Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2023:[1]

• New cases: 297,790.
• Deaths: 43,170.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 55,720 cases of female breast ductal carcinoma in situ (DCIS) and 297,790 cases of invasive disease in 2023.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 59,910 American women will die of lung cancer in 2023.[1] Men account for 1% of breast cancer cases and breast cancer deaths. For more information, see the Special Populations section in Breast Cancer Screening.

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 DCIS. For more information, see the Ductal carcinoma in situ (DCIS) section in Breast Cancer Screening. 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

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

• Family health history.[5]
• Major inheritance susceptibility.[6,7]

  -

  Germline mutation of the BRCA1 and BRCA2 genes and other breast cancer susceptibility genes.[8,9]

• Alcohol intake.
• Breast tissue density (mammographic).[10]
• Estrogen (endogenous).[11-13]

  -

  Menstrual history (early menarche/late menopause).[14,15]

  -

  Nulliparity.

  -

  Older age at first birth.

• Hormone therapy history.

  -

  Combination estrogen plus progestin hormone replacement therapy.

• Obesity (postmenopausal).[16]
• Personal history of breast cancer.[17]
• Personal history of benign breast disease (BBD) (proliferative forms of BBD).[18-20]
• Radiation exposure to breast/chest.

  [21]

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

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2.[24] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[25] The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year.[26] Male BRCA2 mutation carriers also have an increased risk of breast cancer.[27]

Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [27,28] or other primary cancers.[27,28] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing.[29-32]

For more information, see Genetics of Breast and Gynecologic Cancers, Breast Cancer Prevention, and Breast Cancer Screening.

Protective Factors

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

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

For more information about factors that decrease the risk of breast cancer, see Breast Cancer Prevention.

Screening

Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality. For more information, see Breast Cancer Screening.

Diagnosis

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 pathological 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.
• Histological type. Breast cancer is classified into a variety of histological types, some of which have prognostic importance. Favorable histological types include mucinous, medullary, and tubular carcinomas.[61-63]

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

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

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

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

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

Gene profile tests include the following:

• MammaPrint: The first gene profile test to be approved by the U.S. Food and Drug Administration was the MammaPrint gene signature. The 70-gene signature classifies tumors into high- and low-risk prognostic categories. [67-71] The aim of the MINDACT trial (NCT00433589) (see below) was 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 trial (NCT00310180) 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 end point, 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 rate 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 B1]
   • 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 end points 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.
   • Most 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 trial (NCT00433589) 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 C2] 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 end point) of 92% or lower (a noninferiority design).

   • This end point 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).
6. The RxPONDER trial (NCT01272037) included 3,350 postmenopausal and 1,665 premenopausal women with hormone receptor–positive and HER2-negative breast cancer who had a recurrence score of 25 or less. Patients were randomly assigned to receive either endocrine therapy alone or endocrine therapy plus chemotherapy. Results have been reported in abstract form; the primary study end point was invasive disease-free survival (IDFS). Because a prespecified test for interaction between treatment assignment and menopausal status was significant (P = .004), the premenopausal and postmenopausal groups were analyzed separately.[82]

   • In postmenopausal patients, there was no evidence of a benefit with the addition of chemotherapy (HR for endocrine therapy plus chemotherapy vs. endocrine therapy, 0.97; 95% CI, 0.78–1.22; 5-year IDFS rate, 91.6% vs. 91.9%; P = .82).[82][Level of evidence B1]
   • In premenopausal patients, however, there was evidence of a benefit from the addition of chemotherapy to endocrine therapy (HR, 0.54; 95% CI, 0.38–0.76; 5-year IDFS rate, 94.2% vs. 89.0%; P = .0004). OS was also significantly improved in patients who received endocrine therapy plus chemotherapy (HR, 0.47; 95% CI, 0.24–0.94; P = .032).[Level of evidence A1]
7. The West German Study Group Plan B trial (NCT01049425) compared two chemotherapy regimens in patients with node-positive (pN1) or high-risk node-negative disease. Chemotherapy was not offered to patients with recurrence scores below 12, but they were followed. For a full description of the chemotherapy regimens, see Postoperative Systemic Therapy.

   • The 5-year DFS rates were very high in the 348 patients who did not receive chemotherapy and did not differ between node-negative patients (94.5%) and pN1 patients (94.9%).[83][Level of evidence C1]

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. For more information, see the Female Breast Cancer Risks section in BRCA1 and BRCA2: Cancer Risks and Management.

Posttherapy Considerations

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64. Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001. [PMC free article: PMC58566] [PubMed: 11553815]
65. Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018. [PubMed: 29846122]
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. [PMC free article: PMC3073033] [PubMed: 20524868]
67. Buyse M, Loi S, van't Veer L, et al.: Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98 (17): 1183-92, 2006. [PubMed: 16954471]
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. [PMC free article: PMC3089800] [PubMed: 18483364]
69. Mook S, Knauer M, Bueno-de-Mesquita JM, et al.: Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature. Ann Surg Oncol 17 (5): 1406-13, 2010. [PubMed: 20094918]
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72. Fisher B, Jeong JH, Bryant J, et al.: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364 (9437): 858-68, 2004. [PubMed: 15351193]
73. Paik S, Shak S, Tang G, et al.: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351 (27): 2817-26, 2004. [PubMed: 15591335]
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References

1. Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. 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. [PMC free article: PMC1234890] [PubMed: 7574934]
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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.

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. (See 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. (See 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. (See 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

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.

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]

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. [PMC free article: PMC2074773] [PubMed: 8912543]
2. Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018. [PubMed: 29846122]
3. Breast. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 589–628.
4. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31 (31): 3997-4013, 2013. [PubMed: 24101045]
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. [PMC free article: PMC4086638] [PubMed: 24099077]

Treatment Option Overview for Early/Localized/Operable Breast Cancer

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.[1-5]

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]

Partial Breast Irradiation

Evidence (partial breast irradiation):

1. The RAPID trial (NCT00282035) randomly assigned 2,135 women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast-conserving surgery to receive either external-beam accelerated partial breast irradiation (APBI) (38.5 Gy in ten fractions delivered twice per day over 5–8 days) or whole-breast irradiation (42.5 Gy in 16 fractions delivered once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days).[83] Sixty-five ipsilateral breast tumor recurrences were observed, 37 in the APBI group, and 28 in the whole-breast irradiation group.

   • In patients treated with APBI, the 5-year cumulative rate of ipsilateral breast tumor recurrence was 2.3% (95% CI, 1.4%–3.2%) and the 8-year cumulative rate was 3.0% (95% CI, 1.9%–4.0%).
   • In patients treated with whole-breast irradiation, the 5-year cumulative rate of ipsilateral breast tumor recurrence was 1.7% (range, 0.9%–2.5%) and the 8-year cumulative rate was 2.8% (range, 1.8%–3.9%).
   • The HR for APBI versus whole-breast irradiation was 1.27 (90% CI, 0.84–1.91).
   • Thus, the upper bound of the estimated 90% CI did not exceed the noninferiority margin of 2.02. The APBI arm was associated with less short-term, but more long-term toxicity.[83][Level of evidence B1]
2. The NSABP B-39/RTOG 0413 trial (NCT00103181) randomly assigned 4,216 women to whole-breast irradiation or APBI.[84] Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumor bed, and APBI was delivered as 34 Gy of brachytherapy or 38.5 Gy of external-bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period.

   • At a median follow-up of 10.2 years (interquartile range, 7.5–11.5), 90 (4%) of 2,089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2,036 women in the whole-breast irradiation group had an ipsilateral breast tumor recurrence (HR, 1.22; 90% CI, 0.94–1.58). The results did not meet the prespecified criterion for equivalence, an HR of 1.50 or less.
   • Toxicity was not substantially different between the arms.[84][Level of evidence B1]

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. 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.

Many of the studies that support the use of chemotherapy after surgery were conducted before the widespread practice of testing for HER2. In general, their results are still applicable to the management of patients with all three subtypes of breast cancer. Exceptions are described below.

Preoperative Systemic Therapy

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. Treatment with preoperative chemotherapy can also allow for breast conservation therapy in patients who are not candidates for breast conservation at initial presentation. Preoperative chemotherapy may also reduce the need for an ALND in patients presenting with node-positive disease.

Much of the evidence presented in the following sections on preoperative chemotherapy is discussed in an American Society of Clinical Oncology guideline that describes the selection of options for the management of these patients.[182]

A meta-analysis of multiple, randomized clinical trials performed in 2005 demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[183][Level of evidence A1]

In 2019, the Early Breast Cancer Trialists’ Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting.[184] Compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation (65% vs. 49%). There were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause; however, neoadjuvant therapy was associated with higher 15-year local recurrence (21.4% vs. 15.9%; rate ratio, 1.37; 95% CI, 1.17−1.61; P = .001).[184][Level of evidence A1]

pCR has been used as a surrogate end point for long-term outcomes, such as DFS, EFS, and OS, in preoperative clinical trials in breast cancer. A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), provided a better association with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is).[185] pCR could not be validated in this study as a surrogate end point for improved EFS and OS.[185][Level of evidence C2] Because of a strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the FDA has supported use of pCR as an end point in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Categorizing patients as having pCR or residual disease unfortunately offers no distinction among patients with varied amounts of residual disease. The residual cancer burden (RCB) method was designed to address this and other prognostic deficits. The RCB method provides a standard to evaluate and quantify the extent of residual disease in breast and axillary lymph nodes following neoadjuvant chemotherapy. It is reported as a continuous score, with pCR being scored as RCB-0. There are four RCB classes ranging from RCB-0 to RCB-3. Determining RCB after neoadjuvant treatment has been validated as a prognostic predictor in early breast cancer.

A pooled, multinational, multi-institutional analysis was performed, using participant-level RCB results and clinicopathological data. Participant data from 5,161 patients were analyzed to assess the association between the continuous RCB score and the primary study outcome, EFS. With a median follow-up of 56 months, the RCB score was prognostic within each breast cancer subtype, with a higher RCB score significantly associated with worse EFS. RCB score was prognostic for EFS in multivariable models adjusted for age, grade, T category, and nodal status at baseline. The adjusted HR associated with a one-unit increase in RCB ranged from 1.52 in the hormone receptor–positive, HER2-negative group to 2.09 in the hormone receptor–negative, HER2-positive group (P < .0001 for all subtypes).[186]

Neoadjuvant therapy is particularly favored in patients with triple-negative or HER2-positive disease, when pathological response is used as a guide in choosing the optimal adjuvant therapy after surgery. For more information, see the sections on Triple-negative breast cancer and HER2/neu-positive breast cancer.

Omission of postoperative radiation therapy to the regional nodes in patients who initially present as node positive and become node negative after neoadjuvant therapy is currently being evaluated.

Posttherapy Surveillance

The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations.[233-235] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[234] On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

• Physical examination.
• Annual mammography.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.

Treatment options for locally advanced or inflammatory breast cancer may include the following:

1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.
2. Chemotherapy.
3. Radiation therapy.
4. Hormone therapy.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.

The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting, although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy. For more information, see the Postoperative Systemic Therapy section.[1]

For patients whose tumors respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy.[2] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.

Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.

Evidence (multimodality therapy):

1. In a retrospective series, 70 patients with locally advanced breast cancer and supraclavicular metastases received preoperative chemotherapy. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection or breast-conserving surgery and axillary lymph node dissection before or after radiation therapy. Patients whose tumors did not respond to preoperative chemotherapy were treated with surgery and/or radiation therapy. After completion of local therapy, chemotherapy was continued for 4 to 15 cycles, followed by radiation therapy.[3]

   • Approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined-modality therapy.
   • These results have been confirmed in a separate series of patients treated in British Columbia.[4]
2. A series of 178 patients with inflammatory breast cancer were treated with a combined-modality approach. Patients were treated with induction chemotherapy, then local therapy (radiation therapy or mastectomy), followed by chemotherapy, and, if mastectomy was performed, radiation therapy.[5][Level of evidence C2]

Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.[1]

All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016. [PubMed: 27058707]
2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994. [PubMed: 10717111]
3. Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001. [PubMed: 11157012]
4. Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003. [PubMed: 12610184]
5. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997. [PubMed: 9225950]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011. [PMC free article: PMC3254252] [PubMed: 22019144]
2. Buchanan CL, Dorn PL, Fey J, et al.: Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 203 (4): 469-74, 2006. [PubMed: 17000389]
3. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986. [PubMed: 3742446]
4. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993. [PubMed: 8418240]
5. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991. [PubMed: 2061106]
6. Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996. [PubMed: 8823339]
7. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987. [PubMed: 3655856]
8. Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001. [PubMed: 11689583]
9. Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991. [PubMed: 2061107]
10. Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992. [PubMed: 1587748]
11. Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990. [PubMed: 2211253]
12. Aebi S, Gelber S, Anderson SJ, et al.: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15 (2): 156-63, 2014. [PMC free article: PMC3982874] [PubMed: 24439313]
13. Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018. [PMC free article: PMC5891132] [PubMed: 29443653]

Hormone Receptor–Positive Breast Cancer

HER2/neu-Low Breast Cancer

Sixty percent of HER2–negative metastatic breast cancers express low levels of HER2, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization. These are referred to as HER2-low tumors. Historically, HER2-directed therapies have not improved outcomes in these patients. Early-phase trials of trastuzumab deruxtecan showed potential efficacy in this subgroup.[50] A subsequent randomized phase III trial showed OS benefit in this subgroup.[51] Trastuzumab deruxtecan is an antibody-drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase-I inhibitor payload through a cleavable linker. This agent offers bystander effect to surrounding HER2-low cells via uptake into HER2-amplified cells, intracellular cleavage of payload, and release of payload into the surrounding tumor.

Evidence (trastuzumab deruxtecan for hormone receptor–positive and negative HER2-low tumors):

1. The DESTINY-Breast04 trial (NCT03734029) randomly assigned 557 women in a 2:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Patients had received one or two prior lines of chemotherapy. The primary end point was PFS in the hormone receptor–positive group (88.7% of patients). The secondary end points were PFS in the total population, OS in the total population, and OS in the hormone receptor–positive group.[51]

   • In the hormone receptor–positive cohort, the median PFS was 10.1 months for patients who received trastuzumab deruxtecan and 5.4 months for patients who received the physician’s choice of chemotherapy (HR_{disease progression or death}, 0.51; P < .001). The OS was 23.9 months for patients who received trastuzumab deruxtecan and 17.5 months for patients who received the physician's choice of chemotherapy (HR_death, 0.64; P = .003).
   • Among all patients, the median PFS was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (HR_{disease progression or death}, 0.50; P < .001). The OS was 23.4 months in the trastuzumab deruxtecan group and 16.8 months in the physician's choice group (HR_death, 0.64; P = .001).
   • Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.

Triple-Negative Breast Cancer

HER2/neu-Positive Breast Cancer

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Germline BRCA Mutation

For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (ADP-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

High Tumor Mutational Burden

An established biomarker for checkpoint inhibitor immunotherapy is high somatic tumor mutational burden (TMB). TMB is the number of mutations within the coding region of a tumor genome and is reported as mutations per megabase (Mut/Mb). TMB is high (≥10) in approximately 5% of breast cancers.[85] Highest median TMB is noted in triple-negative tumors and lowest median TMB is noted in ER-positive/HER2-negative patients.

Chemotherapy

Patients receiving hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor–negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.[88]

Single agents that have shown activity in metastatic breast cancer include the following:

• Anthracyclines.

  -

  Doxorubicin.

  -

  Epirubicin.

  -

  Liposomal doxorubicin.[89-92]

  -

  Mitoxantrone.

• Taxanes.

  -

  Paclitaxel.[93,94]

  -

  Docetaxel.

  -

  Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[95,96]

• Alkylating agents.

  -

  Cyclophosphamide.

• Fluoropyrimidines.

  -

  Capecitabine.[97-99]

  -

  Fluorouracil (5-FU).

• Antimetabolites.

  -

  Methotrexate.

• Vinca alkaloids.

  -

  Vinorelbine.[100]

  -

  Vinblastine.

  -

  Vincristine.

• Platinum.

  -

  Carboplatin.

  -

  Cisplatin.

• Other.

  -

  Gemcitabine.[101]

  -

  Mitomycin.

  -

  Eribulin mesylate.[102,103]

  -

  Ixabepilone.[104]

Combination regimens that have shown activity in metastatic breast cancer include the following:

• AC: Doxorubicin and cyclophosphamide.[105]
• EC: Epirubicin and cyclophosphamide.[106]
• Docetaxel and doxorubicin.[107]
• CAF: Cyclophosphamide, doxorubicin, and 5-FU.[108]
• CMF: Cyclophosphamide, methotrexate, and 5-FU.[109]
• Doxorubicin and paclitaxel.[110,111]
• Docetaxel and capecitabine.[112]
• Vinorelbine and epirubicin.[113]
• Capecitabine and ixabepilone.[114]
• Carboplatin and gemcitabine.[115]
• Gemcitabine and paclitaxel.[116]

There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An ECOG intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially.[117] Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[117][Level of evidence A1]; [118,119]

The selection of therapy in individual patients is influenced by the following:

• Rate of disease progression.
• Presence or absence of comorbid medical conditions.
• Physician/patient preference.

Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[1,120] A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[121][Level of evidence A1]

Decisions regarding the duration of chemotherapy may consider the following:

• Patient preference and goals of treatment.
• Presence of toxicities from previous therapies.
• Availability of alternative treatment options.

The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[122,123][Level of evidence A1] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies,[123] survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation [124] or a different chemotherapy regimen given at higher versus lower doses.[125][Level of evidence A1] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[126][Level of evidence A1] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Surgery

Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:

• Fungating/painful breast lesions (mastectomy).
• Parenchymal brain or vertebral metastases with spinal cord compression.
• Isolated lung metastases.
• Pathological (or impending) fractures.
• Pleural or pericardial effusions.

For more information about pleural and pericardial effusions, see Cardiopulmonary Syndromes.

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases.[134] Indications for external-beam radiation therapy include the following:

• Painful bony metastases.
• Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
• Bronchial obstruction.
• Fungating/painful breast or chest wall lesions.
• After surgery for decompression of intracranial or spinal cord metastases.
• After fixation of pathological fractures.

Strontium chloride Sr 89, a systemically administered radionuclide, can be given for palliation of diffuse bony metastases.[135,136]

Bone-Modifying Therapy

The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.[137] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[138-140][Level of evidence A3] Zoledronate has been at least as effective as pamidronate.[141]

The optimal dosing schedule for zoledronate was studied in CALGB-70604 (Alliance; NCT00869206), which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks.[142] Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).[142][Level of evidence B1] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.

The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.[143]

For more information about bisphosphonates, see Cancer Pain.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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13. Huober J, Barrios CH, Niikura N, et al.: Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J Clin Oncol 40 (25): 2946-2956, 2022. [PMC free article: PMC9426828] [PubMed: 35763704]
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Introduction

Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to invasive cancer, but estimates of the probability of this vary widely. Some reports include DCIS in breast cancer statistics. In 2023, DCIS is expected to account for about 16% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.[1] For invasive and noninvasive tumors detected by screening, DCIS accounts for approximately 25% of all cases.

The frequency of a DCIS diagnosis has increased markedly in the United States since the use of screening mammography became widespread. Very few cases of DCIS present as a palpable mass, with more than 90% being diagnosed by mammography alone.[2]

DCIS comprises a heterogeneous group of histopathological lesions that have been classified into the following subtypes primarily because of architectural pattern:

• Micropapillary.
• Papillary.
• Solid.
• Cribriform.
• Comedo.

Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.[3]

Treatment Options for Patients With DCIS

Treatment options for DCIS include the following:

1. Breast-conserving surgery or mastectomy plus radiation therapy with or without tamoxifen.
2. Total mastectomy with or without tamoxifen.

In the past, the customary treatment for DCIS was mastectomy.[4] The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy after wide excision alone, and a 25% to 50% incidence of in-breast recurrence after limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[4,5] The combined local and distant recurrence rate after mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation therapy are available.

Because breast-conserving surgery combined with breast radiation therapy is successful for invasive carcinoma, this conservative approach was extended to DCIS. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins after excisional biopsy were randomly assigned to receive either breast radiation therapy (50 Gy) or no further therapy.[6-9]

Evidence (breast-conserving surgery plus radiation therapy to the breast):

1. Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or smaller. Results were reported at the 12-year actuarial follow-up interval.[7]; [9][Level of evidence B1]

   • The overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005).
   • Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).
   • Nine pathological features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
2. Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[9][Level of evidence B1]

   • The overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001), with a similarly effective reduction of invasive recurrence rates (13% to 8%, P = .065) and noninvasive recurrence rates (14% to 7%, P = .001).
   • In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[10]
   In both studies, the effect of radiation therapy was consistent across all assessed risk factors.
3. The benefit of administering radiation therapy has been confirmed in a systematic review of four randomized trials (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001). In this study, the number needed to treat with radiation therapy was nine women to prevent one ipsilateral breast recurrence.[11]
4. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 [NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins of 3 mm or more) were enrolled.[12]

   • With a median follow-up of 7 years, the ipsilateral local failure rate was low with observation (6.7%; 95% CI, 3.2%–9.6%) but was decreased significantly with the addition of radiation therapy (0.9%; 95% CI, 0.0%–2.2%).[12]

The results of the NSABP-B-17 and EORTC-10853 trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (HR, 0.49; 95% CI, 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[13][Level of evidence B1] After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.[11]

To identify a favorable group of patients for whom postoperative radiation therapy could be omitted, several pathological staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[14-17]

The Van Nuys Prognostic Index is one pathological staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathological classification). It was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[17] Using this prognostic index, patients with favorable lesions who received surgical excision alone had a low recurrence rate (i.e., 2%, with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control.[18] Patients whose excised lesions had margin widths of 10 mm or more in every direction had an extremely low probability of local recurrence with surgery alone (4%, with a mean follow-up of 8 years).

Both reviews are retrospective, noncontrolled, and subject to substantial selection bias. In contrast, the prospective NSABP trial did not identify any subset of patients who did not benefit from the addition of radiation therapy to breast-conserving surgery in the management of DCIS.[3,6,13,19]

To determine whether tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24).

Evidence (adjuvant endocrine therapy):

1. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 years).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or smaller, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.

   • Women in the tamoxifen group had fewer breast cancer events at 5 years than did those treated with a placebo (8.2% vs. 13.4%; P = .009).[20][Level of evidence B1]
   • With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03).
   • Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01).
   • The benefit of tamoxifen extended to patients with positive or uncertain margins.[21] For more information, see Breast Cancer Prevention.
   • No survival advantage was demonstrated for the use of tamoxifen.
2. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 y).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or smaller, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.

   • No survival advantage was demonstrated for the use of tamoxifen.
3. In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.

   • The use of anastrozole was associated with significantly fewer breast cancer events (HR, 0.73; P = .023) but no improvement in survival.[22][Level of evidence B1]
4. The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast-conserving surgery, and 71% of them had radiation therapy.[23]

   • No difference in the rate of breast cancer recurrence in favor of anastrozole was found (HR, 0.89; 95% CI, 0.64–1.23; P = .49), and there was no difference in survival.

The decision to prescribe endocrine therapy after a diagnosis of DCIS often involves a discussion with the patient about the potential benefits and side effects of each agent.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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