Purpose of This PDQ Summary
General Information About Breast Cancer

Related Summaries Statistics Genetic Characteristics and Risk Factors Screening Patient Evaluation Prognostic Factors Contralateral Disease Hormone Replacement Therapy Breast Reconstruction Follow-up

Cellular Classification of Breast Cancer
Stage Information for Breast Cancer

TNM Definitions AJCC Stage Groupings

Ductal Carcinoma In Situ

Introduction Treatment Option Overview Treatment Options for Patients with DCIS Current Clinical Trials

Lobular Carcinoma In Situ

Introduction Treatment Option Overview Treatment Options for Patients with LCIS Current Clinical Trials

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

Primary Therapy         Local-regional treatment         Breast reconstruction Adjuvant Radiation Therapy         Post-breast conservation surgery         Postmastectomy         Adjuvant radiation therapy late toxic effects Adjuvant Systemic Therapy         Hormone therapy         Chemotherapy         Monoclonal antibodies Timing of Primary and Adjuvant Therapy         Postoperative adjuvant chemotherapy         Preoperative adjuvant chemotherapy         Adjuvant radiation and chemotherapy         Timing of surgery         Chemotherapy risks         Chemotherapy and tamoxifen risks Treatment Options         Primary therapy Current Clinical Trials

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

Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer         Current Clinical Trials Stage IV, Recurrent, and Metastatic Breast Cancer         Recurrent local-regional breast cancer         Stage IV and metastatic disease         Current Clinical Trials Systemic Therapy         Bisphosphonates         Hormone therapy         Trastuzumab         Lapatinib         Cytotoxic chemotherapy Current Clinical Trials

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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Genetic characteristics and risk factors.
• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information About Breast Cancer

This summary discusses only primary epithelial breast cancers. Rarely, the breast may be involved by other tumors such as lymphomas, sarcomas, or melanomas. (Refer to the PDQ summaries on Adult Hodgkin Lymphoma Treatment ⁵, Adult Soft Tissue Sarcoma Treatment ⁶, and Melanoma Treatment ⁷ for more information.)

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Other PDQ summaries containing information related to breast cancer include:

• Breast Cancer Treatment and Pregnancy ⁸
• Male Breast Cancer Treatment ⁹
• Unusual Cancers of Childhood Treatment ¹⁰ (breast cancer in children)
• Genetics of Breast and Ovarian Cancer ¹¹
• Breast Cancer Prevention ¹²
• Breast Cancer Screening ¹³

Note: Estimated new cases and deaths from breast cancer (women only) in the United States in 2008:[1]

• New cases: 182,460.
• Deaths: 40,480.

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

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

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

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

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by:[16]

• The age and menopausal status of the patient.
• The stage of the disease.
• The histologic and nuclear grade of the primary tumor.
• The ER and PR status of the tumor.
• The measures of proliferative capacity of the tumor.
• HER2/neu gene amplification.

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.[17]

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.[18]

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.[19] The risk of a primary breast cancer in the contralateral breast is approximately 1% per year.[20,21] Patient age younger than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.[22] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[23,24]

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.[25,26]

Two randomized trials (including Regional Oncologic Center-Hormonal Replacement Therapy After Breast Cancer--Is It Safe [ROC-HABITS ¹⁴]) comparing HRT with no hormonal supplementation have been reported.[27,28] 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).[27][Level of evidence: 1iiDii] In total, 26 women in the HRT group and 7 in the non-HRT group developed recurrences or new primaries. This study, however, was not double blinded, and it is possible that patients on HRT were monitored more closely. Because of the results of the first trial, the second trial, which was conducted under a joint steering committee with the first, closed prematurely after the enrollment of 378 patients.[28] 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).[28][Level of evidence: 1iiDii] The trials differed in several ways;[29] 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.[29] 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.[30][Level of evidence: 1iiC]

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[31-34] 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 ¹⁵ 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.[35]

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.[36-38] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[37] 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.

References

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

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:

• Phyllodes tumor.[3,4]
• 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.  [PUBMED Abstract]
   
   
3. Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000.  [PUBMED Abstract]
   
   
4. Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.  [PUBMED Abstract]
   
   

Stage Information for Breast Cancer

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

The AJCC has designated staging by TNM classification.[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]

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.  [Note: 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)
  
  
  

* [Note: 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)

   [Note: 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)**

  * [Note: 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).]

  ** [Note: 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 ten 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 ten 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
  
  
  

* [Note: Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.]

** [Note: 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

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

* [Note: T1 includes T1mic.]

** [Note: 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 ¹⁷. 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 ¹⁸.]

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

Ductal Carcinoma In Situ

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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

Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone.[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]

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.[4-7] Of the 818 women enrolled in the NSABP B-17 ¹⁹ trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[7][Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

Similarly, of the 1,010 patients enrolled in the EORTC-10853 ²⁰ trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[7][Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[8] In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.

Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[9-12] 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 (NSABP-B24 ²¹) 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: 1iDii] With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins.[15] (Refer to the PDQ summary on Breast Cancer Prevention ¹² for more information.)

1. Breast-conserving surgery and radiation therapy with or without tamoxifen.



2. Total mastectomy with or without tamoxifen.



3. Breast-conserving surgery without radiation therapy. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 ²²) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed due to poor accrual and results are pending.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with ductal breast carcinoma in situ ²³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ²⁴.

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    

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).

Most women with LCIS have disease that can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. The use of tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women.[2] The NSABP-P1 ²⁵ 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 ¹² 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.

1. Observation after diagnostic biopsy.



2. Tamoxifen to decrease the incidence of subsequent breast cancers.



3. Ongoing breast cancer prevention trials (including the National Cancer Institute of Canada's trial [CAN-NCIC-MAP3 ²⁶], for example).



4. Bilateral prophylactic total mastectomy, without axillary node dissection.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with lobular breast carcinoma in situ ²⁷. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ²⁴.

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

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 ² for more information.)

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

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials (including the European Organization for Research and Treatment of Cancer's trial [EORTC-10801 ²⁸]).[6-13] 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.[16-18] 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.[22-24] 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: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[26][Level of evidence: 1iiDiii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.[27]

The age of the patient should not be a determining factor in the selection of breast-conserving treatment versus mastectomy. A study has shown that treatment with lumpectomy and radiation therapy in women 65 years and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years.[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: 3iiiDii] 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: 3iiiDii] Because of the available evidence indicating no difference in outcome, women with strong family histories should be considered candidates for breast-conserving treatment. For women with germ-line mutations in BRCA1 and BRCA2, further study of breast-conserving treatment is needed.

Breast-conserving surgery alone without radiation therapy has been compared with breast-conserving surgery followed by radiation therapy in six prospective randomized trials (including the National Surgical Adjuvant Breast and Bowel Project's trial [NSABP-B-06 ²⁹] and the Cancer and Leukemia Group B's trial [CLB-9343 ³⁰]) .[6,32-36] 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.[42-45] 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.[42-45] 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, after a median follow-up of 78 months, no difference in 5-year DFS (92.9% in the SLN biopsy without routine axillary dissection group vs. 88.9% in patients having axillary dissection irrespective of SLN findings, P = .1).[48][Level of evidence: 1iiDii]

The reported false-negative rates (i.e., the number of patients with negative SLN biopsy divided by the number of patients with positive axillary nodes at the time of axillary node dissection) of SLN biopsy range from 0% to 15% with an average of 8.8%.[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 1iiC] Arm function was also better in the SLN group. Ongoing randomized trials will help to determine if both procedures yield comparable survival rates and if a therapeutic benefit comes from complete axillary lymphadenectomy in patients with SLN metastases. Although there are no data on its impact on survival, the SLN biopsy with complete dissection after a positive result is a commonly used alternative to axillary lymph node dissection.[49,51] Prospective trials will be available soon to address the question of survival.

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[52-55] 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 ¹⁵ 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.[56]

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.[57]

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.[58]

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, in the 2005 Early Breast Cancer Trialists' Collaborative Group's (EBCTCG) update, when all relevant trials were combined, 15-year breast cancer mortality was reduced from 35.9% to 30.5% in women receiving radiation therapy (absolute difference of 5.4%; 95% CI, 2.1%–8.7%; breast cancer death rate ratio 0.83; 95% CI, 0.75–0.91; P = .002). There was a similar effect on all-cause mortality.[57]

Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. The National Cancer Institute of Canada's study (CAN-NCIC-MA20 ³¹) has closed, but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure following mastectomy. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy.[59] 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.[60-62]

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.[57][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.[63]

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.[64] 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.[64][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.[59,65-67] 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.[68,69] 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.[70,71][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.[72-74] (Refer to the PDQ summary on Lymphedema ³² 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.[75] The diagnosis of such injury was made clinically with computerized tomography to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0% compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

The rate of second malignancies following adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with the long-term risk at 0.2% at 10 years.[76] One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.[77] No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.[78] Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[79] 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.[80]

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.[81]

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.[82] 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.[82][Level of evidence: 1iiA]

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50 to 69 years, ≥70 years), progesterone receptor status, or other tumor characteristics.[82] This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.[82] 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).[82][Level of evidence: 1iiA] Similar results were found in the International Breast Cancer Study Group-1393 ³³ trial.[83] Of 1,246 women with stage II disease, only the women with ER-positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[82,84-86] 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).[82] Results from the NSABP-B14 ³⁴ 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: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment. In one trial, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation.[