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Breast Cancer Treatment (Adult) (PDQ®): Treatment - Health Professional Information [NCI]

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

General Information About Breast Cancer

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
  • Childhood Breast Cancer Treatment

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2020:[1]

  • New cases: 276,480.
  • Deaths: 42,170.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 48,530 cases of female breast ductal carcinoma in situ and 276,480 cases of invasive disease in 2020.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 63,220 American women will die of lung cancer in 2020.[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

Drawing of female breast anatomy showing the lymph nodes, nipple, areola, chest wall, ribs, muscle, fatty tissue, lobe, ducts, and lobules.
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).[11,12,13]
    • 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).[18,19,20]
  • 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.[29,30,31,32] (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).[33,34,35]
  • Exercise.[36,37,38]
  • Early pregnancy.[39,40,41]
  • 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.[47,48,49,50]

(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.[51,52,53] 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.[57,58,59]

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.[61,62,63]

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. [67,68,69,70,71] 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-14) 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 node-negative, 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-20 trial.[72] Patients in the NSABP B-20 trial were randomly assigned to receive tamoxifen alone or tamoxifen concurrently with methotrexate and 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.
    • A secondary analysis of TAILORx demonstrated that integration of clinical risk (assessed by tumor size and grade) adds prognostic information to the recurrence score in women with a recurrence score of at least 11; however, clinical risk was not predictive of a chemotherapy benefit.[80] The interaction between age and chemotherapy benefit was further explored in this secondary analysis. Among women aged 50 years or younger, rates of distant recurrence were lower with chemotherapy in the setting of recurrence scores of 16 to 20 and high clinical risk; and in the setting of recurrence scores of 21 to 25, regardless of clinical risk.
    • The majority of women received tamoxifen as their endocrine therapy. It is not certain if any of the observed benefits of chemotherapy are attributable to ovarian function suppression and if they could be achieved through endocrine therapy.
  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.[81][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 Cancers summary 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
  • Childhood Breast Cancer Treatment

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  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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 379 (2): 111-121, 2018.
  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.
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  81. 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.

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

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but 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 carcinomain situ.
a Reprinted 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 Lobular carcinomain situ is a benign entity and is removed from TNM staging in theAJCC Cancer Staging Manual, 8th ed.
c Rules 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 theyp 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 prefixc(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 postscriptsf andsn, 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 prefixp(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
a Reprinted 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.
c The 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.
d cN1mi 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;or metastases 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.
a Reprinted 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);or metastases 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
a Reprinted 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 Note 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.
a Reprinted 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 Carcinomain situ: Nuclear Gradea
G G Definition
a Reprinted 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.
a Adapted 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 ayc orypn 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.
a Adapted 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 T1 includes T1mi.
c N1 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.
d N1 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 carcinomain 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 beequivocal byin situ hybridization (fluorescencein situ hybridization or chromogenicin 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 6and 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 6and 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.
a Adapted 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 T1 includes T1mi.
c N1 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.
d N1 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 carcinomain 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 beequivocal byin situ hybridization (fluorescencein 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 6and 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 6and 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.
  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.
  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.
  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.

Early / Localized / Operable Breast Cancer

Treatment Option Overview for Early/Localized/Operable Breast Cancer

Standard treatment options for early, localized, or operable breast cancer may include the following:

Surgery:

  1. Breast-conserving surgery (lumpectomy) and sentinel lymph node (SLN) biopsy with or without axillary lymph node dissection for positive SLNs.
  2. Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Postoperative radiation therapy:

  1. Axillary node–negative breast cancer (postmastectomy):
    • No additional therapy.
    • Radiation therapy.
  2. Axillary node–positive breast cancer (postmastectomy):
    • For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.
    • For four or more nodes or extranodal involvement, regional radiation therapy is advised.
  3. Axillary node–negative or positive breast cancer (post–breast-conserving therapy):
    • Whole-breast radiation therapy.

Postoperative systemic therapy:

  1. Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu–negative] status). Adjuvant treatment options may include the following:
    • Tamoxifen.
    • Aromatase inhibitor (AI) therapy.
    • Ovarian function suppression.
    • Chemotherapy.

Preoperative systemic therapy:

  1. Chemotherapy.
  2. HER2 targeted therapy.
  3. Endocrine therapy.

Surgery

Stages I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:

  • Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.
  • Surgical procedure. After the presence of a malignancy is confirmed by biopsy, the following surgical treatment options can be discussed with the patient before a therapeutic procedure is selected:
    • Breast-conserving surgery.
    • Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.[1,2,3,4,5]

Locoregional treatment

Selection of a local therapeutic approach depends on the following:[6]

  • Location and size of the lesion.
  • Analysis of the mammogram.
  • Breast size.
  • Patient's desire to preserve the breast.

Options for surgical management of the primary tumor include the following:

  • Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[7] However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.
  • Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is equivalent with any of these options, as documented in the trial of the European Organization for Research and Treatment of Cancer (EORTC) (EORTC-10801) [8] and other prospective randomized trials.[9,10,11,12,13,14,15] Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER positive or PR positive; ER negative and PR negative but HER2/neu positive; and triple negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.[16]

The rate of local recurrence in the breast after 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 has been debated.[17,18,19] However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:[20]

  • Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.
  • More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.
  • There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re-excision. A clinical trial of 235 patients with stage 0 to III breast cancer who underwent partial mastectomy, with or without resection of selective margins, randomly assigned patients to have additional cavity shave margins resected (shave group) or not (no-shave group).[21] Patients in the shave group had a significantly lower rate of positive margins than those in the no-shave group (19% vs. 34%, P = .01) and a lower rate of second surgery for clearing margins (10% vs. 21%, P = .02).[21][Level of evidence: 1iiDiv]

Axillary lymph node management

Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. 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%.[22,23] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[24][Level of evidence: 3iiiA]

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-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.[25,26] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.[27,28,29,30]

Because of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

Evidence (SLN biopsy):

  1. A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.[31][Level of evidence: 1iiC]
    • Quality of life (QOL) 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% deteriorating in the SLN biopsy group vs. 35% in the ALND group; P = .001). Arm function was also better in the SLN group.
  2. The National Surgical Adjuvant Breast and Bowel Project's (NSABP-B-32 [NCT00003830]) multicenter, phase III trial randomly assigned women (N = 5,611) to undergo either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.[32][Level of evidence: 1iiA]
    • The study showed no detectable difference in overall survival (OS), disease-free survival (DFS), and regional control. OS was 91.8% for SLN plus ALND versus 90.3% for SLN resection alone (P = .12).

Because of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.

Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):

  1. A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.[33][Level of evidence: 1iiA]
    • At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone.
    • The secondary endpoint of 5-year DFS was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.
  2. In a similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to ALND or no ALND.[34][Level of evidence: 1iiA]
    • Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11).
    • No difference in OS was observed.
  3. The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node.[35][Level of evidence: 1iiA]
    • ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.
    • The use of axillary radiation therapy was also associated with significantly less morbidity.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[36,37,38,39] Breast contour can be restored by the following:

  • Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, 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 U. S. Food and Drug Administration's [FDA] website for more information on breast implants.)
  • Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[40]

Postoperative Radiation Therapy

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[41]

Post–breast-conserving surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women.[42] 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, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death.[43] Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Evidence (breast-conserving surgery followed by radiation therapy):

  1. A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[43][Level of evidence: 1iiA]

    • Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% for whole-breast radiation therapy vs. 35% for breast-conserving surgery alone; relative risk (RR) = 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% for whole-breast radiation therapy vs. 25% for breast-conserving surgery alone; RR, 0.82; 95% CI, 0.75–0.90).

Regarding radiation dosing and schedule, the following has been noted:

  • Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.
  • Radiation boost. 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),[44][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).[45][Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[46][Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.[47]
  • Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.
    • A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule.[48] The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, -2.5 to 3.5).[48][Level of evidence: 1iiDii
    • Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to receive conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.[49][Level of evidence: 1iiDii]
    • A meta-analysis that included the three trials mentioned above plus six others confirmed that differences with respect to local recurrence or cosmesis between shorter and conventional fractionation schedules were neither statistically nor clinically significant.[50]

    Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.[49]

Regional nodal irradiation

Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes; however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear. A randomized trial (NCT00005957) of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence (10-year DFS, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS, 82.8% vs. 81.8%; HR, 0.91; 95% CI, 0.72–1.13; P = .38).[51][Level of evidence: 1iiA]

Similar findings were reported from the EORTC trial (NCT00002851). Women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to receive whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Breast-conserving surgery was performed for 76.1% of the study population, and the remaining study population underwent mastectomy. No improvement in OS was seen at 10 years among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal radiation (82.3% vs. 80.7%, P = .06). Distant DFS was improved among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal irradiation (78% vs. 75%, P = .02).[52][Level of evidence: 1iiA]

A meta-analysis that combined the results of the two trials mentioned above found a marginally statistically significant difference in OS (HR, 0.88; 95% CI, 0.78–0.99; P = .034; absolute difference, 1.6% at 5 years).[53]

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for locoregional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:[54,55,56]

  • Four or more positive axillary nodes.
  • Grossly evident extracapsular nodal extension.
  • Large primary tumors.
  • Very close or positive deep margins of resection of the primary tumor.

In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.[57]

Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.

Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):

  1. The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[41][Level of evidence: 1iiA]
    • For women with node-positive disease postmastectomy and axillary clearance (removal of axillary lymph nodes and surrounding fat), 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 reduction (P = .002) 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%–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 an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P [2-sided significance level] < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).[58][Level of evidence: 1iiA]
    • In contrast, for women at low risk of local recurrence 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 (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 and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.[59]

Timing of postoperative radiation therapy

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

Evidence (timing of postoperative radiation therapy):

  1. In a randomized trial, patients received one of the following regimens:[60][Level of evidence: 1iiA]
    1. Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation.
    2. Breast radiation first (n = 122), followed by the same chemotherapy.

    The following results were observed:

    • With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).
    • The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and 14% in the chemotherapy-first group for local recurrence and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07).
    • Further analyses revealed that differences in recurrence patterns persisted for most subgroups except for those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses was low.
    • Potential explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages because of increased myelosuppression.
  2. Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.
    1. In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of cyclophosphamide, methotrexate, and 5-FU (CMF) (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.[61][Level of evidence: 1iiA]
      • No differences in DFS, distant DFS, and OS were observed between these two arms.
    2. The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.[62]

These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[63][Level of evidence: 1iiA]

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu–positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[64] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Late toxic effects of radiation

Late toxic effects of radiation therapy are uncommon and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:

  • Radiation pneumonitis. 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.[65] 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.[65][Level of evidence: 3iii]
  • Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated 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.[57,66,67,68] 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.[69,70]

    An analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) data from 1973 to 1989 that reviewed deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[71,72][Level of evidence: 3iB]

  • Arm lymphedema. Lymphedema 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. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy.[73,74,75] (Refer to the PDQ summary on Lymphedema for more information.)
  • Brachial plexopathy. Radiation injury to the brachial plexus after 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 monitored for 5.5 years to assess the rate of brachial plexus injury.[76] The diagnosis of such injury was made clinically with computerized tomography (CT) 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.
  • Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy.[77] No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy.[78] Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.[79]
  • Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years.[80] 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.[81]

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.

An international consensus panel proposed a risk classification system and systemic therapy treatment options.[82] This classification, with some modification, is described below:

Table 11. Systemic Treatment for Early Breast Cancer by Subtypea
Subtype Treatment Options Comments
HER2 = human epidermal growth factor receptor 2; LN = lymph node; PR = progesterone receptor.
a Modified from Senkus et al.[82]
Luminal A–like
– Hormone receptor–positive Endocrine therapy alone in most cases Consider chemotherapy if:
– HER2-negative – High tumor burden (=4 LNs, T3 or higher)
– PR >20%
– Ki67 low – Grade 3
Luminal B–like
– Hormone receptor–positive Endocrine therapy plus chemotherapy in most cases  
– HER2-negative
– Either Ki67 high or PR low
HER2-positive Chemotherapy plus anti-HER2 therapy Use endocrine therapy if also hormone receptor–positive
May consider omitting chemotherapy plus anti-HER2 for small node-negative tumors
Triple-negative Chemotherapy May consider omitting chemotherapy for small node-negative tumors

The selection of therapy is most appropriately based on knowledge of an individual's risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their situation. The treatment options described below should be modified based on both patient and tumor characteristics.

Table 12. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast Cancer
Patient Group Treatment Options
ER = estrogen receptor; PR = progesterone receptor.
Premenopausal, hormone receptor–positive (ER or PR) No additional therapy
Tamoxifen
Tamoxifen plus chemotherapy
Ovarian function suppression plus tamoxifen
Ovarian function suppression plus aromatase inhibitor
Premenopausal, hormone receptor–negative (ER or PR) No additional therapy
Chemotherapy
Postmenopausal, hormone receptor–positive (ER or PR) No additional therapy
Upfront aromatase inhibitor therapy or tamoxifen followed by aromatase inhibitor with or without chemotherapy
Postmenopausal, hormone receptor–negative (ER or PR) No additional therapy
Chemotherapy

Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (CMF)

The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and 5-FU). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.[83]

Evidence (anthracycline-based regimens):

  1. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of 5-FU, epirubicin, and cyclophosphamide [FEC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]) with CMF (either PO or intravenous [IV]) in approximately 14,000 women, 64% of whom were younger than 50 years.[83]
    • Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[84][Level of evidence: 1iiA]
    • Of note, few women older than 70 years were studied, and specific conclusions could not be reached for this age group.
    • Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to hormone-receptor status, and the trials were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[83] As a result, the data may not reflect treatment outcomes based on evolving treatment patterns.

Study results suggest that tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.

Evidence (anthracycline-based regimen in women with HER2/neu amplification):

  1. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and 5-FU (CAF),[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]
  2. A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and 5-FU(CEF).[85][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods.
    • The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in relapse-free survival (RFS) and OS.
    • In patients with HER2/neu amplification, the RFS and OS were increased by CEF.
    • In the absence of HER2/neu amplification, CEF and CMF were similar with regard to RFS (HR for relapse, 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HRdeath, 1.06; 95% CI, 0.83–1.44; P = .68).
  3. Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with non–anthracycline-containing regimens.[86]

Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy

Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.

Evidence (adding a taxane to an anthracycline-based regimen):

  1. A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).[87][Level of evidence: 1iiA]
    • Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens.
    • There were no differences in benefit observed in patient subsets defined by nodal status, hormone-receptor status, or age and menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies that were reviewed involved a direct comparison between paclitaxel and docetaxel.
  2. A U.S. intergroup study (CLB-9344 [NT00897026]) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to receive paclitaxel (175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with hormone receptor-positive tumors also received tamoxifen for 5 years.[88][Level of evidence: 1iiA]
    • Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).
  3. The NSABP-B-28 (NCT01420185) trial randomly assigned 3,060 women with node-positive breast cancer to receive four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.[89][Level of evidence: 1iiA]
    • DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%).
    • The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).
  4. In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.[90,91][Level of evidence: 1iiA]
    • There was a 75% DFS rate at 5 years in the TAC group compared with a 68% DFS rate in the FAC group (P = .001).
    • TAC was associated with a 30% overall lower risk of death (5% absolute difference) than was FAC (HR, 0.70; 98% CI, 0.53–0.91; P < .008).
    • Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group. (Refer to the PDQ summary on Fatigue for information on anemia.)

An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[92][Level of evidence: 1iiA] Study findings include the following:

  • There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).
  • There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).
  • Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).
  • Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.

Chemotherapy schedule: Dose-density

Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.

Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):

  1. A U.S. intergroup trial (CLB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[93][Level of evidence: 1iiA]
    • At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P = .018), but not OS (HR, 0.85; P = .12).[94][Level of evidence: 1iiA]
    • There was no interaction between density and sequence.
    • Severe neutropenia was less frequent in patients who received the dose-dense regimens.[95][Level of evidence: 1iiA]
  2. An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.[96]
    • For the dose-density comparison, DFS at 5 years was 81% (95% CI, 79–84) in patients treated every 2 weeks and 76% (95% CI, 74–79) in patients treated every 3 weeks (HR, 0.77; 95% CI, 0.65–0.92; P = .004).
    • OS rates at 5 years were 94% (95% CI, 93–96) and 89% (95% CI, 87–91; HR, 0.65; 0.51–0.84; P = .001).[96][Level of evidence: 1iiA]
  3. A meta-analysis of dose-dense versus standard dosing included data from eight trials including 17,188 patients.[97]
    • The patients who received dose-dense chemotherapy had better OS (HR, 0.86; 95% CI, 0.79–0.93; P = .0001) and DFS (HR, 0.84; 95% CI, 0.77–0.91; P < .0001) than those on the conventional schedule. A statistically significant OS benefit was observed in patients with ER-negative tumors (HR, 0.8; P = .002) but not in those with ER-positive breast cancer (HR, 0.93; 95% CI, 0.82–1.05; P = .25).
  4. A meta-analysis of 26 randomized trials that included 37,298 women treated with anthracycline- and taxane-containing chemotherapy compared standard regimens (administered every 3–4 weeks) with more dose-intense regimens. Regimens that increased dose intensity by shortening the interval between cycles (i.e., dose-dense therapy or administration of the same dose over a shorter time period) and regimens that increased dose intensity by administering individual drugs in sequence to allow for higher doses (i.e., sequential scheduling).[98]
    • Patients who received more dose-intense regimens had superior recurrence-free survival (28.0% vs. 31.4%; RR, 0.86; 95% CI, 0.82–0.89; P < .0001) and OS (18.9% vs. 21.3%; RR, 0.87; 95% CI, 0.83–0.92; P < .0001) at 10 years. The difference was present and statistically significant in receptor-positive and receptor-negative subgroups.
  5. A randomized, phase III, double-blinded study (NCT01519700) demonstrated noninferiority for the duration of severe neutropenia of a biosimilar filgrastim, EP2006, compared with the U.S.-licensed product.[99][Level of evidence: 1iDiv]

Docetaxel and cyclophosphamide

Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):

  1. The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.[100,101][Level of evidence: 1iiA]
    1. At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS.[101]
      • DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033).
      • OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032).
    2. Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.[100]

Timing of postoperative chemotherapy

The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:

  1. A single-institution study of early-stage breast cancer patients diagnosed between 1997 and 2011 revealed that delays in initiation of adjuvant chemotherapy adversely affected survival outcomes.[102][Level of evidence: 3iiiA]
    • Initiation of chemotherapy 61 days or more after surgery was associated with adverse outcomes among patients with stage II breast cancer (distant relapse-free survival: HR, 1.20; 95% CI, 1.02–1.43) and stage III breast cancer (OS: HR, 1.76; 95% CI, 1.26–2.46; RFS: HR, 1.34; 95% CI, 1.01–1.76; and distant relapse-free survival: HR, 1.36; 95% CI, 1.02–1.80).
    • Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.
    • Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.

Toxic effects of chemotherapy

Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include the following:

  • Nausea and vomiting.
  • Myelosuppression.
  • Alopecia.
  • Mucositis.

Less common, but serious, toxic effects include the following:

  • Heart failure (if an anthracycline is used).
  • Thromboembolic events.[103]
  • Premature menopause.[104]
  • Second malignancy (leukemia).[105,106,107]

(Refer to the PDQ summary on Treatment-Related Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)

The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[105,106] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).[107]

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[108] However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.[84] This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistica