Breast Cancer Treatment (PDQ®) 1/3 —Health Professional Version - National Cancer Institute

Breast Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Breast Cancer Treatment (PDQ®)–Health Professional Version

Go to Patient Version

ON THIS PAGE

• General Information About Breast Cancer
• Histopathologic Classification of Breast Cancer
• Stage Information for Breast Cancer
• Early/Localized/Operable Breast Cancer
• Locally Advanced or Inflammatory Breast Cancer
• Locoregional Recurrent Breast Cancer
• Metastatic Breast Cancer
• Ductal Carcinoma In Situ
• Changes to This Summary (03/15/2019)
• About This PDQ Summary

General Information About Breast Cancer

In This Section

• Incidence and Mortality
• Anatomy
• Risk Factors
• Protective Factors
• Screening
• Diagnosis
  • Patient evaluation
  • Contralateral disease
• Prognostic and Predictive Factors
• Posttherapy Considerations
  • Hormone replacement therapy
• Related Summaries

This summary discusses primary epithelial breast cancers in women. The breast is rarely affected by other tumors such as lymphomas, sarcomas, or melanomas. Refer to the following PDQ summaries for more information on these cancer types:

• Adult Hodgkin Lymphoma Treatment
• Adult Soft Tissue Sarcoma Treatment
• Melanoma Treatment

Breast cancer also affects men and children and may occur during pregnancy, although it is rare in these populations. Refer to the following PDQ summaries for more information:

• Male Breast Cancer Treatment
• Breast Cancer Treatment During Pregnancy
• Unusual Cancers of Childhood Treatment

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2019:[1]

• New cases: 268,600.
• Deaths: 41,760.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 62,930 cases of in situ disease and 268,600 cases of invasive disease in 2019.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 66,020 American women will die of lung cancer in 2019.[1] Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).

Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal carcinoma in situ (DCIS) section in the Pathologic Evaluation of Breast Tissue section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States [2] and the United Kingdom [3] demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.[4]

Anatomy

ENLARGE

Anatomy of the female breast. The nipple and areola are shown on the outside of the breast. The lymph nodes, lobes, lobules, ducts, and other parts of the inside of the breast are also shown.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for breast cancer include the following:

• Family health history.[5]
• Major inheritance susceptibility.[6,7]
  • Germline mutation of the BRCA1 and BRCA2 genes and other breast cancer susceptibility genes.[8,9]
• Alcohol intake.
• Breast tissue density (mammographic).[10]
• Estrogen (endogenous).[11-13]
  • Menstrual history (early menarche/late menopause).[14,15]
  • Nulliparity.
  • Older age at first birth.
• Hormone therapy history.
  • Combination estrogen plus progestin hormone replacement therapy.
• Obesity (postmenopausal).[16]
• Personal history of breast cancer.[17]
• Personal history of benign breast disease (BBD) (proliferative forms of BBD).[18-20]
• Radiation exposure to breast/chest.[21]

Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.[22,23]

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2.[24] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[25] 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 high as 5% per year.[26] Male BRCA2 mutation carriers also have an increased risk of breast cancer.[27]

Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [27,28] or other primary cancers.[27,28] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing.[29-32] (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Breast Cancer Prevention; and Breast Cancer Screening for more information.)

(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that increase the risk of breast cancer.)

Protective Factors

Protective factors and interventions to reduce the risk of female breast cancer include the following:

• Estrogen use (after hysterectomy).[33-35]
• Exercise.[36-38]
• Early pregnancy.[39-41]
• Breast feeding.[42]
• Selective estrogen receptor modulators (SERMs).[43]
• Aromatase inhibitors or inactivators.[44,45]
• Risk-reducing mastectomy.[46]
• Risk-reducing oophorectomy or ovarian ablation.[47-50]

(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that decrease the risk of breast cancer.)

Screening

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

Diagnosis

Patient evaluation

When breast cancer is suspected, patient management generally includes the following:

• Confirmation of the diagnosis.
• Evaluation of the stage of disease.
• Selection of therapy.

The following tests and procedures are used to diagnose breast cancer:

• Mammography.
• Ultrasound.
• Breast magnetic resonance imaging (MRI), if clinically indicated.
• Biopsy.

Contralateral disease

Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk.[51-53] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[54] When BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.[55,56]

Patients who have breast cancer will undergo bilateral mammography at the time of diagnosis to rule out synchronous disease. To detect either recurrence in the ipsilateral breast in patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast, patients will continue to have regular breast physical examinations and mammograms.

The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is occurring more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.[57-59]

Prognostic and Predictive Factors

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):[60]

• Menopausal status of the patient.
• Stage of the disease.
• Grade of the primary tumor.
• Estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.
• Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or amplification.
• Histologic type. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. Favorable histologic types include mucinous, medullary, and tubular carcinomas.[61-63]

The use of molecular profiling in breast cancer includes the following:[64]

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

On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the following types:

• Hormone receptor positive.
• HER2/neu positive.
• Triple negative (ER, PR, and HER2/neu negative).

ER, PR, and HER2 status are important in determining prognosis and in predicting response to endocrine and HER2-directed therapy. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines to help standardize the performance, interpretation, and reporting of assays used to assess the ER-PR status by immunohistochemistry and HER2 status by immunohistochemistry and in situ hybridization.[65,66]

Gene profile tests include the following:

• MammaPrint: The first gene profile test to be approved by the U.S. Food and Drug Administration was the MammaPrint gene signature. The 70-gene signature classifies tumors into high- and low-risk prognostic categories. [67-71] The aim of the MINDACT(NCT00433589) trial (see below) is to determine the clinical usefulness and patient benefit of adjuvant chemotherapy .
• Oncotype DX: The Oncotype DX 21 gene assay is the gene profile test with the most extensive clinical validation thus far and applies to hormone receptor–positive breast cancer. A 21-gene recurrence score is generated based on the level of expression of each of the 21 genes:
  • Recurrence score <18: low risk.
  • Recurrence score ≥18 and <31: intermediate-risk.
  • Recurrence score ≥31: high risk.

The following trials describe the prognostic and predictive value of multigene assays in early breast cancer:

1. The prognostic ability of the Oncotype DX 21-gene assay was assessed in two randomized trials.
   • The National Surgical Adjuvant Breast and Bowel Project (NSABP B-14Exit Disclaimer) trial randomly assigned patients to receive tamoxifen or placebo; the results favoring tamoxifen changed clinical practice in the late 1980s.[72] Formalin-fixed, paraffin-embedded tissue was available for 668 patients. The 10-year distant recurrence risk for patients treated with tamoxifen was 7% for those with a low recurrence score, 14% for those with an intermediate recurrence score, and 31% for those with high recurrence score (P < .001).[73]
   • A community-based, case-control study examined the prognostic ability of the recurrence score to predict breast cancer deaths after 10 years in a group of tamoxifen-treated patients and observed a similar prognostic pattern to that seen in patients from NSABP B-14.[74]
2. The use of Oncotype Dx to predict benefit from chemotherapy in patients with nodenegative-, ER-positive breast cancer was initially assessed in a prospective-retrospective way using the tamoxifen alone (n = 227) and the combination arms (n = 424) of the NSABP B-20Exit Disclaimer trial.[72] Patients in the NSABP B-20 trial were randomly assigned to receive tamoxifen alone or tamoxifen concurrently with methotrexate and 5-fluorouracil (MF) or cyclophosphamide with MF (CMF).[75]
   • The 10-year distant disease-free survival (DFS) improved from 60% to 88% by adding chemotherapy to tamoxifen in the high-risk group, while no benefit was observed in the low recurrence score group.[76]
3. Similar findings were reported in the prospective-retrospective evaluation of the Southwestern Oncology Group (SWOG-8814 [NCT00929591]) trial in hormone receptor–positive lymph node-positive postmenopausal patients treated with tamoxifen with or without cyclophosphamide, doxorubicin, and fluorouracil.[77] However, the sample size in this analysis was small, follow-up was only 5 years, and the prognostic impact of having positive nodes needs to be taken into consideration.
   • Of note, both analyses (NSABP B-20 and S8814) were underpowered for any conclusive predictive analysis among patients identified as having an intermediate recurrence score.
4. Results from the prospective, randomized TAILORx (NCT00310180) trial indicate that chemotherapy is unlikely to provide substantial benefit to patients older than 50 years with ER-PR–positive and node-negative disease and a recurrence score of 11 to 25.[78] In this study, a low-risk score was defined as less than 11, an intermediate score was 11 to 25, and a high-risk score was greater than 25. These cut points differ from those described above.
   Patients in this study with a low-risk score were found to have very low rates of recurrence at 5 years with endocrine therapy.[79]
   • Rate of invasive DFS was 93.8% at 5 years and 84.0% at 9 years.
   • Rate of freedom from recurrence of breast cancer at a distant site was 99.3% at 5 years and 96.8% at 9 years.
   • Rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% at 5 years and 95.0% at 9 years.
   • Rate of overall survival (OS) was 98.0% at 5 years and 93.7% at 9 years.
   In the middle-risk group in the TAILORx study (recurrence score, 11–25), 6,907 women were randomly assigned to endocrine therapy alone or endocrine therapy plus chemotherapy.[78] Of these, 3,399 women on the endocrine therapy-alone arm and 3,312 women on the endocrine therapy-plus-chemotherapy arm were available for an analysis according to the randomized treatment assignments. After a median follow-up of 90 months, the difference in invasive DFS, the main study endpoint, met the prespecified noninferiority criterion (P > .10 for a test of no difference after 835 events had occurred) suggesting the noninferiority of endocrine therapy compared with endocrine therapy plus chemotherapy.
   • In this population, the 9-year invasive DFS was 83.3% for endocrine therapy alone and 84.3% for endocrine therapy plus chemotherapy (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.94–1.24; P = .26).[78][Level of evidence: 1iiD]
   • One hundred eighty-five patients in the endocrine-only arm received chemotherapy, and 608 patients in the endocrine therapy-plus-chemotherapy arm did not receive their assigned chemotherapy. In an analysis based on the actual treatment received, the HR for invasive DFS was 1.14 (95% CI, 0.99–1.31; P =.06).
   • Outcomes for the other endpoints examined (freedom of distant breast cancer recurrence, freedom from local and distant recurrence, and OS) were similar between the two treatment arms and none were significant at P < 0.10.
   • There was a significant interaction between treatment assignment and age (P = .03) with respect to invasive DFS, suggesting that chemotherapy might be beneficial in women younger than 50 years with recurrence scores ranging from 11 to 25.
5. The MINDACT (NCT00433589) trial tested whether adding MammaPrint genomic risk to a clinical-risk classification (modified from Adjuvant! Online) might guide more appropriate choices of chemotherapy in women with node negative- or 1-to-3 node-positive disease.[80][Level of evidence: 3iiiDii] Unlike the TAILORx study, which only had hormone receptor–positive patients, this trial included hormone receptor–negative patients. In this prospective study, women with both genomic and clinical high-risk classification received chemotherapy, while those with both genomic and clinical low-risk classification did not receive chemotherapy. Participants with discordant results (clinical high-risk- with genomic low-risk classification, or clinical low-risk- with genomic high-risk classification) were randomly assigned to receive or not receive chemotherapy. A total of 1,550 women with high clinical risk and low genomic risk, and 592 women with low clinical risk and high genomic risk, were randomly assigned to receive or not receive chemotherapy. The primary goal of the study was to determine whether patients with high clinical risk, but low genomic risk, who did not receive chemotherapy had a 5-year survival rate without distant metastases (primary study endpoint) of 92% or lower (a noninferiority design).
   • This endpoint was met because the observed rate in the group was 94.7% (95% CI, 92.5%–96.2%). However, among patients with high clinical risk but low genomic risk, the rate of 5-year survival without distant metastases was 1.5% higher in the arm that did receive chemotherapy than in the arm that did not receive chemotherapy, although the study was not powered to detect a difference between these arms (HR chemotherapy vs. no chemotherapy, 0.78; 95% CI, 0.50–1.21; P = .27)
   • Patients in the low clinical risk group with high genomic risk did well, and there was little evidence of benefit from chemotherapy in this group (5-year survival without distant metastases, 95.8% with chemotherapy vs. 95.0% without; HR, 1.17; 95% CI, 0.59–2.28; P = .66).

Results from the prospective, randomized RxPONDER (NCT01272037) trial will help to determine if there is a benefit from adjuvant chemotherapy in patients with ER-positive-, node-positive early breast cancer treated with endocrine therapy, and a recurrence score below 25.

Many other gene-based assays may guide treatment decisions in patients with early breast cancer (e.g., Predictor Analysis of Microarray 50 [PAM50] Risk of Recurrence [ROR] score, EndoPredict, Breast Cancer Index).

Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting. These women are at greater risk of developing contralateral breast cancer. (Refer to the Prognosis of BRCA1- and BRCA2-related breast cancer section of the PDQ Genetics of Breast and Gynecologic Cancerssummary for more information.)

Posttherapy Considerations

Hormone replacement therapy

After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, refer to the following PDQ summaries:

• Breast Cancer Prevention
• Hot Flashes and Night Sweats

Related Summaries

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

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

References

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed January 23, 2019.
2. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online. Last accessed January 31, 2019.
3. Johnson A, Shekhdar J: Breast cancer incidence: what do the figures mean? J Eval Clin Pract 11 (1): 27-31, 2005. [PUBMED Abstract]
4. Haas JS, Kaplan CP, Gerstenberger EP, et al.: Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med 140 (3): 184-8, 2004. [PUBMED Abstract]
5. Colditz GA, Kaphingst KA, Hankinson SE, et al.: Family history and risk of breast cancer: nurses' health study. Breast Cancer Res Treat 133 (3): 1097-104, 2012. [PUBMED Abstract]
6. Malone KE, Daling JR, Doody DR, et al.: Family history of breast cancer in relation to tumor characteristics and mortality in a population-based study of young women with invasive breast cancer. Cancer Epidemiol Biomarkers Prev 20 (12): 2560-71, 2011. [PUBMED Abstract]
7. Cybulski C, Wokołorczyk D, Jakubowska A, et al.: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29 (28): 3747-52, 2011. [PUBMED Abstract]
8. Goodwin PJ, Phillips KA, West DW, et al.: Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30 (1): 19-26, 2012. [PUBMED Abstract]
9. Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21 (1): 134-47, 2012. [PUBMED Abstract]
10. Razzaghi H, Troester MA, Gierach GL, et al.: Mammographic density and breast cancer risk in White and African American Women. Breast Cancer Res Treat 135 (2): 571-80, 2012. [PUBMED Abstract]
11. Key TJ, Appleby PN, Reeves GK, et al.: Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 105 (5): 709-22, 2011. [PUBMED Abstract]
12. Kaaks R, Rinaldi S, Key TJ, et al.: Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12 (4): 1071-82, 2005. [PUBMED Abstract]
13. Kaaks R, Berrino F, Key T, et al.: Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97 (10): 755-65, 2005. [PUBMED Abstract]
14. Collaborative Group on Hormonal Factors in Breast Cancer: Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 13 (11): 1141-51, 2012. [PUBMED Abstract]
15. Ritte R, Lukanova A, Tjønneland A, et al.: Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study. Int J Cancer 132 (11): 2619-29, 2013. [PUBMED Abstract]
16. Wolin KY, Carson K, Colditz GA: Obesity and cancer. Oncologist 15 (6): 556-65, 2010. [PUBMED Abstract]
17. Kotsopoulos J, Chen WY, Gates MA, et al.: Risk factors for ductal and lobular breast cancer: results from the nurses' health study. Breast Cancer Res 12 (6): R106, 2010. [PUBMED Abstract]
18. Goldacre MJ, Abisgold JD, Yeates DG, et al.: Benign breast disease and subsequent breast cancer: English record linkage studies. J Public Health (Oxf) 32 (4): 565-71, 2010. [PUBMED Abstract]
19. Kabat GC, Jones JG, Olson N, et al.: A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer. Cancer Causes Control 21 (6): 821-8, 2010. [PUBMED Abstract]
20. Worsham MJ, Raju U, Lu M, et al.: Risk factors for breast cancer from benign breast disease in a diverse population. Breast Cancer Res Treat 118 (1): 1-7, 2009. [PUBMED Abstract]
21. Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003. [PUBMED Abstract]
22. 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]
23. 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]
24. Blackwood MA, Weber BL: BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 16 (5): 1969-77, 1998. [PUBMED Abstract]
25. 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]
26. 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]
27. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999. [PUBMED Abstract]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. Anderson GL, Limacher M, Assaf AR, et al.: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291 (14): 1701-12, 2004. [PUBMED Abstract]
34. LaCroix AZ, Chlebowski RT, Manson JE, et al.: Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 305 (13): 1305-14, 2011. [PUBMED Abstract]
35. Anderson GL, Chlebowski RT, Aragaki AK, et al.: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 13 (5): 476-86, 2012. [PUBMED Abstract]
36. Bernstein L, Henderson BE, Hanisch R, et al.: Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 86 (18): 1403-8, 1994. [PUBMED Abstract]
37. Thune I, Brenn T, Lund E, et al.: Physical activity and the risk of breast cancer. N Engl J Med 336 (18): 1269-75, 1997. [PUBMED Abstract]
38. Adams-Campbell LL, Rosenberg L, Rao RS, et al.: Strenuous physical activity and breast cancer risk in African-American women. J Natl Med Assoc 93 (7-8): 267-75, 2001 Jul-Aug. [PUBMED Abstract]
39. Kampert JB, Whittemore AS, Paffenbarger RS Jr: Combined effect of childbearing, menstrual events, and body size on age-specific breast cancer risk. Am J Epidemiol 128 (5): 962-79, 1988. [PUBMED Abstract]
40. Pike MC, Krailo MD, Henderson BE, et al.: 'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer. Nature 303 (5920): 767-70, 1983. [PUBMED Abstract]
41. Lambe M, Hsieh C, Trichopoulos D, et al.: Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331 (1): 5-9, 1994. [PUBMED Abstract]
42. Col: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002. [PUBMED Abstract]
43. Cuzick J, Sestak I, Bonanni B, et al.: Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 381 (9880): 1827-34, 2013. [PUBMED Abstract]
44. Goss PE, Ingle JN, Alés-Martínez JE, et al.: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364 (25): 2381-91, 2011. [PUBMED Abstract]
45. Cuzick J, Sestak I, Forbes JF, et al.: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383 (9922): 1041-8, 2014. [PUBMED Abstract]
46. Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999. [PUBMED Abstract]
47. Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999. [PUBMED Abstract]
48. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002. [PUBMED Abstract]
49. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002. [PUBMED Abstract]
50. Kauff ND, Domchek SM, Friebel TM, et al.: Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26 (8): 1331-7, 2008. [PUBMED Abstract]
51. 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]
52. Abbott A, Rueth N, Pappas-Varco S, et al.: Perceptions of contralateral breast cancer: an overestimation of risk. Ann Surg Oncol 18 (11): 3129-36, 2011. [PUBMED Abstract]
53. Nichols HB, Berrington de González A, Lacey JV Jr, et al.: Declining incidence of contralateral breast cancer in the United States from 1975 to 2006. J Clin Oncol 29 (12): 1564-9, 2011. [PUBMED Abstract]
54. 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]
55. Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009. [PUBMED Abstract]
56. Garber JE, Golshan M: Contralateral breast cancer in BRCA1/BRCA2 mutation carriers: the story of the other side. J Clin Oncol 27 (35): 5862-4, 2009. [PUBMED Abstract]
57. 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]
58. Solin LJ, Orel SG, Hwang WT, et al.: Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J Clin Oncol 26 (3): 386-91, 2008. [PUBMED Abstract]
59. Morrow M: Magnetic resonance imaging in the breast cancer patient: curb your enthusiasm. J Clin Oncol 26 (3): 352-3, 2008. [PUBMED Abstract]
60. 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]
61. 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]
62. Diab SG, Clark GM, Osborne CK, et al.: Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas. J Clin Oncol 17 (5): 1442-8, 1999. [PUBMED Abstract]
63. Rakha EA, Lee AH, Evans AJ, et al.: Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol 28 (1): 99-104, 2010. [PUBMED Abstract]
64. Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001. [PUBMED Abstract]
65. Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018. [PUBMED Abstract]
66. Hammond ME, Hayes DF, Dowsett M, et al.: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 134 (6): 907-22, 2010. [PUBMED Abstract]
67. Buyse M, Loi S, van't Veer L, et al.: Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98 (17): 1183-92, 2006. [PUBMED Abstract]
68. Wittner BS, Sgroi DC, Ryan PD, et al.: Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort. Clin Cancer Res 14 (10): 2988-93, 2008. [PUBMED Abstract]
69. Mook S, Knauer M, Bueno-de-Mesquita JM, et al.: Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature. Ann Surg Oncol 17 (5): 1406-13, 2010. [PUBMED Abstract]
70. Ishitobi M, Goranova TE, Komoike Y, et al.: Clinical utility of the 70-gene MammaPrint profile in a Japanese population. Jpn J Clin Oncol 40 (6): 508-12, 2010. [PUBMED Abstract]
71. Knauer M, Mook S, Rutgers EJ, et al.: The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 120 (3): 655-61, 2010. [PUBMED Abstract]
72. Fisher B, Jeong JH, Bryant J, et al.: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364 (9437): 858-68, 2004. [PUBMED Abstract]
73. Paik S, Shak S, Tang G, et al.: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351 (27): 2817-26, 2004. [PUBMED Abstract]
74. Habel LA, Shak S, Jacobs MK, et al.: A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res 8 (3): R25, 2006. [PUBMED Abstract]
75. Mamounas EP, Tang G, Fisher B, et al.: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 28 (10): 1677-83, 2010. [PUBMED Abstract]
76. Paik S, Tang G, Shak S, et al.: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24 (23): 3726-34, 2006. [PUBMED Abstract]
77. Albain KS, Barlow WE, Shak S, et al.: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11 (1): 55-65, 2010. [PUBMED Abstract]
78. Sparano JA, Gray RJ, Makower DF, et al.: Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med : , 2018. [PUBMED Abstract]
79. Sparano JA, Gray RJ, Makower DF, et al.: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 373 (21): 2005-14, 2015. [PUBMED Abstract]
80. Cardoso F, van't Veer LJ, Bogaerts J, et al.: 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 375 (8): 717-29, 2016. [PUBMED Abstract]

Histopathologic Classification of Breast Cancer

Table 1 describes the histologic classification of breast cancer based on tumor location.[1] Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

Table 1. Tumor Location and Related Histologic Subtype

Tumor Location	Histologic Subtype
NOS = not otherwise specified.
Carcinoma, NOS
Ductal	Intraductal (in situ)
	Invasive with predominant component
	Invasive, NOS
	Comedo
	Inflammatory
	Medullary with lymphocytic infiltrate
	Mucinous (colloid)
	Papillary
	Scirrhous
	Tubular
	Other
Lobular	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
	Metaplastic

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

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

References

1. Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
2. Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222 (4): 549-59; discussion 559-61, 1995. [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

In This Section

• TNM Definitions
• AJCC Anatomic and Prognostic Stage Groups
• AJCC Pathological Prognostic Stage Groups

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 also according to other clinical factors such as the following, some of which are included in the determination of stage:

• Tumor size.
• Lymph node status.
• Estrogen-receptor and progesterone-receptor levels in the tumor tissue.
• Human epidermal growth factor receptor 2 (HER2/neu) status in the tumor.
• Tumor grade.
• Menopausal status.
• General health of the patient.

The standards used to define biomarker status are described as follows:

• Estrogen receptor (ER) expression: ER expression is measured primarily by immunohistochemistry (IHC). Any staining of 1% of cells or more is considered positive for ER.[1]
• Progesterone receptor (PR) expression: PR expression is measured primarily by IHC. Any staining of 1% of cells or more is considered positive for PR.
• HER2 expression: HER2 is measured primarily by either IHC to assess expression of the HER2 protein or by in situ hybridization (ISH) to assess gene copy number. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines for cases when either IHC or ISH testing is equivocal.[2]
  IHC:
  • Negative: 0 or 1+ staining
  • Equivocal: 2+ staining
  • Positive: 3+ staining
  ISH (dual probe):
  • Possible negative results:
    • HER2/chromosome enumeration probe (CEP17) ratio <2.0 AND HER2 copy number <4
  • Possible equivocal results: (requires performing alternative ISH test to confirm equivocal or IHC if not previously performed)
    • HER2/CEP17 ratio <2.0 AND HER2 copy number ≥4 but <6
  • Possible positive results:
    • HER2/CEP17 ratio ≥2.0 by ISH
    • HER2 copy number ≥6 regardless of ratio by ISH
  ISH (single probe):
  • Negative: <4 HER2 copies
  • Equivocal: ≥4 HER2 copies but <6 HER2 copies
  • Positive: ≥6 HER2 copies

TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define breast cancer.[3] The grade of the tumor is determined by its morphologic features, such as tubule formation, nuclear pleomorphism, and mitotic count.

Table 2. Definition of Primary Tumor (T) – Clinical and Pathologicala

T Category	T Criteria
DCIS = ductal carcinoma in situ.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bLobular carcinoma in situ is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th ed.
cRules for Classification - The anatomic TNM system is a method for coding extent of disease. This is done by assigning a category of extent of disease for the tumor (T), regional lymph nodes (N), and distant metastases (M). T, N, and M are assigned by clinical means and by adding surgical findings and pathological information to the clinical information. The documented prognostic impact of postneoadjuvant extent of disease and response to therapy warrant clear definitions of the use of the yp prefix and response to therapy. The use of neoadjuvant therapy does not change the clinical (pretreatment) stage. As per TNM rules, the anatomic component of clinical stage is identified with the prefix c (e.g., cT). In addition, clinical staging can include the use of fine-needle aspiration (FNA) or core-needle biopsy and sentinel lymph node biopsy before neoadjuvant therapy. These are denoted with the postscripts f and sn, respectively. Nodal metastases confirmed by FNA or core-needle biopsy are classified as macrometastases (cN1), regardless of the size of the tumor focus in the final pathological specimen. For example, if, prior to neoadjuvant systemic therapy, a patient with a 1 cm primary has no palpable nodes but has an ultrasound-guided FNA biopsy of an axillary lymph node that is positive, the patient will be categorized as cN1 (f) for clinical (pretreatment) staging and is assigned to Stage IIA. Likewise, if the patient has a positive axillary sentinel node identified before neoadjuvant systemic therapy, the tumor is categorized as cN1 (sn) (Stage IIA). As per TNM rules, in the absence of pathological T evaluation (removal of the primary tumor), which is identified with prefix p (e.g., pT), microscopic evaluation of nodes before neoadjuvant therapy, even by complete removal such as sentinel node biopsy, is still classified as clinical (cN).
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tisb	DCIS.
Tis (Paget)	Paget disease of the nipple NOT associated with invasive carcinoma and/or DCIS in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
T1	Tumor ≤20 mm in greatest dimension.
–T1mi	Tumor ≤1 mm in greatest dimension.
–T1a	Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >1.0–1.9 mm to 2 mm).
–T1b	Tumor >5 mm but ≤10 mm in greatest dimension.
–T1c	Tumor >10 mm but ≤20 mm in greatest dimension.
T2	Tumor >20 mm but ≤50 mm in greatest dimension.
T3	Tumor >50 mm in greatest dimension.
T4	Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4.
–T4a	Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4.
–T4b	Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d'orange) of the skin that does not meet the criteria for inflammatory carcinoma.
–T4c	Both T4a and T4b are present.
–T4d	Inflammatory carcinoma (see Rules for Classificationc).

Table 3. Definition of Regional Lymph Nodes – Clinical (cN)a,b

cN Category	cN Criteria
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively.
cThe cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.
dcN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.
cNXc	Regional lymph nodes cannot be assessed (e.g., previously removed).
cN0	No regional lymph node metastases (by imaging or clinical examination).
cN1	Metastases to movable ipsilateral Level I, II axillary lymph nodes(s).
–cN1mid	Micrometastases (approximately 200 cells, >0.2 mm, but ≤2.0 mm).
cN2	Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;
	or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
–cN2a	Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
–cN2b	Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
cN3	Metastases in ipsilateral infraclavicular (Level Ill axillary) lymph node(s) with or without Level l, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level l, II axillary lymph node metastases; ormetastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.
–cN3a	Metastases in ipsilateral infraclavicular lymph node(s).
–cN3b	Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
–cN3c	Metastases in ipsilateral supraclavicular lymph node(s).

Table 4. Definition of Regional Lymph Nodes – Pathological (pN)a,b

pN Category	pN Criteria
ITCs = isolated tumor cells; RT-PCR = reverse transcriptase-polymerase chain reaction.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively, with NO further resection of nodes.
pNX	Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed).
pN0	No regional lymph node metastasis identified or ITCs only.
–pN0(i+)	ITCs only (malignant cell clusters ≤0.2 mm) in regional lymph node(s).
–pN0(mol+)	Positive molecular findings by RT-PCR; no ITCs detected.
pN1	Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
–pN1mi	Micrometastases (~200 cells, >0.2 mm, but ≤2.0 mm).
–pN1a	Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
–pN1b	Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs.
–pN1c	pN1a and pN1b combined.
pN2	Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
–pN2a	Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
–pN2b	Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes.
pN3	Metastases in ≥10 axillary lymph nodes; or in infraclavicular (Level Ill axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level l, II axillary lymph nodes; or in >3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
–pN3a	Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm); ormetastases to the infraclavicular (Level III axillary lymph) nodes.
–pN3b	pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
	or pN2a in the presence of pN1b.
–pN3c	Metastases in ipsilateral supraclavicular lymph nodes.

Table 5. Definition of Distant Metastasis (M)a

M Category	M Criteria
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
M0	No clinical or radiographic evidence of distant metastases.b
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1	Distant metastases detected by clinical and radiographic means.
pM1	Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.

Table 6. Definition of Histologic Grade (G)a

G	G Definition
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.

Table 7. Ductal Carcinoma in situ: Nuclear Gradea

G	G Definition
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.

AJCC Anatomic and Prognostic Stage Groups

There are three stage group tables for invasive cancer:[3]

• Anatomic Stage Group. The Anatomic Stage Group table is used in regions of the world where tumor grading and/or biomarker testing for ER, PR, and HER2 are not routinely available. (Refer to Table 8.)
• Clinical Prognostic Stage Group. The Clinical Prognostic Stage Group table is used for all patients in the United States. Patients who have neoadjuvant therapy as their initial treatment should have the clinical prognostic stage and the observed degree of response to treatment recorded, but these patients are not assigned a pathological prognostic stage. (Refer to Table 9.)
• Pathological Prognostic Stage Group. The Pathological Prognostic Stage Group table is used for all patients in the United States who have surgery as initial treatment and have pathological T and N information reported. (Refer to Table 10.)

In the United States, cancer registries and clinicians must use the Clinical and Pathological Prognostic Stage Group tables for reporting. It is expected that testing is performed for grade, HER2, ER, and PR status and that results are reported for all cases of invasive cancer in the United States.

AJCC Anatomic Stage Groups

Table 8. Definition of Anatomic Stage Groupsa

Stage	TNM
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
Notes:
1. T1 includes T1mi.
2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.
4. M0 includes M0(i+).
5. The designation pM0 is not valid; any M0 is clinical.
6. If a patient presents with M1 disease before receiving neoadjuvant systemic therapy, the stage is Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.
7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.
8. Staging following neoadjuvant therapy is denoted with a yc or ypn prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoadjuvant therapy, for example, ypT0, ypN0, cM0.
0	Tis, N0, M0
IA	T1, N0, M0
IB	T0, N1mi, M0
	T1, N1mi, M0
IIA	T0, N1, M0
	T1, N1, M0
	T2, N0, M0
IIB	T2, N1, M0
	T3, N0, M0
IIIA	T0, N2, M0
	T1, N2, M0
	T2, N2, M0
	T3, N1, M0
	T3, N2, M0
IIIB	T4, N0, M0
	T4, N1, M0
	T4, N2, M0
IIIC	Any T (Tis, T1, T0, T2, T3, T4; N3, M0)
IV	Any T (Tis, T1, T0, T2, T3, T4; Any N = N0, N1mi, N1, N2, N3, M1)

AJCC Prognostic Stage Groups

The Clinical Prognostic Stage is used for clinical classification and staging of patients in the United States with invasive breast cancer. It uses TNM information based on the patient’s history, physical examination, imaging results (not required for clinical staging), and biopsies.

Table 9. Definition of Clinical Prognostic Stage Groupsa

TNM	Grade	HER2 Status	ER Status	PR Status	Stage Group
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0, and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. Because N1mi categorization requires evaluation of the entire node, and cannot be assigned on the basis of an fine-needle aspiration or core biopsy, N1mi can only be used with Clinical Prognostic Staging when clinical staging is based on a resected lymph node in the absence of resection of the primary cancer, such as in the situation where sentinel node biopsy is performed before receiving neoadjuvant chemotherapy or endocrine therapy.
2. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
3. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.[4,5]
4. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).
Tis, N0, M0	Any (refer to Table 6 and Table 7)	Any	Any	Any	0
T1b, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IA
T0, N1mi, M0			Negative	Positive	IA
				Negative	IA
T1b, N1mi, M0		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G2	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IB
T0, N1c, M0; T1b, N1c, M0; T2, N0, M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
	G3	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
T2, N1d, M0; T3, N0, M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIIB
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
T0, N2, M0; T1b, N2, M0; T2, N2, M0; T3, N1d, M0; T3, N2, M0	G1	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G2	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G3	Positive	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIC
			Negative	Positive	IIIC
				Negative	IIIC
Any T, Any N, M1	Any (refer to Table 6 and Table 7)	Any	Any	Any	IV

AJCC Pathological Prognostic Stage Groups

The Pathological Prognostic Stage applies to patients with invasive breast cancer initially treated with surgery. It includes all information used for clinical staging, surgical findings, and pathological findings following surgery to remove the tumor. Pathological Prognostic Stage is not used for patients treated with neoadjuvant therapy before surgery to remove the tumor.[3]

Table 10. Definition of Pathological Prognostic Stage Groupsa

TNM	Grade	HER2 Status	ER Status	PR Status	Stage Group
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0 and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
2. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.[4,5]
3. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).
Tis, N0, M0	Any (refer to Table 6 and Table 7)	Any	Any	Any	0
T1b, N0, M0; T0, N1mi, M0; T1b, N1mi, M0	G1	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
	G2	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
T0, N1c , M0; T1b, N1c, M0; T2, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
	G2	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
	G3	Positive	Positive	Positive	IA
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
T2, N1c, M0; T3, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G2	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIIA
T0, N2, M0; T1b, N2, M0; T2, N2, M0, T3, N1d, M0; T3, N2, M0	G1	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
	G2	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G3	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIC
			Negative	Positive	IIIC
				Negative	IIIC
Any T, Any N, M1	Any (refer to Table 6 and Table 7)	Any	Any	Any	IV

References

1. Barnes DM, Harris WH, Smith P, et al.: Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 74 (9): 1445-51, 1996. [PUBMED Abstract]
2. Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018. [PUBMED Abstract]
3. Breast. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 589–628.
4. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31 (31): 3997-4013, 2013. [PUBMED Abstract]
5. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138 (2): 241-56, 2014. [PUBMED Abstract]