Breast cancer: Treatment - Health Professional Information [NCI PDQ]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER

Breast Cancer Treatment (PDQ®)

General Information About Breast Cancer

Related Summaries

Other PDQ summaries containing information related to breast cancer include:

• Breast Cancer and Pregnancy
• Male Breast Cancer Treatment
• Breast Cancer Screening
• Breast Cancer Prevention

Statistics

Note: Estimated new cases and deaths from breast cancer (women only) in the United States in 2007: [1]

• New cases: 178,480.
• Deaths: 40,460.

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.)

Several well-established factors have been associated with an increased risk of breast cancer. These include family history, nulliparity, early menarche, advanced age, and a personal history of breast cancer (in situ or invasive). (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer 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.) Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the age and menopausal status of the patient, stage of the disease, histologic and nuclear grade of the primary tumor, estrogen-receptor (ER) and progesterone-receptor (PR) status, measures of proliferative capacity, and HER2/neu gene amplification.[2] 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.[3] This section will discuss only primary epithelial breast cancers. Rarely, the breast may be involved by other tumors such as lymphoma, sarcoma, or melanoma. (Refer to the PDQ summaries on Adult Hodgkin Lymphoma Treatment, Adult Soft Tissue Sarcoma Treatment, and Melanoma Treatment for more information.)

Patient Evaluation

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

Contralateral Disease

Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. Patients who have breast cancer should have bilateral mammography at the time of diagnosis to rule out synchronous disease. The role of magnetic resonance imaging (MRI) in screening and follow-up continues to evolve. Having demonstrated an increased detection rate of mammographically occult disease, the selective use of MRI for additional screening is being 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.[4] 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.[5] The risk of a primary breast cancer in the contralateral breast is approximately 1% per year.[6,7] Patient age younger than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.[8] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[9,10]

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.[11,12] Two randomized trials 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).[13][Level of evidence: 1iiDi] 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.[14] 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).[14][Level of evidence: 1iiDi] The trials differed in several ways; [15] 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.[15] 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.[16][Level of evidence: 1iiC]

Genetics

Women with a family history of breast cancer may have an increased risk of disease. Age-specific risk estimates are available to help counsel and design screening strategies for these women.[17,18] Of all women with breast cancer, 5% to 10% may have a germ-line mutation of the genes, BRCA1 and BRCA2.[19] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[20] 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.[21] Male carriers of BRCA2 mutations are also at increased risk for breast cancer.[22] Mutations in either gene also confer an increased risk of ovarian cancer.[22,23,24] In addition, mutation carriers may be at increased risk of other primary cancers.[22,24] Genetic testing is available to detect mutations in members of high-risk families.[25,26,27,28,29] Such individuals should first be referred for counseling.[30] (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer;Breast Cancer Screening; and Breast Cancer Prevention for more information.)

Follow-up

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared to routine physical examinations.[31,32,33] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[32] 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.

Breast Reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[34,35,36,37] 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.[38]

References:

1. American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed September 7, 2007.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Chlebowski RT, Anderson GL: Progestins and recurrence in breast cancer survivors. J Natl Cancer Inst 97 (7): 471-2, 2005.
16. 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.
17. Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.
18. 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.
19. Blackwood MA, Weber BL: BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 16 (5): 1969-77, 1998.
20. Offit K, Gilewski T, McGuire P, et al.: Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347 (9016): 1643-5, 1996.
21. 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.
22. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.
23. 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.
24. 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.
25. 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.
26. Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.
35. 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.
36. Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.
37. Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.
38. 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.

Cellular Classification of Breast Cancer

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

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

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

• Cystosarcoma phyllodes.[3]
• Angiosarcoma.
• Primary lymphoma.

References:

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.

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, menopausal status, and the general health of the patient.

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

TNM Definitions

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.

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Intraductal carcinoma, lobular carcinoma in situ, or Paget disease of the nipple with no associated invasion of normal breast tissue
  • Tis (DCIS): Ductal carcinoma in situ
  • Tis (LCIS): Lobular carcinoma in situ
  • Tis (Paget): Paget disease of the nipple with no tumor. Paget disease associated with a tumor is classified according to the size of the tumor.
• T1: Tumor not larger than 2.0 cm in greatest dimension
  • T1mic: Microinvasion not larger than 0.1 cm in greatest dimension
  • T1a: Tumor larger than 0.1 cm but not larger than 0.5 cm in greatest dimension
  • T1b: Tumor larger than 0.5 cm but not larger than 1.0 cm in greatest dimension
  • T1c: Tumor larger than 1.0 cm but not larger than 2.0 cm in greatest dimension
• T2: Tumor larger than 2.0 cm but not larger than 5.0 cm in greatest dimension
• T3: Tumor larger than 5.0 cm in greatest dimension
• T4: Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below
  • T4a: Extension to chest wall, not including pectoralis muscle
  • T4b: Edema (including peau d’orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast
  • T4c: Both T4a and T4b
  • T4d: Inflammatory carcinoma

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed (e.g., previously removed)
• N0: No regional lymph node metastasis
• N1: Metastasis to movable ipsilateral axillary lymph node(s)
• N2: Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent* ipsilateral internal mammary nodes in the absence of clinically evident lymph node metastasis
  • N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
  • N2b: Metastasis only in clinically apparent* ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis
• N3: Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparent* ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or, metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
  • N3a: Metastasis in ipsilateral infraclavicular lymph node(s)
  • N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
  • N3c: Metastasis in ipsilateral supraclavicular lymph node(s)

*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.

Pathologic classification (pN)*

• pNX: Regional lymph nodes cannot be assessed (e.g., not removed for pathologic study or previously removed)
• pN0: No regional lymph node metastasis histologically, and no additional examination for isolated tumor cells (ITC)

  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.

• pN0(I-): No regional lymph node metastasis histologically, negative IHC
• pN0(I+): No regional lymph node metastasis histologically, positive IHC, and no IHC cluster larger than 0.2 mm
• pN0(mol-): No regional lymph node metastasis histologically, and negative molecular findings (RT-PCR)**
• pN0(mol+): No regionally lymph node metastasis histologically, and positive molecular findings (RT-PCR)**

  *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.

• pN1: Metastasis in one to three axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by SLN dissection but not clinically apparent**
  • pN1mi: Micrometastasis (larger than 0.2 mm but not larger than 2.0 mm)
  • pN1a: Metastasis in one to three axillary lymph nodes
  • pN1b: Metastasis in internal mammary nodes with microscopic disease detected by SLN dissection but not clinically apparent**
  • pN1c: Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by SLN dissection but not clinically apparent** (If associated with more than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden.)
• pN2: Metastasis in four to nine axillary lymph nodes, or in clinically apparent ** internal mammary lymph nodes in the absence of axillary lymph node metastasis to ipsilateral axillary lymph node(s) fixed to each other or to other structures
  • pN2a: Metastasis in four to nine axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)
  • pN2b: Metastasis in clinically apparent* internal mammary lymph nodes in the absence of axillary lymph node metastasis
• pN3: Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent* ipsilateral internal mammary lymph node(s) in the presence of one or more positive axillary lymph node(s); or, in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or, in ipsilateral supraclavicular lymph nodes
  • pN3a: Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or, metastasis to the infraclavicular lymph nodes
  • pN3b: Metastasis in clinically apparent* ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph node(s); or, in more than three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent**
  • pN3c: Metastasis in ipsilateral supraclavicular lymph nodes

*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.

Distant metastasis (M)

• MX: Presence of distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC Stage Groupings

Stage 0

• Tis, N0, M0

Stage I

• T1*, N0, M0

Stage IIA

• T0, N1, M0
• T1*, N1, M0
• T2, N0, M0

Stage IIB

• T2, N1, M0
• T3, N0, M0

Stage IIIA

• T0, N2, M0
• T1*, N2, M0
• T2, N2, M0
• T3, N1, M0
• T3, N2, M0

Stage IIIB

• T4, N0, M0
• T4, N1, M0
• T4, N2, M0

Stage IIIC**

• Any T, N3, M0

Stage IV

• Any T, Any N, M1

*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.

References:

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.

Treatment Option Overview

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Ductal Carcinoma In Situ

Introduction

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

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

Treatment Option Overview

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

In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.[4,5,6,7] Of the 818 women enrolled in the NSABP B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[7][Level of evidence: 1iiDi] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

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

Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[9,10,11,12] The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[12] Using this prognostic index, patients with favorable lesions, who received surgical excision alone, had a low recurrence rate (i.e., 2% with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control.[13] Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.[2,4]

To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial of 1,804 women.[14] Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years).[14] 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).[14][Level of evidence: 1iDi] 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.[15] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Treatment Options for Patients with DCIS

1. Breast-conserving surgery and radiation therapy with or without tamoxifen.
2. Total mastectomy with or without tamoxifen.
3. Breast-conserving surgery without radiation therapy. A large national clinical trial comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed due to poor accrual and results are pending.[16]

References:

1. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997.
2. Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999.
3. Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982.
4. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998.
5. Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001.
6. Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000.
7. Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006.
8. Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001.
9. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995.
10. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75(6): 1223-1227, 1995.
11. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994.
12. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996.
13. Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999.
14. 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.
16. McCormick B, Radiation Therapy Oncology Group: Phase III Randomized Study of Whole Breast Radiotherapy Versus Observation With or Without Optional Tamoxifen in Women With Good-Risk Ductal Carcinoma In Situ of the Breast, RTOG-9804, Clinical trial, Closed.

Lobular Carcinoma In Situ

Introduction

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

Treatment Option Overview

Most women with LCIS can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. Tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women.[2] The NSABP P-1 trial of 13,388 high-risk women comparing tamoxifen to placebo demonstrated an overall 49% decrease in invasive breast cancer, with a mean follow-up of 47.7 months.[2] Risk was reduced by 56% in the subset of 826 women with a history of LCIS, and the average annual hazard rate for invasive cancer fell from 12.99 per 1,000 women to 5.69 per 1,000 women. In women older than 50 years, this benefit was accompanied by an annual incidence of 1 to 2 per 1,000 women of endometrial cancer and thrombotic events. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) Bilateral prophylactic mastectomy is sometimes considered an alternative approach for women at high risk for breast cancer. Many breast surgeons, however, now consider this to be an overly aggressive approach. Axillary lymph node dissection is not necessary in the management of LCIS.

Treatment Options for Patients with LCIS

1. Observation after diagnostic biopsy.
2. Tamoxifen to decrease the incidence of subsequent breast cancers.
3. Ongoing breast cancer prevention trials.[3]
4. Bilateral prophylactic total mastectomy, without axillary node dissection.

References:

1. Fisher ER, Redmond C, Fisher B, et al.: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Projects (NSABP). Prognostic discriminants for 8-year survival for node-negative invasive breast cancer patients. Cancer 65 (9 Suppl): 2121-8, 1990.
2. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.
3. Goss PE, NCIC-Clinical Trials Group: Phase III Randomized Study of Exemestane in Postmenopausal Women at Increased Risk of Developing Breast Cancer, CAN-NCIC-MAP3, Clinical trial, Active.

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

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

Primary Therapy

Local-regional treatment

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

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials.[6,7,8,9,10,11,12,13] Selection of a local therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, and the patient’s attitude toward preserving the breast. The presence of multifocal disease in the breast or a history of collagen vascular disease are relative contraindications to breast-conserving therapy.[14]

All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[15] 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.[16,17,18] Retrospective studies have shown that certain tumor characteristics, such as large tumors (T2 lesions), positive axillary nodes, tumors with an extensive intraductal component,[19] 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.[20,21]

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.[22,23,24] 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),[25][Level of evidence: 1iiDii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[26][Level of evidence: 1iiDii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.[27]

A patient’s age 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.[28] 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.[29,30][Level of evidence: 3iiiDi] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years.[29] This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[31][Level of evidence: 3iiiDi] 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.[6,32,33,34,35,36] In two of these trials, all patients also received adjuvant tamoxifen.[35,36] 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 [35] and those older than 70 years,[37] 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.[38] 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).[38] The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.[37]

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.[39] 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%.[39,40] In another series, the incidence of axillary node relapse in patients with T1a tumors treated without axillary node dissection was 2%.[41][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.[42,43,44,45] 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.[46,47] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection.[42,43,44,45] 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 no axillary recurrences in either group and no difference in the 3-year disease-free survival (DFS).[48][Level of evidence: 1iiDi]

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%.[49] 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).[50][Level of evidence IiiC] 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.[48,49] Prospective trials will be available soon to address the question of survival.

Reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[51,52,53,54] 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.[55]

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.[56]

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.[57]

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 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.[56]

Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. Such a study is under way, CAN-NCIC-MA20 but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation 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.[58] 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.[59,60,61]

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.[56][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.[62]

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.[63][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.[58,64,65,66] 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.[67,68] 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.[69,70][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.[71,72,73] (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.[74]

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.[75] One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.[76] No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.[77] Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[78] 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.[79]

Adjuvant Systemic Therapy

Hormone therapy

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[80]

Tamoxifen

The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. The most recent analysis, which included information on 80,273 women in 71 trials of adjuvant tamoxifen, was published in 2005.[81] 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.[81][Level of evidence: 1iiA] Similar results were found in the International Breast Cancer Study Group 13-93 trial.[82] Of 1,246 women with stage II disease, only the women with ER-positive disease benefited from tamoxifen.

The most recent EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.[83] 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).[83][Level of evidence: 1iiA]

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 B-14 study, which compared 5 years of adjuvant tamoxifen to 10 years of adjuvant tamoxifen for women with early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[84][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.[85][Level of evidence: 1iiDi] 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.[86] In the ER-positive subgroup, a longer time-to-relapse was associated with continued tamoxifen use, but no improvement in OS was observed.[86] The optimal duration of tamoxifen treatment for node-positive women is still controversial and is being studied in ongoing clinical trials.[87,88,89] The current recommendation is that adjuvant tamoxifen be discontinued after 5 years in all patients as current standard therapy.[89]

(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.[90,91] In a trial 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).[92][Level of evidence: 1iiA] The NSABP B-20 study compared tamoxifen alone with tamoxifen plus chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU] [CMF] or sequential methotrexate and 5-FU) in women with node-negative, ER-positive breast cancer. Throughout 5 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 91% DFS and 96% OS compared with an 87% DFS and 94% OS with tamoxifen alone.[93][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.[94][Level of evidence: 1iiDi] Another study in a similar patient population, in which women were randomized to receive adjuvant tamoxifen with or without CMF, however, showed no benefit in the chemotherapy arm; in this study, intravenous (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[95][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 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.[96,97,98,99] 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.[96,100,101] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer randomized 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.[102] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[103,104] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.[105]

Tamoxifen 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%.[84,92,93,106,107] 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.[108] The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen may also be associated with an increased risk of strokes.[107,109,110] In the NSABP Breast Cancer Prevention Trial, this increase was not statistically significant.[109]

Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[111] The relationship between tamoxifen and ovarian tumors requires further study.[112] Short-term toxic effects of tamoxifen may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation).[113] Clonidine can ameliorate hot flashes in some patients.[114]

Opthalmologic toxic effects have been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[115,116,117] 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.[118,119] 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.[120] 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.[119] In the NSABP B-14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant.[121] To date, three large controlled trials have shown a decrease in heart disease.[119,120,121]

Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[122,123,124] In premenopausal women, decreased bone mineral density is a possibility.[125]

Ovarian ablation

The EBCTCG meta-analysis included almost 8,000 premenopausal women 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.[126][Level of evidence: 1iiA]

Ovarian ablation, tamoxifen, and chemotherapy

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.[127][Level of evidence: 1iiA] Three trials 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.[126,128,129][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.[130][Level of evidence: 1iiA] 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.[131][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,[126,132][Level of evidence: 2Di] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.[133][Level of evidence: 1iiDi] 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.[134] These issues are the subject of several trials.

Aromatase inhibitors

Anastrozole

A large randomized trial of 9,366 patients has compared the use of the aromatase inhibitor anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative and node-positive disease.[135,136] Most (84%) of the patients in the study were hormone-receptor positive. Slightly more than 20% had received chemotherapy. At the time of the planned initial analysis of the trial, with a median follow-up of 33.3 months, no benefit was observed for the combination arm relative to tamoxifen.[135] 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,[136] 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).[136][Level of evidence: 1iDi] No difference in OS (HR = 0.97; 95% CI, 0.85–1.12; P = .7 ) was shown. An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[137,138]

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.[139][Level of evidence: 1iiA] The other two trials were reported together.[140] 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. A statistically significant reduction in event-free survival (EFS) (local or distant recurrence or contralateral breast cancer) was seen in the patients who received anastrozole (HR = 0.60; 95% CI, 0.44–0.81; P < .009).[140][Level of evidence: 1iiA] No significant difference was seen in OS.

Letrozole

A large double-blinded randomized trial compared the use of letrozole versus tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years in 8,010 postmenopausal women with hormone receptor-positive breast cancer.[141] In an updated analysis 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%).[142][Level of evidence: 1iDi] OS was not significantly different. Patients on letrozole had significantly fewer thromboembolic events, endometrial cancers, and less vaginal bleeding. Patients on tamoxifen had significantly fewer bone and cardiac events.

A large double-blinded randomized trial 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.[143] 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.[143][Level of evidence: 1iDi] 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.[144,145] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis.[146] 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, node-positive patients on letrozole also experienced a possible improvement in OS that was statistically significant (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.[137,138]

Exemestane

A large double-blinded randomized trial 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.[147,148] After the second planned interim analysis, when median follow-up for patients on 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.[147][Level of evidence: 1iDi] 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.[149] 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).[149][Level of evidence: 1iA] Women on exemestane had significantly more visual disturbances, arthralgia, diarrhea, and osteoporosis, but women on tamoxifen had significantly more gynecologic symptoms, muscle cramps, vaginal bleeding, thromboembolic disease, and second malignancies other than breast cancer. Women on exemestane also had more myocardial infarctions than those on tamoxifen (1.39% vs. 0.8%; P = .08).

Chemotherapy

Candidates for chemotherapy

The EBCTCG meta-analysis summarized results of any randomized trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared.[150] In 47 trials comparing combination chemotherapy with no chemotherapy, a significant reduction in mortality occurred in patients receiving chemotherapy irrespective of nodal status (negative vs. positive), ER status (ER-rich vs. ER-unknown, or ER-poor), and whether tamoxifen was given. The benefit of chemotherapy, however, did vary substantially according to patient age and menopausal status. For all women younger than 50 years at randomization, combination chemotherapy improved 10-year survival from 71% to 78% for those with node-negative disease (an absolute benefit of 7%), and from 42% to 53% for those with node-positive disease (an absolute benefit of 11%).[150][Level of evidence: 1iiA] For women 50 to 69 years at randomization, combination chemotherapy improved 10-year survival from 67% to 69% for those with node-negative disease (an absolute gain of 2%) and from 46% to 49% for those with node-positive disease (an absolute gain of 3%).[150][Level of evidence: 1iiA]

The meta-analysis showed that the reduction in risk of recurrence was similar in the presence or absence of tamoxifen, irrespective of age (<50 years vs. 50–69 years), though the result did not attain statistical significance in women younger than 50 years at randomization. This finding, however, is most likely due to the relatively small number of younger women in trials of combined chemoendocrine therapy.

Results of individual trials are generally in agreement with the conclusions of the meta-analysis. The NSABP B-13 study demonstrated a benefit for chemotherapy with sequential methotrexate and 5-FU versus surgery alone in patients with node-negative, ER-negative tumors. At 8 years, statistically significant improvements in DFS were demonstrated in women of all ages who received chemotherapy. A survival advantage was evident in older patients (89% vs. 80%; P = .03) but not in the younger group (78% vs. 76%; P = .48).[151][Level of evidence: 1iiA] A U.S. Intergroup study (INT-0011) compared CMFP with no chemotherapy in women with node-negative, high-risk (i.e., tumors that were ER-negative or =3 cm) breast cancer. At 10 years, this trial showed statistically significant differences in DFS and OS.[152][Level of evidence: 1iiA] The NSABP B-20 study compared tamoxifen alone with tamoxifen plus chemotherapy (CMF or sequential methotrexate and 5-FU) in patients with node-negative, ER-positive breast cancer. Throughout 5 years of follow-up, both chemotherapy plus tamoxifen regimens resulted in similar statistically significant DFS and OS advantages compared with tamoxifen alone.[93][Level of evidence: 1iiA] The benefit, however, was greatest in women 49 years or younger. NSABP B-16, a trial of women 50 to 59 years with node-positive, PR-positive tumors and women 60 years and older irrespective of ER or PR status, demonstrated improved DFS and OS for women treated with tamoxifen and chemotherapy (doxorubicin plus cyclophosphamide) compared with those treated with tamoxifen alone.[92][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 (9–24 months). No survival benefit was demonstrated for durations greater than 6 months.[150][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. At 5 years, the recurrence-free survival and OS differences favored the anthracycline-containing regimens, 57% versus 54% (P = .006) and 72% versus 69% (P = .02), respectively.[150][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. At 5 years, CAF was marginally superior to CMF for both DFS (86% vs. 84%; P = .03) and OS (92% vs. 91%; P = .03).[153][Level of evidence: 1iiA] For comparison, the low-risk subset of patients (both the small tumor and low S-phase fraction groups) had a 96% 5-year survival rate without chemotherapy.

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). No differences were noted in relapse-free survival (RFS) or OS.[154] 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 B-15 trial randomized 2,194 patients with axillary node-positive breast cancer and tumors determined nonresponsive to tamoxifen to cyclophosphamide and doxorubicin (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.[155][Level of evidence: 1iiA] This study has also shown no difference in survival rates between four cycles of AC and six cycles of CMF.

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

Evidence suggests that particular tumor characteristics may predict anthracycline-responsiveness. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant CAF,[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA] A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[156][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).

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.[157,158] The data for the benefit of dose escalation in breast cancer, however, are more controversial. The Cancer and Leukemia Group B 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.[157][Level of evidence: 1iiA] The higher dose levels used in this trial are currently considered standard, so it is unclear whether this trial is supportive of the value of dose intensity or, rather, supportive of the concept of a threshold level below which treatment becomes ineffective.

Other trials have clearly escalated doses beyond the standard range. The NSABP B-22 and NSABP B-25 trials 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.[159,160][Level of evidence: 1iiA]

U.S. Intergroup study C9344 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.[161] In contrast, a Canadian trial in which epirubicin was combined with cyclophosphamide and 5-FU (FEC) and given to a total dose of 720 mg/m² for a period of six 4-week cycles demonstrated superior RFS (63% vs. 53%; P = .009) and OS (77% vs. 70%; P = .03) compared with CMF.[162][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.[163] A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.[164]

Intergroup trial C9741 compared, in a 2 × 2 factorial design, the use of adriamycin (A), cyclophosphamide (C), and paclitaxel (T) concurrently (AC followed by T) versus sequentially (A?T?C), given every 3 weeks or every 2 weeks with filgrastim, in 2,005 node-positive premenopausal and postmenopausal patients. No difference was found in DFS or OS between patients in the concurrent and sequential regimens. Patients treated with the every-2-week regimen, however, had superior DFS (HR = 0.74; 95% CI, 0.58–0.93) and OS (HR = 0.69; 95% CI, 0.50–0.92), with 3-year differences in DFS and OS of 3% and 2%, respectively.[165][Level of evidence: 1iiA] The use of the every-2-week regimen was not accompanied by increased toxic effects except that 13% of the patients on the concurrent dose-dense arm required red blood cell transfusions.

Several clinical trials 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.[166,167,168,169,170,171,172,173] 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.[173][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 indicate no overall or EFS benefit from the high-dose chemotherapy with BMT or stem cell support.[167,168,169,170,171,172,174][Level of evidence: 1iiA] Although further follow-up of these studies is required to resolve the role of high-dose consolidation therapy in this setting, the information to date does not support the use of high-dose chemotherapy outside the context of a randomized clinical trial. Women will also need to consider the substantial toxic effects incurred by high-dose chemotherapy, including the possibility of treatment-related death, which occurred in about 5% of women.[167,175]

Other chemotherapy regimens

The NSABP B-19 trial compared CMF to sequential methotrexate followed by 5-FU in 1,095 women with node-negative, ER-negative tumors. At 5 years, a DFS advantage (82% vs. 73%; P < .001) and a borderline OS advantage (88% vs. 85%; P = .06) were apparent for CMF.[151][Level of evidence: 1iiA] The DFS and OS benefits were similar for the subgroup of women 49 years and younger, but in women 50 years and older, the DFS and OS benefit were not statistically significant. 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.

U.S. Intergroup study C9344 randomized 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%).[161][Level of evidence: 1iiA] The results of a second trial, NSABP B-28, have also been reported.[176] This trial randomized 3,060 women with node-positive breast cancer to 4 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).[176][Level of evidence: 1iiA]

Cyclophosphamide, adriamycin, and 5-FU (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 trial (BCIRG 001). 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.[177,178][Level of evidence: 1iiA]

Monoclonal Antibodies

Three clinical trials addressing the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers released the results of interim analyses.[179,180] In two of the trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC Taxol regimen; in the third trial, 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 with or without locoregional radiation therapy. A joint analysis of the first two studies, with a combined enrollment of 3,676 patients, 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%).[180] In the other trial, which included 3,387 patients in the interim analysis, a highly significant improvement also was seen in DFS (HR = 0.54; P < .001; 2-year DFS = 86% vs. 77%).[179][Level of evidence: 1iiA] In an updated analysis, after a median follow-up of 23.5 months, a statistically significant survival benefit for the trastuzumab arm was observed (HR = 0.66; 95% CI, 0.47–0.91; P = .016; absolute difference at 3 years' follow-up = 92.4% vs. 89.7%).[181] In all three trials, patients on trastuzumab had an increased frequency of cardiac toxicity. In the two combined trials, the incidence of congestive heart failure or death on the control versus trastuzumab arms was 0.8% versus 4.1% and 0 versus 2.9%.[180][Level of evidence: 1iiA] In the third trial, the incidence of a decrease in left ventricular ejection fraction was 2.2% versus 7.1%.[179][Level of evidence: 1iiA]

A fourth trial assessed the impact of a much shorter course of trastuzumab.[182] In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER-2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC. 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).[