Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary 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.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
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.)
Other PDQ summaries containing information related to breast cancer include:
Note: Estimated new cases and deaths from breast cancer (women only) in the United States in 2008: 
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.   Of all women with breast cancer, 5% to 10% may have a germ-line mutation of the genes BRCA1 and BRCA2.  Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.  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.  Male carriers of BRCA2 mutations are also at increased risk for breast cancer. 
Mutations in either the BRCA1 or BRCA2 gene also confer an increased risk of ovarian cancer.    In addition, mutation carriers may be at increased risk of other primary cancers.   Genetic testing is available to detect mutations in members of high-risk families.      Such individuals should first be referred for counseling.  (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer; Breast Cancer Prevention; and Breast Cancer Screening for more information.)
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 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.
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: 
Although certain rare inherited mutations such as those of BRCA1 and BRCA2 predispose women to develop breast cancer, prognostic data on mutation carriers who have developed breast cancer are conflicting. 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. 
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 suggested. 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. 
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.  The risk of a primary breast cancer in the contralateral breast is approximately 1% per year.   Patient age younger than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.  The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.  
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.  
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.   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).  [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.  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).  [Level of evidence: 1iiDii] The trials differed in several ways;  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.  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.  [Level of evidence: 1iiC]
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).     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. 
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.    Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.  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.
1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed May 30, 2008.
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. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. Chlebowski RT, Anderson GL: Progestins and recurrence in breast cancer survivors. J Natl Cancer Inst 97 (7): 471-2, 2005.
30. 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.
31. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.
32. 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.
33. Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.
34. Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.
35. 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.
36. 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.
37. 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.
38. 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.  Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.
The following are tumor subtypes that occur in the breast but are not considered to be typical breast cancers:
1. Breast. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 171-180.
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.
The AJCC has designated staging by TNM classification.  This system was modified in 2002 and classifies some nodal categories as stage III that were previously considered stage II.  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. 
Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). If other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1 cm increment.
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.
ITCs are defined as single tumor cells or small cell clusters not larger than 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular methods but that may be verified on hematoloxylin & eosin (H&E) stains. ITCs do not usually show evidence of malignant activity, e.g., proliferation or stromal reaction.
*Classification is based on axillary lymph node dissection with or without sentinel lymph node (SLN) dissection. Classification based solely on SLN dissection without subsequent axillary lymph node dissection is designated (sn) for sentinel node, e.g., pN0(I+) (sn).
**RT-PCR: reverse transcriptase-polymerase chain reaction.
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.
**Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.
AJCC Stage Groupings
*T1 includes T1mic.
**Stage IIIC breast cancer includes patients with any T stage who have pN3 disease. Patients with pN3a and pN3b disease are considered operable and are managed as described in the section on Stage I, II, IIIA, and operable IIIC breast cancer. Patients with pN3c disease are considered inoperable and are managed as described in the section on Inoperable stage IIIB or IIIC or inflammatory breast cancer.
1. Breast. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 171-180.
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.)
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.  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. 
Treatment Option Overview
Until recently, the customary treatment of DCIS was mastectomy.  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.   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.     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).  [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.  [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.  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.     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.  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.  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.  
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-B24) of 1,804 women.  Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years).  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).  [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.  (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Treatment Options for Patients with DCIS
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
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. 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.
15. 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
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).  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.  The NSABP-P1 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.  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
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
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.)
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.  Additional pathologic characteristics, including grade, proliferative activity, and human epidermal growth factor receptor 2 (HER2/neu) status, may also be of value.    
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]).         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. 
All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.  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.    Retrospective studies have shown that certain tumor characteristics, such as large tumors (T2 lesions), positive axillary nodes, tumors with an extensive intraductal component,  palpable tumors, and lobular histology correlate with a greater likelihood of finding persistent tumor on re-excision. Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.  
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.    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),  [Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.  [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. 
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.  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.   [Level of evidence: 3iiiDii] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years.  This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.  [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]) .       In two of these trials, all patients also received adjuvant tamoxifen.   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  and those older than 70 years,  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.  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).  The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications. 
The axillary lymph nodes should be staged to aid in determining prognosis and therapy. Although most authorities agree that an axillary node dissection in the presence of clinically negative nodes is a necessary staging procedure, controversy exists as to the extent of the procedure because of long-term morbidity (e.g., arm discomfort and swelling) associated with it. Data suggest that the level of lymph node involvement (stage I vs. stage II vs. stage III) does not add independent prognostic information to the total number of positive axillary nodes.  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 a minimum), 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%.   In another series, the incidence of axillary node relapse in patients with T1a tumors treated without axillary node dissection was 2%.  [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.
To decrease the morbidity of axillary lymphadenectomy while maintaining accurate staging, several investigators have studied lymphatic mapping and sentinel lymph node (SLN) biopsy in women with invasive breast cancer.     The SLN is defined as the first node in the lymphatic basin that receives primary lymphatic flow. 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.   These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection.     The results of a 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).  [Level of evidence: 1iiDii]
The reported false-negative rates (i.e., the number of patients with negative SLN biopsy divided by the number of patients with positive axillary nodes at the time of axillary node dissection) of SLN biopsy range from 0% to 15% with an average of 8.8%.  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).  [Level of evidence 1iiC] Arm function was also better in the SLN group. Ongoing randomized trials will help to determine if both procedures yield comparable survival rates and if a therapeutic benefit comes from complete axillary lymphadenectomy in patients with SLN metastases. Although there are no data on its impact on survival, the SLN biopsy with complete dissection after a positive result is a commonly used alternative to axillary lymph node dissection.   Prospective trials will be available soon to address the question of survival.
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).     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. 
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. 
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. 
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. 
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) 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.
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.  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.   
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.  [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% 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 loco-regional recurrence was low enough (7.1%) that routine loco-regional radiation therapy was not warranted. 
Adjuvant radiation therapy late toxic effects
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.  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.  [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.     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.   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 due to ischemic heart disease in women who received left chest wall or breast radiation was found.   [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.    (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.  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.  One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.  No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.  Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.  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. 
Adjuvant Systemic 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. 
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.  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.  [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 to 69 years, ≥70 years), progesterone receptor status, or other tumor characteristics.  This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.  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).  [Level of evidence: 1iiA] Similar results were found in the International Breast Cancer Study Group-1393 trial.  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.     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).  Results from the NSABP-B14 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.  [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.  [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, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation.  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.  Clinical trials, such as the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment--Offer More? (CRC-TU-ATTOM ) trial are addressing 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.   In a trial (NSABP-B16) 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).  [Level of evidence: 1iiA] The NSABP-B20 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.  After 12 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 89% DFS and 87% OS compared with an 79% DFS and 83% OS with tamoxifen alone.  [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.  [Level of evidence: 1iiDii] However, another study in a similar patient population, in which women were randomized 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.  [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.     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.    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, 3–75 months; median, 24 months), while no cases occurred on the control arm.  The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.   Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed. 
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%.      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.  The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.    In the NSABP Breast Cancer Prevention Trial (NSABP-P1), this increase was not statistically significant. 
Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.  The relationship between tamoxifen and ovarian tumors requires further study.  Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation). 
Opthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.    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.   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.  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.  In the NSABP-B14 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.  To date, three large controlled trials have shown a decrease in heart disease.   
Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.    In premenopausal women, decreased bone mineral density is a possibility. 
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).  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.  [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.  [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.    [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.  [Level of evidence: 1iiA] A Danish trial compared ovarian ablation or suppression to CMF (nine cycles intravenously every 3 weeks) in premenopausal, ER-positive women and found no difference in OS or DFS in the two study groups.   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.  [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,   [Level of evidence: 2Dii] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.  [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.  These issues are the subject of several trials.
Based on disease-free survival 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.
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.   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,  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.  [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.  An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.  
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.    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.  [Level of evidence: 1iiA] The other two trials (including the Austrian Breast and Colorectal Cancer Study Group's trial [ ABCSG-8]) were reported together.  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. 
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. 
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.  In an updated analysis from the Breast International Group (BIG-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%).  [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. 
A large double-blinded randomized trial (CAN-NCIC-MA17) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who had received tamoxifen for approximately 5 (4.5–6.0) years.  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.  [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.   An updated analysis including all events prior to unblinding confirmed the results of the interim analysis.  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.  
A large double-blinded randomized trial (BIG-9702) 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.   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.  [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.  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).  [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.
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.  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.  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 due to 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.  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-B13 study demonstrated a benefit for chemotherapy with sequential methotrexate and 5-FU versus surgery alone in patients with node-negative, ER-negative tumors.     [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.  [Level of evidence: 1iiA]
Anthracycline-based versus CMF-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.  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.  [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 (INT-0102), which was not included in the meta-analysis.  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, hazard ratio [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 is effective in high-risk node-positive disease but not in high-risk node-negative disease.  [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.   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).  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.  Women who received doxorubicin followed by CMF had better RFS (42% vs. 28%; P = .002) and OS (58% vs. 44%; P = .002).  [Level of evidence: 1iiA]
The NSABP-B15 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).  No differences were seen in DFS or OS among the three groups.  [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,  or the addition of doxorubicin to the adjuvant regimen,  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).  [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 was increased by CEF. In the absence of HER2/neu amplification, CEF and CMF were similiar 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).
The role of adding taxanes to adjuvant therapy
Four randomized trials (including CLB-9344, NSABP-B28, and the Programmes d'Actions Concertées Sein trial [PACS-01]) have examined the benefit of adding taxanes (either paclitaxel or docetaxel) to anthracycline-based adjuvant chemotherapy regimens for more than 8,000 node-positive breast cancer patients.     [Level of evidence: 1iiA] The benefits of adding paclitaxel or docetaxel to standard anthracycline-based adjuvant chemotherapy have been demonstrated in patients with node-positive disease. All four trials showed a benefit in 5-year DFS, with a range of absolute benefits of 4% to 5%. HRs from each of the trials range from 0.73 to 0.83, and all P values were less than .03. Three of the trials showed a benefit in 5-year OS, with a range of absolute benefits of 3% to 5%. HRs from each of the trials range from 0.72 to 0.80, and all P values were less than .01.    A retrospective subset analysis of one trial suggested that treatment with paclitaxel resulted in a greater benefit in DFS (P = .0093) and OS (P = .0056) in HER2-positive patients versus HER2-negative patients.  No OS advantage was found for the docetaxel plus cyclophosphamide (TC) regimen versus standard-doseAC,  and the doxorubicin plus docetaxel (AT) regimen in the Eastern Cooperative Oncology Group's trial (E-2197) was found to be excessively toxic in regards to septicemic deaths compared with standard-dose AC. 
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.   The data for the benefit of dose escalation in breast cancer, however, are more controversial. The CALGB-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.  [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-B22 and NSABP-B25 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.   [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.  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).  The 10-year OS for patients who received CEF and CMF are 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 are slightly higher (four patients [1.1%] in the CEF group vs. one patient [0.3%] in the CMF group).  [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.  A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women. 
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.  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.   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.  [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.         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.  [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.          [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 systemic 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.  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). 
Other chemotherapy regimens
The NSABP-B19 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.  [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%).  [Level of evidence: 1iiA] The results of a second trial, the NSABP-B28 trial, have also been reported.  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).  [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.   [Level of evidence: 1iiA]
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 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).  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%.  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-B31 and Intergroup N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.  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%).  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 BCIRG-006study is 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].  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.  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).  [Level of evidence: 1iiA]
Currently being investigated in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization's trial (ALTTO) is the role of lapatinib (in combination with, in sequence to, in comparison to, or as an alternative to trastuzumab) in the adjuvant setting. 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%).  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.  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.
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.  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-B31 trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.  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 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 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.  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 BCIRG 006 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:
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.  A single cycle of immediate postoperative chemotherapy alone was inferior. 
Preoperative adjuvant chemotherapy
A randomized clinical trial (NSABP-B18) has been performed to evaluate preoperative chemotherapy in the management of patients with stage I or stage II breast cancer.  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 receiving preoperative chemotherapy as compared with those receiving postoperative chemotherapy.   [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.  [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.  Although preoperative chemotherapy affects the results of SLN biopsy, one small study indicated that SLN biopsy technique was feasible in this setting.  Before SLN biopsy can replace complete axillary lymphadenectomy, randomized trials are needed to confirm that both procedures yield comparable survival rates.
Adjuvant radiation and chemotherapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial.  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).  [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.   In the NSABP-B15 trial, patients undergoing 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.  [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.  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 appears safe and may be preferable for patients at high risk of distant dissemination.
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.    [Level of evidence: 1iiA]  Several other studies, however, have failed to support this finding or have found opposite results.     [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.
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,  and premature menopause. 
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.  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.  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.   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). 
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).  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-B16 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.  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).  [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.  A U.S. Intergroup study (INT-0102) 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.   
Adjuvant radiation therapy postmastectomy in axillary node-positive tumors:
Adjuvant systemic therapy:
An International Consensus Panel proposed a three-tiered risk classification for patients with negative axillary lymph nodes.  This classification, with some modification, is described below:
Table 1: 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 2: Adjuvant Systemic Treatment Options for Women With Axillary Node-Negative Breast Cancer
|Patient group||Low risk||Intermediate risk||High risk|
|Premenopausal, ER-positive or PR-positive||None or tamoxifen||Tamoxifen plus chemotherapy, tamoxifen alone, ovarian ablation, GnRH analog*||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|
|* Note: This treatment option is under clinical evaluation.|
Table 3: Treatment Options for Women With Axillary Node-Positive Breast Cancer
|Premenopausal, ER-positive or PR-positive||Chemotherapy plus tamoxifen, chemotherapy plus ovarian ablation/GnRH analog, chemotherapy plus tamoxifen plus ovarian ablation/GnRH analog*, 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|
|* Note: This treatment option is under clinical evaluation.|
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
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223. 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.
224. Dixon JM: Treatment of elderly patients with breast cancer. BMJ 304 (6833): 996-7, 1992.
225. Fisher B, Anderson S, Tan-Chiu E, et al.: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19 (4): 931-42, 2001.
Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer
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.  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.   In one series of 178 patients with inflammatory breast cancer, DFS was 28% at 15 years with a combined-modality approach.  [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.  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 PDQ Cancer Clinical Trials Registry 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 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 (CALGB-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.  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. 
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.  Nine percent to 25% of these patients will have distant metastases or locally extensive disease at the time of recurrence.    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%.  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.  [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.   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.  The 5-year DFS rate in one series of such patients was 25%, with a 10-year rate of 15%.  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.  No randomized controlled studies are available to guide patient care in this situation.
Stage IV and metastatic 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,  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.  [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 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.
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 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.  
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
The use of bisphosphonates to reduce skeletal morbidity in patients with bone metastases should be considered.  Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.    [Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate. 
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 for the aromatase inhibitors compared to tamoxifen.    [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 randomized to a third-generation drug (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).  [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.    The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors.  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).  [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;          and the ER down-regulator, fulvestrant.   In comparison to megestrol acetate, all three currently available aromatase inhibitors have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.         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).  [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.   The proper sequence of these therapies is currently not known. 
Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist).  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.  Patients with extensive bony disease are at risk for the development of symptomatic hypercalcemia early in the course of hormone therapy.  Early failure (e.g., <6 months) on hormone therapy suggests that cytotoxic chemotherapy should be the next modality employed.
Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu.  Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.  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%.  [Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomized 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).  [Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.  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.  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.  [Level of evidence: 1iDiii]
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.  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 overall survival (HR = 0.92; 95% CI, 0.58–1.46; P = .72).  [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.
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.
Single agents that have shown activity in metastatic breast cancer:
Combination regimens that have shown activity in metastatic breast cancer:
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.  Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.  [Level of evidence: 1iiA]   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.   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.  [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.   [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,  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  or a different chemotherapy regimen given at higher versus lower doses.  [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.     Dexrazoxane has a similar protective effect in patients receiving epirubicin.  The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion. 
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.   [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.  
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
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Changes to This Summary (04/03/2008)
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 I, II, IIIA, and Operable IIIC Breast Cancer
Added text about a Danish trial that compared ovarian ablation or suppression to cyclophosphamide, methotrexate, and fluorouracil in premenopausal, ER-positive women and found no difference in overall survival or disease-free survival in the two study groups; taxanes and anthracyclines were not included in the study (cited Ejlerstsen et al. as reference 129 and Wolff et al. as reference 130).
Added Moore et al. as reference 187.
Added Tan-Chiu et al. as reference 196.
Additional PDQ Summaries
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Date last modified 2008-04-03