1iiA] The higher dose levels used in this trial are currently considered standard, so it is unclear whether this trial is supportive of the value of dose intensity or, rather, supportive of the concept of a threshold level below which treatment becomes ineffective.

Other trials have clearly escalated doses beyond the standard range. The NSABP-B-22 and NSABP-B-25 trials, for example, escalated the dose of cyclophosphamide to 1,200 mg/m² (without granulocyte-colony stimulating factor [G-CSF]) and 2,400 mg/m² (with G-CSF), respectively, with no significant advantage observed in DFS or OS compared with the standard dose of 600 mg/m².[172,173][Level of evidence: 1iiA]

A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m²). Following treatment with doxorubicin, a second randomization occurred to paclitaxel or to no further therapy. After chemotherapy, patients with ER-positive tumors were offered a planned course of tamoxifen for 5 years. No difference in DFS related to the dose of doxorubicin was found.[174] In contrast, a Canadian trial (CAN-NCIC-MA5) in which cyclophosphamide, epirubicin, and 5-FU (CEF) were given to a total dose of 720 mg/m² for a period of six 4-week cycles demonstrated at a median follow-up of 10 years for live patients, a 10-year RFS of 52% for patients who received CEF compared with 45% for CMF patients (HR for CMF vs. CEF = 1.31; stratified log-rank, P = .007).[175] The 10-year OS for patients who received CEF and CMF was 62% and 58%, respectively (HR for CMF vs. CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure were slightly higher (four patients [1.1%] in the CEF group vs. one patient [0.3%] in the CMF group).[175][Level of evidence: 1iiA] The design of the trial does not allow a determination of whether anthracycline or dose-intensity or both is responsible for the improved outcome. A French trial showed that higher doses of epirubicin led to a high survival rate in women with poor-prognosis disease.[176] A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.[177]

A U.S. Intergroup trial (CLB-9741) compared, in a 2 × 2 factorial design, the use of adriamycin, cyclophosphamide, and paclitaxel concurrently (adriamycin and cyclophosphamide followed by paclitaxel) versus sequentially (adriamycin followed by paclitaxel followed by cyclophosphamide), given every 3 weeks or every 2 weeks with filgrastim, in 2,005 node-positive premenopausal and postmenopausal patients.[178] At a median follow-up of 68 months, dose-dense treatment improved the primary end point, DFS in all patient population (HR = 0.80; P =.018) but not OS (HR = 0.85; P =.12). There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens.[178,179] Grade 2 anemia (hemoglobin <10g/dL) was more frequent in the adriamycin and cyclophosphamide followed by paclitaxel every 2 weeks' arm (P < .001). At cycle five, this same arm had the lowest nadir hemoglobin of 10.7 g/dL, 0.9 g/dL lower than the other arms. Also, epoetin alpha use was highest in this arm compared with the three other arms (P = .013). In conclusion, dose-dense adriamycin and cyclophosphamide followed by paclitaxel every 14 days in C2 was associated with a greater incidence of moderate anemia, higher use of epoetin alpha, and more red cell transfusions than the other arms.[180][Level of evidence: 1iiA]

Several clinical trials (including EST-2190) have tested high-dose chemotherapy with bone marrow transplant (BMT) or stem cell support in women with more than ten positive lymph nodes and in women with four to nine positive lymph nodes.[181,182,183,184,185,186,187,188] A prospective randomized trial of 403 patients testing the use of two tandem high-dose chemotherapy courses demonstrated a statistically significant (P = .02) difference in 5-year survival (75% vs. 70%) with a 49-month median follow-up.[187][Level of evidence: 1iiA] The remaining trials comparing conventional chemotherapy to high-dose chemotherapy with BMT or stem cell support in high-risk patients in the adjuvant setting indicated no OS or EFS benefit from the high-dose chemotherapy with BMT or stem cell support.[181,182,183,184,185,186,188,189,190][Level of evidence: 1iiA] The information to date does not support the use of high-dose chemotherapy outside the context of a randomized clinical trial.

Also, a systematic review of nine randomized controlled trials comparing the effectiveness of high-dose chemotherapy and autograft with conventional chemotherapy for women with early poor prognosis breast cancer was performed.[188] In total 1,758 women were randomly assigned to receive high-dose chemotherapy with autograft, and 1,767 women were randomly assigned to receive conventional chemotherapy. There were 48 noncancer-related deaths on the high dose arm and four on the conventional dose arm (RR = 7.74; 95% CI, 3.43–17.50). There was no statistically significant difference in OS between women who received high-dose chemotherapy with autograft and women who received conventional chemotherapy, either at 3 years (RR = 1.02; 95% CI, 0.98–1.06), or at 5 years (RR = 0.98, 95% CI, 0.93–1.05). There was a statistically significant benefit in EFS at 3 years for the group who received high dose chemotherapy (RR = 1.11; 95% CI, 1.05–1.18). However, this significance was lost at 5 years (RR = 1.00; 95% CI, 0.92–1.08).[188]

Other chemotherapy regimens

The NSABP-B-19 trial compared CMF to sequential methotrexate followed by 5-FU in 1,095 women with node-negative, ER-negative tumors. After 13 years of follow-up, an overall benefit was seen for CMF relative to methotrexate plus 5-FU (MF) (RFS: HR = 0.59; 95% CI, 0.45–0.77, P < .001; OS: HR = 0.71; 95% CI, 0.55–0.92; P = .01). All age and menopausal groups demonstrated an RFS benefit, and most demonstrated an OS benefit.[159][Level of evidence: 1iiA] Serious toxicity (=grade 3), especially febrile neutropenia, was more frequent among CMF-treated patients. With no outcome advantage in older women and more toxic effects from the CMF regimen, the results of this study suggested that methotrexate followed by 5-FU was a reasonable substitute for CMF for older women.

A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m²) and a fixed dose of cyclophosphamide (600 mg/m²) every 3 weeks for four cycles. After AC chemotherapy, patients underwent a second randomization to paclitaxel (175 mg/m²) every 3 weeks for four cycles, and women with ER-positive tumors also received tamoxifen for 5 years. Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).[174][Level of evidence: 1iiA] The results of a second trial, the NSABP-B-28 trial, have also been reported.[191] This trial randomized 3,060 women with node-positive breast cancer to four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. All women older than 50 years, and those younger than 50 years with receptor-positive disease, received tamoxifen. In this trial, DFS was significantly improved by the addition of paclitaxel (hazard ratio [HR] = 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS = 76% vs. 72%). The difference in OS was small (HR = 0.93), however, and not statistically significant (P = .46).[191][Level of evidence: 1iiA]

The regimen of 5-FU, adriamycin, and cyclophosphamide (FAC) compared with docetaxel plus doxorubicin and cyclophosphamide (TAC) has been studied in 1,491 women with node-positive disease in the Breast Cancer International Research Group's (BCIRG-001) trial. Six cycles of either regimen were given as adjuvant postoperative therapy. A 75% DFS rate existed at 5 years in the TAC group compared with a 68% survival in the FAC group (P = .001). TAC was associated with a 30% overall lower risk of death (5% absolute difference) than FAC (HR = .70; 98% CI, 0.53–0.91; P < .008). Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group.[192,193][Level of evidence: 1iiA] (For information on anemia, refer to the PDQ summary on Fatigue.)

The regimen of docetaxel and cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy. At 5 years, DFS was statistically significantly superior for TC compared with AC (86% vs. 80%, HR= 0.67; 95% CI, 0.50–0.94; P = .015).[194][Level of evidence: 1iiA] However, OS was not statistically significantly improved. With TC, patients had fewer cardiotoxic effects but other side effects included more myalgia, arthralgia, edema, and febrile neutropenia compared with AC.

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early stage breast cancer is currently under clinical study. The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with ER+ breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second randomization to receive zoledronic acid (4 mg intravenously every 6 months) versus no zoledronic acid.[195][Level of Evidence: 1iiA] There was no significant difference in DFS between the anastrozole and tamoxifen groups. However, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in a relative reduction of 36% in the risk of disease progression (HR = 0.64; P = .01) but did not significantly reduce the risk of death.

While bisphosphonates appear to improve DFS in a population with low-to-intermediate risk breast cancer, it is not yet clear whether this benefit is generalizable to all patients with breast cancer. Results are pending from the SHEFF-AZURE trial, a randomized phase III trial of patients with stage II or III breast cancer who received chemotherapy and/or hormone therapy plus zoledronic acid versus no zoledronic acid.

Monoclonal antibodies

Five clinical trials addressing the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2 -overexpressing cancers have released the results of interim analyses.

In the HERceptin Adjuvant (HERA) (BIG-01-01) trial, which is the largest study (5,090 patients), trastuzumab was given every 3 weeks within 7 weeks of the completion of primary therapy that included an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively plus or minus locoregional radiation therapy. Although the results of the comparison of 1 year versus 2 years of trastuzumab have not been released yet, there are available data for 3,387 patients (1,694 in the 1-year trastuzumab arm and 1,693 in the observation arm).[196] Of these patients, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)-negative disease. Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (hazard ratio [HR] = 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months' follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95%CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%.[197] There were 218 DFS events reported with trastuzumab compared with 321 DFS events reported with observation. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%.

In the combined analysis of the NSABP-B-31 (NCT00004067) and Intergroup NCCTG-N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[198] The results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients, that demonstrated a highly significant improvement in DFS (HR = 0.48; P < .001; 3-year DFS = 87% vs. 75%), as well as a significant improvement in OS (HR = 0.67; P = .015; 3-year OS = 94.3% vs. 91.7%; 4-year OS = 91.4% vs. 86.6%).[199] Patients treated with trastuzumab experienced a longer DFS with a 52% lower risk of a DFS event (HR = 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence was 53% lower (HR = 0.47; 95%CI, 0.37–0.61; P < .001) in patients treated with trastuzumab, and the risk of death was 33% lower (HR = 0.67; 95%CI, 0.48–0.93; P = .015) in these patients.

The AVENTIS-TAX-GMA-302 study was a three-arm large trial containing two anthracycline arms (AC-D: doxorubicin, cyclophosphamide, docetaxel or AC-DH: doxorubicin, cyclophosphamide, docetaxel, and trastuzumab) and a nonanthracycline one (DCbH: docetaxel, carboplatin, trastuzumab).[200] In its second interim efficacy analysis with a median follow-up of 36 months, there were 462 DFS events and 185 deaths. For DFS, the HR was 0.61 for patients in the AC-DH arm (95%CI, 0.48–0.76; P < .001) and 0.67 for patients in the DCbH arm (95%CI, 0.54–0.83; P =.003), compared with the AC-D. This translated to absolute benefits (from years 2 to 4) of 6% and 5%, respectively with the addition of trastuzumab. Nevertheless, longer follow-up is needed in patients in the DCbH arm to warrant the omission of anthracyclines in these patients.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab.[201] In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2 -overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC. At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR = 0.41; P = .01; 95% CI, 0.21–0.83; 3 year DFS = 89% vs. 78%). The difference in OS (HR = 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).[201][Level of evidence: 1iiA]

In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison to, or as an alternative to trastuzumab) in the adjuvant setting is being investigated. Lapatinib is a small molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both EGFR and HER2 and seems to be less cardiotoxic than trastuzumab. In phase I/II studies as a single agent, lapatinib has resulted in objective responses between 4.3% and 7.8% in ER2-positive patients who had progressed on multiple trastuzumab-containing regimens with a substantial number having stable disease at 4 months (34%–41%) and 6 months (18%–21%).[202] In a phase III trial (GSK-EGF100151), lapatinib plus capecitabine was superior to capecitabine alone in women with HER2 -positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.[203] The hazard ratio for time to progression was 0.49 (95% CI, 0.34–0.71; P < .001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group.

The combination of lapatinib and trastuzumab in the ALTTO trial is further supported by a demonstration that lapatinib combined with trastuzumab confers a significantly improved progression-free survival in patients with metastatic breast cancer who experience progression on prior trastuzumab-containing treatment when compared to lapatinib alone.[204]

In September 2011, the ALTTO trial was amended to discontinue the lapatinib alone arm of the trial. The Independent Data Monitoring Committee of the trial determined that the patients assigned to the lapatinib alone arm were not likely to do as well as the patients assigned to the trastuzumab alone control arm. Final results of this trial are pending.

Cardiotoxicity with adjuvant trastuzumab

In the HERA (BIG-01-01) trial, severe congestive heart failure (CHF NYHA class III–IV) occurred in 0.6% of patients treated with trastuzumab.[196] Symptomatic CHF occurred in 1.7% and 0.06% of patients in the trastuzumab and observation arms, respectively. Fifty-one patients experienced a confirmed left ventricular ejection fraction (LVEF) decrease (defined as an EF decrease of >10 points from baseline to an LVEF <50%) with trastuzumab, which recovered or stabilized within 3 to 6 weeks of initial treatment in 86% of cases. In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.[205] The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%). Asymptomatic decline in LVEF (defined by >10% decline or to 55%) occurred in 17% of patients in the trastuzumab arm (95% CI, 15%–20%) and 34% of patients in the control arm (95%CI, 31%–38%), with a HR = 2.1 (95%CI, 1.7–2.6; P < .001). In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events in arm A was 0.35% (no trastuzumab), arm B, 3.5% (trastuzumab following paclitaxel) and arm C, 2.5% (trastuzumab concomitant with paclitaxel).

In the AVENTIS-TAX-GMA-302 (BCIRG 006) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC-D arm, 1.87% of patients in the AC-DH arm, and 0.37% of patients in the DCbH arm.[200] There was also a statistically significant higher incidence of asymptomatic and persistent decrease in LVEF in the AC-DH arm than with either the AC-D or DCbH arms. No cardiac deaths were reported in the AVENTIS-TAX-GMA-302 trial.

In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. In fact, LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.

Treatment options for HER2-positive early breast cancer:

• Standard treatment is 1 year of adjuvant trastuzumab therapy. Results of the 1 year versus 2 years of trastuzumab of the HERA trial are awaited, as are the results of the Protocol of Herceptin Adjuvant with Reduced Exposure (INCA-PHARE) trial, which compared 1 year versus 6 months of adjuvant trastuzumab.

Timing of Primary and Adjuvant Therapy

Postoperative adjuvant chemotherapy

The optimal time to initiate adjuvant therapy is uncertain. A single study that addressed the use of perioperative adjuvant chemotherapy in node-positive patients showed no advantage in DFS when a single cycle of perioperative chemotherapy was given in addition to standard therapy initiated 4 weeks after surgery.[206] A single cycle of immediate postoperative chemotherapy alone was inferior.[207]

Preoperative adjuvant chemotherapy

A randomized clinical trial (NSABP-B-18) has been performed to evaluate preoperative chemotherapy in the management of patients with stage I or stage II breast cancer.[208] After preoperative therapy with four cycles of doxorubicin and cyclophosphamide, 80% of the assessable patients had a reduction in tumor size of at least 50%, and 36% of the patients had a complete clinical response. More patients treated with preoperative chemotherapy were able to have breast-conservation procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%). Twenty-seven percent of the women in the preoperative therapy group for whom a mastectomy had been planned prior to being randomly assigned underwent a lumpectomy. No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.[208,209,210][Level of evidence: 1iiA]

An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS, but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[211][Level of evidence: 1iiA] Preoperative chemotherapy may be beneficial in women who desire breast conservation surgery but who would otherwise not be considered candidates because of the size of their tumor. In a meta-analysis including all trials that compared the use of the same chemotherapy preoperatively and postoperatively, the use of preoperative chemotherapy was associated with a higher rate of local recurrence.[212] Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting.[213] Before SLN biopsy can replace complete axillary lymphadenectomy, randomized trials are needed to confirm that both procedures yield comparable survival rates.

In HER2 -overexpressed disease, pilot studies have demonstrated remarkable clinical and pathologic responses when trastuzumab is given preoperatively in combination with chemotherapy.[214] A randomized study in patients with HER2 -positive locally advanced or inflammatory breast cancers confirmed that the addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy with sequential doxorubicin plus paclitaxel followed by CMF resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (38% vs. 19%) but also in the primary outcome: event-free survival (EFS).[215] This was defined as the time from random assignment to disease recurrence or progression—whether local, regional, distant, or contralateral—or death from any cause.

At 3 years, of all of the patients, 71% (95% CI, 61–78) showed improvement in EFS with trastuzumab versus 56% without trastuzumab (95% CI, 46–65), HR = 0.59 (95% CI, 0.38–0.90, P = .013), thereby favoring the addition of trastuzumab. The 3-year OS was 87% versus 79% at the time of the report (P = .114, not significant). Symptomatic cardiac failure developed in two patients receiving concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of left ventricular ejection fraction (LVEF) and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (See the Cardiotoxicity with adjuvant trastuzumab section in this summary.)[215][Level of evidence: 1iiD]

Adjuvant radiation and chemotherapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.[216] Patients received either chemotherapy first (n = 122), consisting of CMFP plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation, or breast radiation first (n = 122), followed by the same chemotherapy. With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).[216][Level of evidence: 1iiA] The 5-year crude rates of first recurrence by site in the radiation-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, though the statistical power of these subgroup analyses was low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages due to increased myelosuppression.

Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.[165,217] In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of CMF (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of AC (n = 199) followed by radiation therapy. No differences in DFS, distant DFS, and OS were observed between these two arms.[165][Level of evidence: 1iiA] The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy.[217] These studies showed that delays from 2 to 7 months in radiation therapy after surgery had no effect on the rate of local recurrence.

Based on the above studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving therapy may be preferable for patients at high risk of distant dissemination.

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu -positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[218] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Timing of surgery

Several retrospective reviews have indicated that statistically significantly better DFS is achieved for premenopausal women with breast cancer and positive axillary lymph nodes if breast surgery is performed during the luteal phase (days 15–36) as compared with the follicular phase (days 0–14) of the menstrual cycle.[219,220,221][Level of evidence: 1iiA][222] Several other studies, however, have failed to support this finding or have found opposite results.[223,224,225,226][Level of evidence: 1iiA] Because of the inconsistent findings of these studies, it would be premature to mandate a modification in the scheduling of breast cancer operations according to the patient's menstrual cycle. A prospectively controlled trial (UCLA-9810046) has been completed but is not yet analyzed.

Chemotherapy risks

Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious, toxic effects include heart failure (if an anthracycline is used), thromboembolic events,[227] and premature menopause.[228] (Refer to the PDQ summary on Nausea and Vomiting ; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation ; and for information on symptoms associated with premature menopause, refer to the PDQ summary on Fever, Sweats, and Hot Flashes.)

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[229] However, data on this topic from prospective randomized studies are lacking. (Refer to the PDQ summary on Cognitive Disorders and Delirium for more information.)

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.[161] This small proportional reduction translated into an absolute benefit that was only marginally statistically significant, but it indicates that chemotherapy does not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy. The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[230,231] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m²) and cyclophosphamide (>6,300 mg/m²).[232]

Chemotherapy and tamoxifen risks

Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to enhance efficacy may also have enhanced toxic effects. A single study randomly assigned postmenopausal women with node-positive, ER-positive tumors to receive tamoxifen (30 mg/day for 2 years) plus CMF (intravenously for 6 months) (n = 353) or tamoxifen alone (n = 352).[227] Of the women receiving combined chemohormonal therapy, 13.6% developed one or more thromboembolic events compared with 2.6% in the tamoxifen-alone group (P < .001). Also, statistically significantly more women were on combined treatment who developed severe thromboembolic events (grade 3–5), most of which (39 of 54) occurred while the women were actually receiving chemotherapy. Not all studies that compared concurrent chemotherapy plus tamoxifen with tamoxifen alone, however, have reported such high rates. In the NSABP-B-16 study that compared tamoxifen (20 mg/day for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (four cycles) with tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus 2.1% of women on tamoxifen alone.[93] Whether tamoxifen should be given concurrently or after the completion of chemotherapy has been addressed in an Intergroup trial (INT-0100), published in abstract form only, that compared the concurrent and sequential administration of CAF and tamoxifen in postmenopausal hormone receptor-positive patients. Sequential administration resulted in superior DFS that was significant at 8 years (67% vs. 62%; P = .045).[233][Level of evidence: 1iiDii]

Candidates for whom adjuvant therapy may not be necessary include individuals with small primary tumors (<1 cm) and negative axillary nodes who have an excellent prognosis, with nearly 90% of patients alive and free of disease at 20 years in one series.[234] A U.S. Intergroup study (SWOG-8897) observed patients off treatment with tumors of low-risk (tumors too small for biochemical ER/PR assay) and uncertain-risk (tumors <2 cm, ER-positive and PR-positive, and low S-phase fractions). This low-risk and uncertain-risk subset had a 96% 5-year survival rate without adjuvant therapy. Whether this group of patients would derive long-term benefit from tamoxifen for either its adjuvant or preventive effects remains uncertain. Clearly, this group has a risk of developing a new breast cancer that would meet the eligibility criteria that were used in the Breast Cancer Prevention Trial that demonstrated a benefit with tamoxifen.

Proposals have been made to treat elderly patients with tamoxifen alone and without surgery. This approach has unacceptably high local failure rates and, outside of a clinical trial setting, should be used only for patients who are not candidates for mastectomy or breast-conserving surgery plus radiation therapy, or for those who refuse these options.[235,236,237]

Treatment Options

Primary therapy

Local-regional treatment:

• Breast-conserving therapy (lumpectomy, breast radiation, and surgical staging of the axilla).
• Modified radical mastectomy (removal of the entire breast with level I–II axillary dissection) with or without breast reconstruction.
• Sentinel node biopsy.

Adjuvant radiation therapy postmastectomy in axillary node-positive tumors:

• For one to three nodes: unclear role for regional radiation (infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall).
• For more than four nodes or extranodal involvement: regional radiation is advised.

Adjuvant systemic therapy:

An International Consensus Panel proposed a three-tiered risk classification for patients with negative axillary lymph nodes.[54] This classification, with some modification, is described below:

Table 6. Risk Categories for Women With Node-Negative Breast Cancer

	Low risk (has all listed factors)	Intermediate risk (risk classified between the other two categories)	High risk (has at least one listed factor)
Tumor size	=1 cm	1–2 cm	>2 cm
ER or PR Status	positive	positive	negative
Tumor grade	grade 1	grade 1–2	grade 2–3

The original Consensus Panel classification also required that women be 35 years or older to be included in the low-risk group and included women 35 years and younger in the high-risk group, based admittedly on indirect evidence. Traditionally, certain uncommon histologies (e.g., tubular, medullary, and mucinous) have also been associated with favorable prognosis and may be considered as low-risk factors. Some additional tumor characteristics that may eventually prove helpful in the prognosis of node-negative disease include the tumor proliferative fraction (S-phase) and the level of HER2/neu expression.

Regardless of how one chooses to characterize node-negative tumors, evidence from clinical trials suggests that various types of adjuvant therapies benefit certain subgroups of patients with these kinds of tumors. The same is true for women with node-positive breast cancer. What has become clear after reviewing results from multiple breast cancer treatment trials is that hormone therapy and chemotherapy regimens generally offer the same proportional benefit to women irrespective of their axillary lymph node status. The selection of therapy is most appropriately based upon knowledge of an individual's risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach should allow clinicians to help individuals to determine if the gains anticipated from treatment are reasonable for their particular situation. The treatment options presented below should be modified based upon both patient and tumor characteristics.

Table 7. Adjuvant Systemic Treatment Options for Women With Axillary Node-Negative Breast Cancer

Patient group	Low risk	Intermediate risk	High risk
a Note: This treatment option is under clinical evaluation.
Premenopausal, ER-positive or PR-positive	None or tamoxifen	Tamoxifen plus chemotherapy, tamoxifen alone, ovarian ablation, GnRH analoga	Chemotherapy plus tamoxifen, chemotherapy plus ablation or GnRH analog*, chemotherapy plus tamoxifen plus ovarian ablation or GnRH*, or ovarian ablation alone or with tamoxifen or GnRH alone or with tamoxifen
Premenopausal, ER-negative or PR-negative	—	—	Chemotherapy
Postmenopausal, ER-positive or PR-positive	None or tamoxifen	Tamoxifen plus chemotherapy, tamoxifen alone	Tamoxifen plus chemotherapy, tamoxifen alone
Postmenopausal, ER-negative or PR-negative	—	—	Chemotherapy
Older than 70 years	None or tamoxifen	Tamoxifen alone, tamoxifen plus chemotherapy	Tamoxifen; consider chemotherapy if ER-negative or PR-negative

Table 8. Treatment Options for Women With Axillary Node-Positive Breast Cancer

Patient group	Treatments
a Note: This treatment option is under clinical evaluation.
Premenopausal, ER-positive or PR-positive	Chemotherapy plus tamoxifen, chemotherapy plus ovarian ablation/GnRH analog, chemotherapy plus tamoxifen plus ovarian ablation/GnRH analog,a ovarian ablation alone or with tamoxifen or GnRH alone or with tamoxifen
Premenopausal, ER-negative or PR-negative	Chemotherapy
Postmenopausal, ER-positive or PR-positive	Tamoxifen plus chemotherapy, tamoxifen alone
Postmenopausal, ER-negative or PR-negative	Chemotherapy
Older than 70 years	Tamoxifen alone; consider chemotherapy if receptor-negative

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage IIIC breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Fisher B, Fisher ER, Redmond C, et al.: Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 7 (3): 147-60, 1986.
2.	Thor AD, Berry DA, Budman DR, et al.: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90 (18): 1346-60, 1998.
3.	Paik S, Bryant J, Park C, et al.: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90 (18): 1361-70, 1998.
4.	Hutchins L, Green S, Ravdin P, et al.: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node negative patients: first results of intergroup trial INT 0102. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A2, 1a, 1998.
5.	Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000.
6.	Fisher B, Anderson S, Bryant J, et al.: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347 (16): 1233-41, 2002.
7.	Blichert-Toft M, Rose C, Andersen JA, et al.: Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr (11): 19-25, 1992.
8.	van Dongen JA, Bartelink H, Fentiman IS, et al.: Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr (11): 15-8, 1992.
9.	Sarrazin D, Lê MG, Arriagada R, et al.: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14 (3): 177-84, 1989.
10.	Jacobson JA, Danforth DN, Cowan KH, et al.: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332 (14): 907-11, 1995.
11.	Veronesi U, Cascinelli N, Mariani L, et al.: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347 (16): 1227-32, 2002.
12.	Veronesi U, Salvadori B, Luini A, et al.: Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 31A (10): 1574-9, 1995.
13.	van Dongen JA, Voogd AC, Fentiman IS, et al.: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92 (14): 1143-50, 2000.
14.	Abrams JS, Phillips PH, Friedman MA: Meeting highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 87 (24): 1837-45, 1995.
15.	Freedman GM, Anderson PR, Li T, et al.: Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 115 (5): 946-51, 2009.
16.	Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. Int J Radiat Oncol Biol Phys 23 (5): 941-7, 1992.
17.	Schmidt-Ullrich R, Wazer DE, Tercilla O, et al.: Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys 17 (4): 733-8, 1989.
18.	Solin LJ, Fowble BL, Schultz DJ, et al.: The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 279-87, 1991.
19.	Wazer DE, Schmidt-Ullrich RK, Schmid CH, et al.: The value of breast lumpectomy margin assessment as a predictor of residual tumor burden. Int J Radiat Oncol Biol Phys 38 (2): 291-9, 1997.
20.	Holland R, Connolly JL, Gelman R, et al.: The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 8 (1): 113-8, 1990.
21.	Jardines L, Fowble B, Schultz D, et al.: Factors associated with a positive reexcision after excisional biopsy for invasive breast cancer. Surgery 118 (5): 803-9, 1995.
22.	Renton SC, Gazet JC, Ford HT, et al.: The importance of the resection margin in conservative surgery for breast cancer. Eur J Surg Oncol 22 (1): 17-22, 1996.
23.	Whelan TJ, MacKenzie RG, Levine M, et al.: A randomized trial comparing two fractionation schedules for breast irradiation postlumpectomy in node-negative breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-5, 2a, 2000.
24.	Whelan T, MacKenzie R, Julian J, et al.: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94 (15): 1143-50, 2002.
25.	Owen JR, Ashton A, Bliss JM, et al.: Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 7 (6): 467-71, 2006.
26.	Romestaing P, Lehingue Y, Carrie C, et al.: Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 15 (3): 963-8, 1997.
27.	Bartelink H, Horiot JC, Poortmans P, et al.: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345 (19): 1378-87, 2001.
28.	Wazer DE, Kramer B, Schmid C, et al.: Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy. Int J Radiat Oncol Biol Phys 39 (2): 381-93, 1997.
29.	Solin LJ, Schultz DJ, Fowble BL: Ten-year results of the treatment of early-stage breast carcinoma in elderly women using breast-conserving surgery and definitive breast irradiation. Int J Radiat Oncol Biol Phys 33 (1): 45-51, 1995.
30.	Chabner E, Nixon A, Gelman R, et al.: Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 16 (6): 2045-51, 1998.
31.	Haas JA, Schultz DJ, Peterson ME, et al.: An analysis of age and family history on outcome after breast-conservation treatment: the University of Pennsylvania experience. Cancer J Sci Am 4 (5): 308-15, 1998 Sep-Oct.
32.	Robson M, Gilewski T, Haas B, et al.: BRCA-associated breast cancer in young women. J Clin Oncol 16 (5): 1642-9, 1998.
33.	Veronesi U, Luini A, Del Vecchio M, et al.: Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 328 (22): 1587-91, 1993.
34.	Liljegren G, Holmberg L, Bergh J, et al.: 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 17 (8): 2326-33, 1999.
35.	Clark RM, McCulloch PB, Levine MN, et al.: Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst 84 (9): 683-9, 1992.
36.	Fyles AW, McCready DR, Manchul LA, et al.: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351 (10): 963-70, 2004.
37.	Hughes KS, Schnaper LA, Berry D, et al.: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351 (10): 971-7, 2004.
38.	Smith IE, Ross GM: Breast radiotherapy after lumpectomy--no longer always necessary. N Engl J Med 351 (10): 1021-3, 2004.
39.	Smith BD, Gross CP, Smith GL, et al.: Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 98 (10): 681-90, 2006.
40.	Kern KA: Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189 (6): 539-45, 1999.
41.	Rubio IT, Korourian S, Cowan C, et al.: Sentinel lymph node biopsy for staging breast cancer. Am J Surg 176 (6): 532-7, 1998.
42.	Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349 (9069): 1864-7, 1997.
43.	Albertini JJ, Lyman GH, Cox C, et al.: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276 (22): 1818-22, 1996.
44.	Krag D, Weaver D, Ashikaga T, et al.: The sentinel node in breast cancer--a multicenter validation study. N Engl J Med 339 (14): 941-6, 1998.
45.	Veronesi U, Paganelli G, Viale G, et al.: Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 91 (4): 368-73, 1999.
46.	Krag DN, Anderson SJ, Julian TB, et al.: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11 (10): 927-33, 2010.
47.	Veronesi U, Paganelli G, Viale G, et al.: Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study. Lancet Oncol 7 (12): 983-90, 2006.
48.	Lyman GH, Giuliano AE, Somerfield MR, et al.: American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 23 (30): 7703-20, 2005.
49.	Mansel RE, Fallowfield L, Kissin M, et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98 (9): 599-609, 2006.
50.	Krag DN, Anderson SJ, Julian TB, et al.: Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol 8 (10): 881-8, 2007.
51.	Giuliano AE, Hunt KK, Ballman KV, et al.: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305 (6): 569-75, 2011.
52.	Barth RJ Jr, Danforth DN Jr, Venzon DJ, et al.: Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival. Arch Surg 126 (5): 574-7, 1991.
53.	Rivadeneira DE, Simmons RM, Christos PJ, et al.: Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg 191 (1): 1-6; discussion 6-8, 2000.
54.	Greco M, Agresti R, Cascinelli N, et al.: Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 232 (1): 1-7, 2000.
55.	Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, eds.: Advances in Breast and Endocrine Surgery. Chicago, Ill: Year Book Medical Publishers, 1986, pp 213-226.
56.	Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.
57.	Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.
58.	Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.
59.	Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991.
60.	Clarke M, Collins R, Darby S, et al.: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366 (9503): 2087-106, 2005.
61.	Eifel P, Axelson JA, Costa J, et al.: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93 (13): 979-89, 2001.
62.	Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 355 (9217): 1757-70, 2000.
63.	Ragaz J, Jackson SM, Le N, et al.: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337 (14): 956-62, 1997.
64.	Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337 (14): 949-55, 1997.
65.	Fowble B, Gray R, Gilchrist K, et al.: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6 (7): 1107-17, 1988.
66.	Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006.
67.	Lingos TI, Recht A, Vicini F, et al.: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21 (2): 355-60, 1991.
68.	Paszat LF, Mackillop WJ, Groome PA, et al.: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16 (8): 2625-31, 1998.
69.	Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61 (6): 866-8, 1990.
70.	Darby SC, McGale P, Taylor CW, et al.: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6 (8): 557-65, 2005.
71.	Højris I, Overgaard M, Christensen JJ, et al.: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354 (9188): 1425-30, 1999.
72.	Nixon AJ, Manola J, Gelman R, et al.: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16 (4): 1374-9, 1998.
73.	Giordano SH, Kuo YF, Freeman JL, et al.: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97 (6): 419-24, 2005.
74.	Harris EE, Correa C, Hwang WT, et al.: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24 (25): 4100-6, 2006.
75.	Meek AG: Breast radiotherapy and lymphedema. Cancer 83 (12 Suppl American): 2788-97, 1998.
76.	Larson D, Weinstein M, Goldberg I, et al.: Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12 (9): 1575-82, 1986.
77.	Swedborg I, Wallgren A: The effect of pre- and postmastectomy radiotherapy on the degree of edema, shoulder-joint mobility, and gripping force. Cancer 47 (5): 877-81, 1981.
78.	Powell S, Cooke J, Parsons C: Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 18 (3): 213-20, 1990.
79.	Taghian A, de Vathaire F, Terrier P, et al.: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 361-7, 1991.
80.	Boice JD Jr, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326 (12): 781-5, 1992.
81.	Storm HH, Andersson M, Boice JD Jr, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84 (16): 1245-50, 1992.
82.	Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11 (3): 485-97, 1985.
83.	Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 86 (13): 983-8, 1994.
84.	Harvey JM, Clark GM, Osborne CK, et al.: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17 (5): 1474-81, 1999.
85.	Early Breast Cancer Trialists' Collaborative Group (EBCTCG).: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): 1687-717, 2005.
86.	Colleoni M, Gelber S, Goldhirsch A, et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006.
87.	Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93 (9): 684-90, 2001.
88.	Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 93 (6): 456-62, 2001.
89.	Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): 1828-33, 1996.
90.	Swain SM: Tamoxifen: the long and short of it. J Natl Cancer Inst 88 (21): 1510-2, 1996.
91.	Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339 (8784): 1-15, 1992.
92.	Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339 (8785): 71-85, 1992.
93.	Fisher B, Redmond C, Legault-Poisson S, et al.: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8 (6): 1005-18, 1990.
94.	Fisher B, Jeong JH, Bryant J, et al.: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364 (9437): 858-68, 2004.
95.	Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. International Breast Cancer Study Group. J Clin Oncol 15 (4): 1385-94, 1997.
96.	Pritchard KI, Paterson AH, Fine S, et al.: Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J Clin Oncol 15 (6): 2302-11, 1997.
97.	Fornander T, Rutqvist LE, Cedermark B, et al.: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1 (8630): 117-20, 1989.
98.	Magriples U, Naftolin F, Schwartz PE, et al.: High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11 (3): 485-90, 1993.
99.	Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994.
100.	van Leeuwen FE, Benraadt J, Coebergh JW, et al.: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343 (8895): 448-52, 1994.
101.	Barakat RR, Wong G, Curtin JP, et al.: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55 (2): 164-8, 1994.
102.	Cuenca RE, Giachino J, Arredondo MA, et al.: Endometrial carcinoma associated with breast carcinoma: low incidence with tamoxifen use. Cancer 77 (10): 2058-63, 1996.
103.	Kedar RP, Bourne TH, Powles TJ, et al.: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343 (8909): 1318-21, 1994.
104.	Neven P, De Muylder X, Van Belle Y, et al.: Tamoxifen and the uterus. Br Med J 309 (6965): 1313-1314, 1994.
105.	Bertelli G, Venturini M, Del Mastro L, et al.: Tamoxifen and the endometrium: findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients. Breast Cancer Res Treat 47 (1): 41-6, 1998.
106.	Rutqvist LE, Johansson H, Signomklao T, et al.: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J Natl Cancer Inst 87 (9): 645-51, 1995.
107.	Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89 (22): 1673-82, 1997.
108.	Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.
109.	Saphner T, Tormey DC, Gray R: Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 9 (2): 286-94, 1991.
110.	Love RR, Surawicz TS, Williams EC: Antithrombin III level, fibrinogen level, and platelet count changes with adjuvant tamoxifen therapy. Arch Intern Med 152 (2): 317-20, 1992.
111.	Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.
112.	Dignam JJ, Fisher B: Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 355 (9206): 848-9, 2000.
113.	Shushan A, Peretz T, Uziely B, et al.: Ovarian cysts in premenopausal and postmenopausal tamoxifen-treated women with breast cancer. Am J Obstet Gynecol 174 (1 Pt 1): 141-4, 1996.
114.	Cohen I, Beyth Y, Tepper R, et al.: Ovarian tumors in postmenopausal breast cancer patients treated with tamoxifen. Gynecol Oncol 60 (1): 54-8, 1996.
115.	Love RR, Cameron L, Connell BL, et al.: Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151 (9): 1842-7, 1991.
116.	Bentley CR, Davies G, Aclimandos WA: Tamoxifen retinopathy: a rare but serious complication. BMJ 304 (6825): 495-6, 1992.
117.	Nayfield SG, Gorin MB: Tamoxifen-associated eye disease. A review. J Clin Oncol 14 (3): 1018-26, 1996.
118.	Noureddin BN, Seoud M, Bashshur Z, et al.: Ocular toxicity in low-dose tamoxifen: a prospective study. Eye 13 ( Pt 6): 729-33, 1999.
119.	Love RR, Wiebe DA, Newcomb PA, et al.: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115 (11): 860-4, 1991.
120.	McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 303 (6800): 435-7, 1991.
121.	Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85 (17): 1398-406, 1993.
122.	Costantino JP, Kuller LH, Ives DG, et al.: Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89 (11): 776-82, 1997.
123.	Love RR, Mazess RB, Barden HS, et al.: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326 (13): 852-6, 1992.
124.	Kristensen B, Ejlertsen B, Dalgaard P, et al.: Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J Clin Oncol 12 (5): 992-7, 1994.
125.	Love RR, Barden HS, Mazess RB, et al.: Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch Intern Med 154 (22): 2585-8, 1994.
126.	Powles TJ, Hickish T, Kanis JA, et al.: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14 (1): 78-84, 1996.
127.	Castiglione-Gertsch M, O'Neill A, Price KN, et al.: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 95 (24): 1833-46, 2003.
128.	Chemotherapy with or without oophorectomy in high-risk premenopausal patients with operable breast cancer. Ludwig Breast Cancer Study Group. J Clin Oncol 3 (8): 1059-67, 1985.
129.	Arriagada R, Lê MG, Spielmann M, et al.: Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol 16 (3): 389-96, 2005.
130.	Davidson NE, O'Neill AM, Vukov AM, et al.: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol 23 (25): 5973-82, 2005.
131.	Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Lancet 341 (8856): 1293-8, 1993.
132.	Schmid P, Untch M, Kossé V, et al.: Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol 25 (18): 2509-15, 2007.
133.	Ejlertsen B, Mouridsen HT, Jensen MB, et al.: Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer. J Clin Oncol 24 (31): 4956-62, 2006.
134.	Wolff AC, Davidson NE: Still waiting after 110 years: the optimal use of ovarian ablation as adjuvant therapy for breast cancer. J Clin Oncol 24 (31): 4949-51, 2006.
135.	Boccardo F, Rubagotti A, Amoroso D, et al.: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. boccardo@hp380.ist.unige.it. J Clin Oncol 18 (14): 2718-27, 2000.
136.	Jonat W, Kaufmann M, Sauerbrei W, et al.: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20 (24): 4628-35, 2002.
137.	Jakesz R, Hausmaninger H, Kubista E, et al.: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20 (24): 4621-7, 2002.
138.	Pritchard KI: Adjuvant therapy for premenopausal women with breast cancer: is it time for another paradigm shift? J Clin Oncol 20 (24): 4611-4, 2002.
139.	Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al.: Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 361 (8): 766-76, 2009.
140.	Burstein HJ, Prestrud AA, Seidenfeld J, et al.: American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 28 (23): 3784-96, 2010.
141.	The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination.: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 (9324): 2131-9, 2002.
142.	Howell A, Cuzick J, Baum M, et al.: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (9453): 60-2, 2005.
143.	Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 20 (15): 3317-27, 2002.
144.	Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 23 (3): 619-29, 2005.
145.	Boccardo F, Rubagotti A, Guglielmini P, et al.: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17 (Suppl 7): vii10-4, 2006.
146.	Jakesz R, Jonat W, Gnant M, et al.: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 (9484): 455-62, 2005 Aug 6-12.
147.	Boccardo F, Rubagotti A, Aldrighetti D, et al.: Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer 109 (6): 1060-7, 2007.
148.	Jonat W, Gnant M, Boccardo F, et al.: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 7 (12): 991-6, 2006.
149.	Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005.
150.	Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007.
151.	Goss PE, Ingle JN, Martino S, et al.: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349 (19): 1793-802, 2003.
152.	Bryant J, Wolmark N: Letrozole after tamoxifen for breast cancer--what is the price of success? N Engl J Med 349 (19): 1855-7, 2003.
153.	Burstein HJ: Beyond tamoxifen--extending endocrine treatment for early-stage breast cancer. N Engl J Med 349 (19): 1857-9, 2003.
154.	Goss PE, Ingle JN, Martino S, et al.: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97 (17): 1262-71, 2005.
155.	Coombes RC, Hall E, Gibson LJ, et al.: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350 (11): 1081-92, 2004.
156.	Piccart-Gebhart MJ: New stars in the sky of treatment for early breast cancer. N Engl J Med 350 (11): 1140-2, 2004.
157.	Coombes RC, Kilburn LS, Snowdon CF, et al.: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559-70, 2007.
158.	van de Velde CJ, Rea D, Seynaeve C, et al.: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377 (9762): 321-31, 2011.
159.	Fisher B, Jeong JH, Anderson S, et al.: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96 (24): 1823-31, 2004.
160.	Mansour EG, Gray R, Shatila AH, et al.: Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: ten-year analysis--an intergroup study. J Clin Oncol 16 (11): 3486-92, 1998.
161.	Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352 (9132): 930-42, 1998.
162.	Hutchins LF, Green SJ, Ravdin PM, et al.: Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23 (33): 8313-21, 2005.
163.	Bonadonna G, Zambetti M, Moliterni A, et al.: Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer. J Clin Oncol 22 (9): 1614-20, 2004.
164.	Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA 273 (7): 542-7, 1995.
165.	Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990.
166.	Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006.
167.	Gennari A, Sormani MP, Pronzato P, et al.: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100 (1): 14-20, 2008.
168.	De Laurentiis M, Cancello G, D'Agostino D, et al.: Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26 (1): 44-53, 2008.
169.	Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358 (16): 1663-71, 2008.
170.	Budman DR, Berry DA, Cirrincione CT, et al.: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90 (16): 1205-11, 1998.
171.	Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4 (8): 1162-70, 1986.
172.	Fisher B, Anderson S, Wickerham DL, et al.: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15 (5): 1858-69, 1997.
173.	Fisher B, Anderson S, DeCillis A, et al.: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17 (11): 3374-88, 1999.
174.	Henderson IC, Berry DA, Demetri GD, et al.: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21 (6): 976-83, 2003.
175.	Levine MN, Pritchard KI, Bramwell VH, et al.: Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23 (22): 5166-70, 2005.
176.	Bonneterre J, Roché H, Kerbrat P, et al.: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23 (12): 2686-93, 2005.
177.	Fumoleau P, Kerbrat P, Romestaing P, et al.: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21 (2): 298-305, 2003.
178.	Citron ML, Berry DA, Cirrincione C, et al.: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21 (8): 1431-9, 2003.
179.	Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-41, 2005.
180.	Citron ML, Berry DA, Cirrincione C, et al.: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD treatment: update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. [Abstract] J Clin Oncol 23 (Suppl 16): A-620, 33s, 2005.
181.	Tallman MS, Gray R, Robert NJ, et al.: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349 (1): 17-26, 2003.
182.	Bergh J, Wiklund T, Erikstein B, et al.: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 356 (9239): 1384-91, 2000.
183.	Hortobagyi GN, Buzdar AU, Theriault RL, et al.: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 92 (3): 225-33, 2000.
184.	Rodenhuis S, Bontenbal M, Beex LV, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 349 (1): 7-16, 2003.
185.	Schrama JG, Faneyte IF, Schornagel JH, et al.: Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up. Ann Oncol 13 (5): 689-98, 2002.
186.	Coombes RC, Howell A, Emson M, et al.: High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol 16 (5): 726-34, 2005.
187.	Nitz UA, Mohrmann S, Fischer J, et al.: Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet 366 (9501): 1935-44, 2005.
188.	Zander AR, Kröger N, Schmoor C, et al.: High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol 22 (12): 2273-83, 2004.
189.	Peters WP, Rosner GL, Vredenburgh JJ, et al.: Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 23 (10): 2191-200, 2005.
190.	Moore HC, Green SJ, Gralow JR, et al.: Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol 25 (13): 1677-82, 2007.
191.	Mamounas EP, Bryant J, Lembersky B, et al.: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23 (16): 3686-96, 2005.
192.	Martin M, Pienkowski T, Mackey J, et al.: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352 (22): 2302-13, 2005.
193.	Perez EA: TAC--a new standard in adjuvant therapy for breast cancer? N Engl J Med 352 (22): 2346-8, 2005.
194.	Jones SE, Savin MA, Holmes FA, et al.: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24 (34): 5381-7, 2006.
195.	Gnant M, Mlineritsch B, Schippinger W, et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360 (7): 679-91, 2009.
196.	Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16): 1659-72, 2005.
197.	Smith I, Procter M, Gelber RD, et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369 (9555): 29-36, 2007.
198.	Romond EH, Perez EA, Bryant J, et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353 (16): 1673-84, 2005.
199.	Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007.
200.	Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-52, 2006.
201.	Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al.: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354 (8): 809-20, 2006.
202.	Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9 (Suppl 3): 10-5, 2004.
203.	Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26): 2733-43, 2006.
204.	Blackwell KL, Burstein HJ, Storniolo AM, et al.: Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28 (7): 1124-30, 2010.
205.	Tan-Chiu E, Yothers G, Romond E, et al.: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23 (31): 7811-9, 2005.
206.	Combination adjuvant chemotherapy for node-positive breast cancer. Inadequacy of a single perioperative cycle. The Ludwig Breast Cancer Study Group. N Engl J Med 319 (11): 677-83, 1988.
207.	Clahsen PC, van de Velde CJ, Julien JP, et al.: Improved local control and disease-free survival after perioperative chemotherapy for early-stage breast cancer. A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study. J Clin Oncol 14 (3): 745-53, 1996.
208.	Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998.
209.	Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002.
210.	Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008.
211.	van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001.
212.	Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97 (3): 188-94, 2005.
213.	Haid A, Tausch C, Lang A, et al.: Is sentinel lymph node biopsy reliable and indicated after preoperative chemotherapy in patients with breast carcinoma? Cancer 92 (5): 1080-4, 2001.
214.	Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005.
215.	Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010.
216.	Recht A, Come SE, Henderson IC, et al.: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334 (21): 1356-61, 1996.
217.	Wallgren A, Bernier J, Gelber RD, et al.: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35 (4): 649-59, 1996.
218.	Halyard MY, Pisansky TM, Dueck AC, et al.: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol 27 (16): 2638-44, 2009.
219.	Veronesi U, Luini A, Mariani L, et al.: Effect of menstrual phase on surgical treatment of breast cancer. Lancet 343 (8912): 1545-7, 1994.
220.	Badwe RA, Gregory WM, Chaudary MA, et al.: Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet 337 (8752): 1261-4, 1991.
221.	Senie RT, Rosen PP, Rhodes P, et al.: Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival. Ann Intern Med 115 (5): 337-42, 1991.
222.	Goldhirsch A, Gelber RD, Castiglione M, et al.: Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Ann Oncol 8 (8): 751-6, 1997.
223.	McGuire WL, Hilsenbeck S, Clark GM: Optimal mastectomy timing. J Natl Cancer Inst 84 (5): 346-8, 1992.
224.	Nathan B, Bates T, Anbazhagan R, et al.: Timing of surgery for breast cancer in relation to the menstrual cycle and survival of premenopausal women. Br J Surg 80 (1): 43, 1993.
225.	Brown GS, Kramer S, Brady L, et al.: Primary irradiation of stage I and stage II adenocarcinoma of the breast. Int J Radiat Oncol Biol Phys 2 (11-12): 1145-8, 1977 Nov-Dec.
226.	Hagen AA, Hrushesky WJ: Menstrual timing of breast cancer surgery. Am J Surg 175 (3): 245-61, 1998.
227.	Pritchard KI, Paterson AH, Paul NA, et al.: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14 (10): 2731-7, 1996.
228.	Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19 (14): 3306-11, 2001.
229.	Schagen SB, Muller MJ, Boogerd W, et al.: Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst 98 (23): 1742-5, 2006.
230.	Smith RE, Bryant J, DeCillis A, et al.: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 21 (7): 1195-204, 2003.
231.	Crump M, Tu D, Shepherd L, et al.: Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21 (16): 3066-71, 2003.
232.	Praga C, Bergh J, Bliss J, et al.: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23 (18): 4179-91, 2005.
233.	Albain KS, Green SJ, Ravdin PM, et al.: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-143, 2002.
234.	Rosen PP, Groshen S, Saigo PE, et al.: Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7 (9): 1239-51, 1989.
235.	Gazet JC, Ford HT, Coombes RC, et al.: Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. Eur J Surg Oncol 20 (3): 207-14, 1994.
236.	Akhtar SS, Allan SG, Rodger A, et al.: A 10-year experience of tamoxifen as primary treatment of breast cancer in 100 elderly and frail patients. Eur J Surg Oncol 17 (1): 30-5, 1991.
237.	Dixon JM: Treatment of elderly patients with breast cancer. BMJ 304 (6833): 996-7, 1992.

Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer

Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease. In a retrospective series, approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined modality therapy.[1] Although these results have not been replicated in another series, this result suggests such patients should be treated with the same intent.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard.[2,3] In one series of 178 patients with inflammatory breast cancer, DFS was 28% at 15 years with a combined-modality approach.[2][Level of evidence: 3iiiDii] For patients who respond to neoadjuvant chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered in patients with a good partial or complete response to neoadjuvant chemotherapy.[3] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy should be administered to patients whose tumors are ER-positive or unknown. All patients should be considered candidates for clinical trials to evaluate the most appropriate fashion in which to administer the various components of multimodality regimens.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer and inflammatory breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage IV, Recurrent, and Metastatic Breast Cancer

Recurrent breast cancer is often responsive to therapy, though treatment is rarely curative at this stage of disease. Patients with localized breast or chest wall recurrences, however, may be long-term survivors with appropriate therapy. Prior to treatment for recurrent or metastatic cancer, restaging to evaluate extent of disease is indicated. Cytologic or histologic documentation of recurrent or metastatic disease should be obtained whenever possible. The ER levels and PR levels, HER2/neu positivity at the time of recurrence, and previous treatment should be considered, if known, when selecting therapy. ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.[4] Patients in this study had no interval treatment. If ER and PR status is unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in selecting chemotherapy or hormone therapy.[5]

Recurrent local-regional breast cancer

Patients with local-regional breast cancer recurrence may become long-term survivors with appropriate therapy. A clinical trial indicated that between 10% and 20% of patients will have locally recurrent disease in the breast between 1 and 9 years after breast-conservation surgery plus radiation therapy.[6] Nine percent to 25% of these patients will have distant metastases or locally extensive disease at the time of recurrence.[7,8,9] Patients with local-regional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.[8] A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[10][Level of evidence: 1iiDiii]

Local chest wall recurrence following mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[11,12] Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year disease-free interval prior to recurrence have the best chance for prolonged survival.[12] The 5-year DFS rate in one series of such patients was 25%, with a 10-year rate of 15%.[13] The local-regional control rate was 57% at 10 years. Systemic therapy should be considered in patients with local regional recurrence caused by the high risk of subsequent metastases.[14] No randomized controlled studies are available to guide patient care in this situation.

Stage IV and metastatic disease

Systemic disease

Treatment for systemic disease is palliative in intent. Goals of treatment include improving quality of life and prolongation of life. Although median survival has been reported to be 18 to 24 months,[15] some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[16][Level of evidence: 3iiDiii]

Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. Radiation therapy and/or surgery may be indicated for patients with limited symptomatic metastases. All patients with metastatic or recurrent breast cancer should be considered candidates for ongoing clinical trials.

Surgery

Surgery may be indicated for selected patients. Examples include patients who need mastectomies for fungating/painful breast lesions, parenchymal brain or vertebral metastases with spinal cord compression, isolated lung metastases, pathologic (or impending) fractures, or pleural or pericardial effusions. (Refer to the PDQ summary on Pain for more information; for information on pleural and pericardial effusions, refer to the PDQ summary on Cardiopulmonary Syndromes.)

Radiation therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications include painful bony metastases, unresectable central nervous system metastases (i.e., brain, meningeal, and spinal cord), bronchial obstruction, and fungating/painful breast or chest wall lesions. Radiation therapy should also be given following surgery for decompression of intracranial or spinal cord metastases and following fixation of pathologic fractures. Clinical trials (including the completed Radiation Therapy Oncology Group's trial [RTOG-9714]) are exploring the optimal radiation fractionation schedule. Strontium 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[17,18] (Refer to the PDQ summary on Pain for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV breast cancer and recurrent breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Systemic Therapy

Bisphosphonates

The use of bisphosphonates to reduce skeletal morbidity in patients with bone metastases should be considered.[19] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[20,21,22][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[23] (Refer to the PDQ summary on Pain for more information on bisphosphonates.)

Hormone therapy

Hormone therapy should generally be considered as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient's tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient's disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year. While tamoxifen has been used in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors compared to tamoxifen.[24,25,26][Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an aromatase inhibitor as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death = 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA]

Several randomized but underpowered trials have tried to determine if combined hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach alone in premenopausal women. Results have been inconsistent.[28,29,30] The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors.[31] Patients receiving buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those receiving tamoxifen or buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[31][Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.

Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year, should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective aromatase inhibitors, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[32,33,34,35,36,37,38,39,40] and the ER down-regulator, fulvestrant.[41,42] In comparison to megestrol acetate, all three currently available aromatase inhibitors have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[32,33,34,35,36,37,38,43] In a meta-analysis that included randomized trials of patients who were receiving an aromatase inhibitor as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HR for death 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451 patients who had progressed after receiving tamoxifen demonstrated that fulvestrant yielded similar results to anastrozole in terms of its impact on PFS.[44,45] The proper sequence of these therapies is currently not known.[43,46]

Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist).[47] Patients with lymphangitic pulmonary metastases, major liver involvement, and/or central nervous system involvement should not receive hormone therapy as a single modality. Patients with structural compromise of weight-bearing bones should be considered for surgical intervention and/or radiation in addition to systemic therapy. Patients with vertebral body involvement should be evaluated for impending cord compression even in the absence of neurologic symptoms. Increasing bone pain and increasing alkaline phosphatase within the first several weeks of hormone therapy does not necessarily imply disease progression.[48] Patients with extensive bony disease are at risk for the development of symptomatic hypercalcemia early in the course of hormone therapy.[48] Early failure (e.g., <6 months) on hormone therapy suggests that cytotoxic chemotherapy should be the next modality employed.

Trastuzumab

Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu.[49] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[49] In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[50][Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab. Patients treated with chemotherapy plus trastuzumab had an overall survival (OS) advantage as compared with those receiving chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[51][Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[52] Consequently, patients with metastatic breast cancer with substantial overexpression of HER2/neu are candidates for treatment with the combination of trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with taxanes and other chemotherapeutic agents.[53]

In a randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time-to-progression with the addition of carboplatin to trastuzumab and paclitaxel.[54][Level of evidence: 1iDiii]

Lapatinib

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib has shown activity in combination with capecitabine in patients who have HER2 -positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[55] At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR = 0.49; 95% CI, 0.34–0.71; P < .001). There was no difference in OS (HR = 0.92; 95% CI, 0.58–1.46; P = .72).[55][Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (For information on diarrhea, refer to the PDQ summary on Gastrointestinal Complications.)

A double-blind, randomized phase III study compared paclitaxel and lapatinib for first-line therapy in patients with metastatic breast cancer.[56] There was no benefit for patients with HER2/neu metastatic breast cancer. Specimens were evaluated retrospectively to determine HER2/neu status. When used with HER2/neu -positive patients, treatment with paclitaxel and lapatinib showed improvement in time to progression, event-free survival, response rate, and clinical benefit rate; OS did not increase. Toxicities, specifically alopecia, diarrhea, and rash were higher in the HER2/neu -positive lapatinib group. A series of adverse events were low and existed in both arms.[56][Level of evidence: 1iDiii]

Cytotoxic chemotherapy

Patients whose tumors have progressed on hormone therapy are candidates for cytotoxic chemotherapy. Patients with hormone receptor–negative tumors and those with visceral metastases are also candidates for cytotoxic agents.[57]

Single agents that have shown activity in metastatic breast cancer include the following:

• Anthracyclines.
  • Doxorubicin.
  • Epirubicin.
  • Liposomal doxorubicin.[58,59,60,61]
  • Mitoxantrone.
• Taxanes.
  • Paclitaxel.[62,63]
  • Docetaxel.
  • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[64,65]
• Alkylating agents.
  • Cyclophosphamide.
• Fluoropyrimidines.
  • Capecitabine.[66,67,68]
  • 5-FU.
• Antimetabolites.
  • Methotrexate.
• Vinca alkaloids.
  • Vinorelbine.[69]
  • Vinblastine.
  • Vincristine.
• Platinum.
  • Carboplatin.
  • Cisplatin.
• Other.
  • Gemcitabine.[70]
  • Mitomycin C.

Combination regimens that have shown activity in metastatic breast cancer:

• CA: cyclophosphamide and doxorubicin.[71]
• Docetaxel and doxorubicin.[72]
• CAF: cyclophosphamide, doxorubicin, 5-fluorouracil.[73]
• CMF: cyclophosphamide, methotrexate, 5-fluorouracil.[74]
• Doxorubicin and paclitaxel.[75,76]
• Docetaxel and capecitabine.[77]
• Vinorelbine and epirubicin.[78]
• Capecitabine and ixabepilone.[79]

Whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment is unclear. An Eastern Cooperative Oncology Intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin given both as a combination and sequentially.[80] Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.[80][Level of evidence: 1iiA][81,82] The rate of disease progression, the presence or absence of comorbid medical conditions, and physician/patient preference will influence the choice of therapy in individual patients. At this time, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[15,83] A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[84][Level of evidence: 1iiA]

The optimal treatment duration for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS from immediate treatment with a different chemotherapy regimen compared to observation with treatment upon relapse.[85,86][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment, and in one of these studies,[86] survival was actually worse in the immediately treated group. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomized to receive either a different chemotherapy versus observation [87] or a different chemotherapy regimen given at higher versus lower doses.[88][Level of evidence: 1iiA] These four studies indicate that different combination regimens of additional chemotherapy immediately following a patient's best response to an induction chemotherapy regimen does not improve OS. In view of the lack of a standard approach, patients requiring second-line regimens are good candidates for clinical trials.

The potential for doxorubicin-induced cardiotoxicity should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest-wall radiation therapy, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin.[89,90,91,92] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[93] The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[94]

Studies comparing high-dose chemotherapy with stem cell support to conventional chemotherapy in patients with metastatic disease indicate no OS or relapse-free survival benefit for patients receiving high-dose chemotherapy with stem cell support.[95,96][Level of evidence: 1iiA] In the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this remains an area of clinical evaluation.[97,98]

Bevacizumab

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A. Its role in the treatment of metastatic breast cancer remains controversial. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[99] The study enrolled 462 patients who had received prior anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. The study failed to demonstrate a statistically significant effect on PFS (4.86 months vs. 4.17 months; HR = 0.98) or OS (15.1 months vs. 14.5 months).[99][Level of Evidence: 1iiA]

ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR = 0.60; P <.001).[100][Level of Evidence: 1iiA] However, the addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months, P = .16). Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.

The AVADO (NCT00333775) trial randomly assigned 736 patients to docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer. The combination of bevacizumab at 15 mg/kg, but not 7.5 mg/kg, with docetaxel modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[101][Level of Evidence: 1iiA] Again, more toxicity was seen in patients in the bevacizumab-containing arms with significantly higher rates of bleeding and hypertension compared with the placebo arms.

Similarly, the RIBBON-1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[102] Median PFS was longer for each bevacizumab-containing combination (Cape cohort: increased from 5.7 mo. to 8.6 mo.; HR = 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and Taxane/Anthracycline cohort: increased from 8.0 mo. to 9.2 mo.; HR = 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[102][Level of Evidence: 1iiA] However, no statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed. Toxicities associated with bevacizumab were similar to those seen in prior bevacizumab clinical trials.

In November 2011, based on the consistent finding that bevacizumab only modestly improved PFS but not OS, and given bevacizumab's considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer and metastatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001.
2.	Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997.
3.	Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994.
4.	Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996.
5.	Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987.
6.	Lichter AS, Lippman ME, Danforth DN Jr, et al.: Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 10 (6): 976-83, 1992.
7.	Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986.
8.	Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993.
9.	Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991.
10.	Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001.
11.	Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991.
12.	Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992.
13.	Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990.
14.	Waeber M, Castiglione-Gertsch M, Dietrich D, et al.: Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 14 (8): 1215-21, 2003.
15.	Honig SF: Hormonal therapy and chemotherapy. In: Harris JR, Morrow M, Lippman ME, et al., eds.: Diseases of the Breast. Lippincott-Raven Publishers: Philadelphia, Pa, 1996, pp 669-734.
16.	Greenberg PA, Hortobagyi GN, Smith TL, et al.: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14 (8): 2197-205, 1996.
17.	Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993.
18.	Quilty PM, Kirk D, Bolger JJ, et al.: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31 (1): 33-40, 1994.
19.	Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042-57, 2003.
20.	Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11 (1): 59-65, 1993.
21.	Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16 (6): 2038-44, 1998.
22.	Powles T, Paterson A, McCloskey E, et al.: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8 (2): R13, 2006.
23.	Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.
24.	Bonneterre J, Thürlimann B, Robertson JF, et al.: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18 (22): 3748-57, 2000.
25.	Nabholtz JM, Buzdar A, Pollak M, et al.: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18 (22): 3758-67, 2000.
26.	Mouridsen H, Gershanovich M, Sun Y, et al.: Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21 (11): 2101-9, 2003.
27.	Mauri D, Pavlidis N, Polyzos NP, et al.: Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 98 (18): 1285-91, 2006.
28.	Boccardo F, Rubagotti A, Perrotta A, et al.: Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 5 (4): 337-42, 1994.
29.	Jonat W, Kaufmann M, Blamey RW, et al.: A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer 31A (2): 137-42, 1995.
30.	Klijn JG, Blamey RW, Boccardo F, et al.: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19 (2): 343-53, 2001.
31.	Klijn JG, Beex LV, Mauriac L, et al.: Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 92 (11): 903-11, 2000.
32.	Buzdar AU, Jones SE, Vogel CL, et al.: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer 79 (4): 730-9, 1997.
33.	Dombernowsky P, Smith I, Falkson G, et al.: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16 (2): 453-61, 1998.
34.	Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A (3): 404-12, 1996.
35.	Gershanovich M, Chaudri HA, Campos D, et al.: Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 9 (6): 639-45, 1998.
36.	Peethambaram PP, Ingle JN, Suman VJ, et al.: Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 54 (2): 117-22, 1999.
37.	Kaufmann M, Bajetta E, Dirix LY, et al.: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18 (7): 1399-411, 2000.
38.	Kvinnsland S, Anker G, Dirix LY, et al.: High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment. Eur J Cancer 36 (8): 976-82, 2000.
39.	Buzdar A, Douma J, Davidson N, et al.: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19 (14): 3357-66, 2001.
40.	Gibson LJ, Dawson CK, Lawrence DH, et al.: Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev (1): CD003370, 2007.
41.	Howell A, Robertson JF, Abram P, et al.: Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 22 (9): 1605-13, 2004.
42.	Perey L, Paridaens R, Hawle H, et al.: Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 18 (1): 64-9, 2007.
43.	Henderson IC: A rose is no longer a rose. J Clin Oncol 20 (16): 3365-8, 2002.
44.	Osborne CK, Pippen J, Jones SE, et al.: Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20 (16): 3386-95, 2002.
45.	Howell A, Robertson JF, Quaresma Albano J, et al.: Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20 (16): 3396-403, 2002.
46.	Flemming J, Madarnas Y, Franek JA: Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Breast Cancer Res Treat 115 (2): 255-68, 2009.
47.	Bajetta E, Zilembo N, Buzzoni R, et al.: Goserelin in premenopausal advanced breast cancer: clinical and endocrine evaluation of responsive patients. Oncology 51 (3): 262-9, 1994 May-Jun.
48.	Clarysse A: Hormone-induced tumor flare. Eur J Cancer Clin Oncol 21 (5): 545-7, 1985.
49.	Pegram MD, Pauletti G, Slamon DJ: HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52 (1-3): 65-77, 1998.
50.	Cobleigh MA, Vogel CL, Tripathy D, et al.: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17 (9): 2639-48, 1999.
51.	Slamon DJ, Leyland-Jones B, Shak S, et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344 (11): 783-92, 2001.
52.	Seidman A, Hudis C, Pierri MK, et al.: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20 (5): 1215-21, 2002.
53.	Burstein HJ, Kuter I, Campos SM, et al.: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19 (10): 2722-30, 2001.
54.	Robert N, Leyland-Jones B, Asmar L, et al.: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24 (18): 2786-92, 2006.
55.	Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26): 2733-43, 2006.
56.	Di Leo A, Gomez HL, Aziz Z, et al.: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26 (34): 5544-52, 2008.
57.	Wilcken N, Dear R: Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000-2007. Eur J Cancer 44 (15): 2218-25, 2008.
58.	Ranson MR, Carmichael J, O'Byrne K, et al.: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 15 (10): 3185-91, 1997.
59.	Harris L, Batist G, Belt R, et al.: Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94 (1): 25-36, 2002.
60.	Keller AM, Mennel RG, Georgoulias VA, et al.: Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22 (19): 3893-901, 2004.
61.	Sparano JA, Makhson AN, Semiglazov VF, et al.: Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 27 (27): 4522-9, 2009.
62.	Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26 (10): 1642-9, 2008.
63.	Gonzalez-Angulo AM, Hortobagyi GN: Optimal schedule of paclitaxel: weekly is better. J Clin Oncol 26 (10): 1585-7, 2008.
64.	Gradishar WJ, Tjulandin S, Davidson N, et al.: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23 (31): 7794-803, 2005.
65.	Ibrahim NK, Samuels B, Page R, et al.: Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23 (25): 6019-26, 2005.
66.	Blum JL, Jones SE, Buzdar AU, et al.: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17 (2): 485-93, 1999.
67.	Blum JL, Dieras V, Lo Russo PM, et al.: Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92 (7): 1759-68, 2001.
68.	Venturini M, Paridaens R, Rossner D, et al.: An open-label, multicenter study of outpatient capecitabine monotherapy in 631 patients with pretreated advanced breast cancer. Oncology 72 (1-2): 51-7, 2007.
69.	Degardin M, Bonneterre J, Hecquet B, et al.: Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 5 (5): 423-6, 1994.
70.	Carmichael J, Walling J: Advanced breast cancer: investigational role of gemcitabine. Eur J Cancer 33 (Suppl 1): S27-30, 1997.
71.	Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in advanced breast cancer. A Southwest Oncology Group Study. Cancer 49 (5): 835-9, 1982.
72.	Misset JL, Dieras V, Gruia G, et al.: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10 (5): 553-60, 1999.
73.	Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 12 (2): 123-8, 1989.
74.	Tormey DC, Gelman R, Band PR, et al.: Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial. Cancer 50 (7): 1235-44, 1982.
75.	Jassem J, Pieńkowski T, Płuzańska A, et al.: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19 (6): 1707-15, 2001.
76.	Biganzoli L, Cufer T, Bruning P, et al.: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 20 (14): 3114-21, 2002.
77.	O'Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20 (12): 2812-23, 2002.
78.	Serin D, Verrill M, Jones A, et al.: Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study. Br J Cancer 92 (11): 1989-96, 2005.
79.	Thomas ES, Gomez HL, Li RK, et al.: Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25 (33): 5210-7, 2007.
80.	Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21 (4): 588-92, 2003.
81.	Seidman AD: Sequential single-agent chemotherapy for metastatic breast cancer: therapeutic nihilism or realism? J Clin Oncol 21 (4): 577-9, 2003.
82.	Overmoyer B: Combination chemotherapy for metastatic breast cancer: reaching for the cure. J Clin Oncol 21 (4): 580-2, 2003.
83.	Perez EA: Current management of metastatic breast cancer. Semin Oncol 26 (4 Suppl 12): 1-10, 1999.
84.	Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemotherapy regimen for metastatic breast cancer. Cochrane Database Syst Rev 3: CD003368, 2006.
85.	Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998.
86.	Peters WP, Jones RB, Vrendenburgh J, et al.: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-149, 121, 1996.
87.	Muss HB, Case LD, Richards F 2nd, et al.: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 325 (19): 1342-8, 1991.
88.	Falkson G, Gelman RS, Glick J, et al.: Metastatic breast cancer: higher versus low dose maintenance treatment when only a partial response or a no change status is obtained following doxorubicin induction treatment. An Eastern Cooperative Oncology Group study. Ann Oncol 3 (9): 768-70, 1992.
89.	Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15 (4): 1333-40, 1997.
90.	Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997.
91.	Hensley ML, Schuchter LM, Lindley C, et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17 (10): 3333-55, 1999.
92.	Marty M, Espié M, Llombart A, et al.: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17 (4): 614-22, 2006.
93.	Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996.
94.	Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989.
95.	Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 342 (15): 1069-76, 2000.
96.	Schmid P, Schippinger W, Nitsch T, et al.: Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol 23 (3): 432-40, 2005.
97.	Berry DA, Broadwater G, Klein JP, et al.: High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 20 (3): 743-50, 2002.
98.	Farquhar C, Marjoribanks J, Basser R, et al.: High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Syst Rev (3): CD003142, 2005.
99.	Miller KD, Chap LI, Holmes FA, et al.: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23 (4): 792-9, 2005.
100.	Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357 (26): 2666-76, 2007.
101.	Miles DW, Chan A, Dirix LY, et al.: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20): 3239-47, 2010.
102.	Robert NJ, Diéras V, Glaspy J, et al.: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29 (10): 1252-60, 2011.

Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is defined as the absence of staining for estrogen receptor, progesterone receptor, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2 -directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors. Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.[1] A prospective analysis of 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC, found that patients with TNBC had higher pathologic complete response (pCR) rates compared with non-TNBC patients (22% vs. 11%; P = 0.034).[2][Level of evidence: 3iiDiv] Improved pCR rates may be important since in some studies, pCR is associated with improved long-term outcomes.

Platinum agents have recently emerged as drugs of interest for the treatment of TNBC. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[3][Level of evidence: 3iiiDiv] An ongoing randomized clinical trial, CALGB-40603, is evaluating the benefit of carboplatin added to paclitaxel and adriamycin plus cyclophosphamide chemotherapy in the neoadjuvant setting. Another trial, entitled the Triple Negative Trial (NCT00532727), is evaluating carboplatin against docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC. Currently, there is no established role for adding platinum agents to the treatment of early-stage TNBC outside of a clinical trial.

The poly (ADP-ribose) polymerase (PARP) inhibitors are emerging as promising therapeutics for the treatment of TNBC.[4] PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. PARP inhibitors are currently being evaluated in clinical trials for patients with BRCA mutations and in TNBC.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with triple-negative breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Mehta RS: Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: a step toward reversing triple-negative paradox. J Clin Oncol 26 (19): 3286-8; author reply 3288, 2008.
2.	Liedtke C, Mazouni C, Hess KR, et al.: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26 (8): 1275-81, 2008.
3.	Silver DP, Richardson AL, Eklund AC, et al.: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28 (7): 1145-53, 2010.
4.	Anders CK, Winer EP, Ford JM, et al.: Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res 16 (19): 4702-10, 2010.

Changes to This Summary (11 / 21 / 2011)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer

Added text to state that in November 2011, based on the consistent finding that bevacizumab only modestly improved progression-free survival but not overall survival, and given bevacizumab's considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewer for Breast Cancer Treatment is:

• Beverly Moy, MD, MPH (Massachusetts General Hospital)

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National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2011-11-21