Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2018:[1]

• New cases: 268,670.
• Deaths: 41,400.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 63,960 cases of in situ disease and 266,120 cases of invasive disease in 2018.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 70,500 American women will die of lung cancer in 2018.[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

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] (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Breast Cancer Prevention; and Breast Cancer Screening for more information.)

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

Protective Factors

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

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

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

Screening

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

Diagnosis

Prognostic and Predictive Factors

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

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

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

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

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

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

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

Gene profile tests include the following:

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

  -

  Recurrence score <18: low risk.

  -

  Recurrence score ≥18 and <31: intermediate-risk.

  -

  Recurrence score ≥31: high risk.

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

1. The prognostic ability of the Oncotype DX 21-gene assay was assessed in two randomized trials.

   • The National Surgical Adjuvant Breast and Bowel Project (NSABP B-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 nodenegative-, ER-positive breast cancer was initially assessed in a prospective-retrospective way using the tamoxifen alone (n = 227) and the combination arms (n = 424) of the NSABP B-20 trial.[72] Patients in the NSABP B-20 trial were randomly assigned to receive tamoxifen alone or tamoxifen concurrently with methotrexate and 5-fluorouracil (MF) or cyclophosphamide with MF (CMF).[75]

   • The 10-year distant disease-free survival (DFS) improved from 60% to 88% by adding chemotherapy to tamoxifen in the high-risk group, while no benefit was observed in the low recurrence score group.[76]
3. Similar findings were reported in the prospective-retrospective evaluation of the Southwestern Oncology Group (SWOG-8814 [NCT00929591]) trial in hormone receptor–positive lymph node-positive postmenopausal patients treated with tamoxifen with or without cyclophosphamide, doxorubicin, and fluorouracil.[77] However, the sample size in this analysis was small, follow-up was only 5 years, and the prognostic impact of having positive nodes needs to be taken into consideration.

   • Of note, both analyses (NSABP B-20 and S8814) were underpowered for any conclusive predictive analysis among patients identified as having an intermediate recurrence score.
4. Results from the prospective, randomized TAILORx (NCT00310180) trial indicate that chemotherapy is unlikely to provide substantial benefit to patients older than 50 years with ER-PR–positive and node-negative disease and a recurrence score of 11 to 25.[78] In this study, a low-risk score was defined as less than 11, an intermediate score was 11 to 25, and a high-risk score was greater than 25. These cut points differ from those described above.
   Patients in this study with a low-risk score were found to have very low rates of recurrence at 5 years with endocrine therapy.[79]

   • Rate of invasive DFS was 93.8% at 5 years and 84.0% at 9 years.
   • Rate of freedom from recurrence of breast cancer at a distant site was 99.3% at 5 years and 96.8% at 9 years.
   • Rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% at 5 years and 95.0% at 9 years.
   • Rate of overall survival (OS) was 98.0% at 5 years and 93.7% at 9 years.
   In the middle-risk group in the TAILORx study (recurrence score, 11–25), 6,907 women were randomly assigned to endocrine therapy alone or endocrine therapy plus chemotherapy.[78] Of these, 3,399 women on the endocrine therapy-alone arm and 3,312 women on the endocrine therapy-plus-chemotherapy arm were available for an analysis because the treatments were randomly assigned. After a median follow-up of 90 months, the difference in invasive DFS, the main study endpoint, met the prespecified noninferiority criterion (P > .10 for a test of no difference after 835 events had occurred) suggesting the noninferiority of endocrine therapy compared with endocrine therapy plus chemotherapy.

   • In this population, the 9-year invasive DFS was 83.3% for endocrine therapy alone and 84.3% for endocrine therapy plus chemotherapy (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.94–1.24; P = .26).[78][Level of evidence: 1iiD]
   • One hundred eighty-five patients in the endocrine-only arm received chemotherapy, and 608 patients in the endocrine therapy-plus-chemotherapy arm did not receive their assigned chemotherapy. In an analysis based on the actual treatment received, the HR for invasive DFS was 1.14 (95% CI, 0.99–1.31; P =.06).
   • Outcomes for the other endpoints examined (freedom of distant breast cancer recurrence, freedom from local and distant recurrence, and OS) were similar between the two treatment arms and none were significant at P < 0.10.
   • There was a significant interaction between treatment assignment and age (P = .03) with respect to invasive DFS, suggesting that chemotherapy might be beneficial in women younger than 50 years with recurrence scores ranging from 11 to 25.
5. The MINDACT (NCT00433589) trial tested whether adding MammaPrint genomic risk to a clinical-risk classification (modified from Adjuvant! Online) might guide more appropriate choices of chemotherapy in women with node negative- or 1-to-3 node-positive disease.[80][Level of evidence: 3iiiDii] Unlike the TAILORx study, which only had hormone receptor–positive patients, this trial included hormone receptor–negative patients. In this prospective study, women with both genomic and clinical high-risk classification received chemotherapy, while those with both genomic and clinical low-risk classification did not receive chemotherapy. Participants with discordant results (clinical high-risk- with genomic low-risk classification, or clinical low-risk- with genomic high-risk classification) were randomly assigned to receive or not receive chemotherapy. A total of 1,550 women with high clinical risk and low genomic risk, and 592 women with low clinical risk and high genomic risk, were randomly assigned to receive or not receive chemotherapy. The primary goal of the study was to determine whether patients with high clinical risk, but low genomic risk, who did not receive chemotherapy had a 5-year survival rate without distant metastases (primary study endpoint) of 92% or lower (a noninferiority design).

   • This endpoint was met because the observed rate in the group was 94.7% (95% CI, 92.5%–96.2%). However, among patients with high clinical risk but low genomic risk, the rate of 5-year survival without distant metastases was 1.5% higher in the arm that did receive chemotherapy than in the arm that did not receive chemotherapy, although the study was not powered to detect a difference between these arms (HR chemotherapy vs. no chemotherapy, 0.78; 95% CI, 0.50–1.21; P = .27)
   • Patients in the low clinical risk group with high genomic risk did well, and there was little evidence of benefit from chemotherapy in this group (5-year survival without distant metastases, 95.8% with chemotherapy vs. 95.0% without; HR, 1.17; 95% CI, 0.59–2.28; P = .66).

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

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

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

Posttherapy Considerations

Related Summaries

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

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

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70. Ishitobi M, Goranova TE, Komoike Y, et al.: Clinical utility of the 70-gene MammaPrint profile in a Japanese population. Jpn J Clin Oncol 40 (6): 508-12, 2010. [PubMed: 20110242]
71. Knauer M, Mook S, Rutgers EJ, et al.: The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 120 (3): 655-61, 2010. [PubMed: 20204499]
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]
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. [PMC free article: PMC1557737] [PubMed: 16737553]
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. [PMC free article: PMC2849763] [PubMed: 20065188]
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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. [PMC free article: PMC1234890] [PubMed: 7574934]
3. Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000. [PubMed: 11013364]
4. Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004. [PubMed: 15343504]

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. (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

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. New York, NY: Springer, 2017, pp. 589–628.
4. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31 (31): 3997-4013, 2013. [PubMed: 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

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.[1-5]

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]

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:

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.

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. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple, randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[172][Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[173,174][Level of evidence: 1iiDiv]

A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains.

pCR has been utilized as a surrogate endpoint 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).[175] pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.[175][Level of evidence: 3iiiD] 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 endpoint in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.

Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.

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.[211-213] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[212] 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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172. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97 (3): 188-94, 2005. [PubMed: 15687361]
173. Bear HD, Anderson S, Brown A, et al.: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21 (22): 4165-74, 2003. [PubMed: 14559892]
174. Smith IE, Dowsett M, Ebbs SR, et al.: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23 (22): 5108-16, 2005. [PubMed: 15998903]
175. Cortazar P, Zhang L, Untch M, et al.: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384 (9938): 164-72, 2014. [PubMed: 24529560]
176. Carlson RW, Allred DC, Anderson BO, et al.: Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 7 (2): 122-92, 2009. [PubMed: 19200416]
177. Boughey JC, Suman VJ, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA 310 (14): 1455-61, 2013. [PMC free article: PMC4075763] [PubMed: 24101169]
178. Kuehn T, Bauerfeind I, Fehm T, et al.: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 14 (7): 609-18, 2013. [PubMed: 23683750]
179. Alvarado R, Yi M, Le-Petross H, et al.: The role for sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with node-positive breast cancer. Ann Surg Oncol 19 (10): 3177-84, 2012. [PubMed: 22772869]
180. Lyman GH, Temin S, Edge SB, et al.: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32 (13): 1365-83, 2014. [PubMed: 24663048]
181. Smith IC, Heys SD, Hutcheon AW, et al.: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20 (6): 1456-66, 2002. [PubMed: 11896092]
182. von Minckwitz G, Kümmel S, Vogel P, et al.: Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 100 (8): 552-62, 2008. [PubMed: 18398094]
183. Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998. [PubMed: 9704717]
184. Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002. [PubMed: 12209710]
185. Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008. [PubMed: 18258986]
186. van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001. [PubMed: 11709566]
187. Vriens BE, Aarts MJ, de Vries B, et al.: Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer 49 (15): 3102-10, 2013. [PubMed: 23850450]
188. Untch M, Jackisch C, Schneeweiss A, et al.: Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17 (3): 345-56, 2016. [PubMed: 26869049]
189. von Minckwitz G, Rezai M, Loibl S, et al.: Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28 (12): 2015-23, 2010. [PubMed: 20308671]
190. von Minckwitz G, Schneeweiss A, Loibl S, et al.: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15 (7): 747-56, 2014. [PubMed: 24794243]
191. Sikov WM, Berry DA, Perou CM, et al.: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33 (1): 13-21, 2015. [PMC free article: PMC4268249] [PubMed: 25092775]
192. Rastogi P, Buyse ME, Swain SM, et al.: Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. Clin Breast Cancer 11 (4): 228-34, 2011. [PubMed: 21684812]
193. Untch M, Loibl S, Bischoff J, et al.: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13 (2): 135-44, 2012. [PubMed: 22257523]
194. Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005. [PubMed: 15738535]
195. Untch M, Rezai M, Loibl S, et al.: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28 (12): 2024-31, 2010. [PubMed: 20308670]
196. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010. [PubMed: 20113825]
197. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15 (6): 640-7, 2014. [PubMed: 24657003]
198. Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013. [PMC free article: PMC4176878] [PubMed: 24239210]
199. Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012. [PubMed: 22884505]
200. Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012. [PubMed: 22153890]
201. Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012. [PMC free article: PMC5705192] [PubMed: 22257673]
202. Gianni L, Pienkowski T, Im YH, et al.: 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17 (6): 791-800, 2016. [PubMed: 27179402]
203. Schneeweiss A, Chia S, Hickish T, et al.: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24 (9): 2278-84, 2013. [PubMed: 23704196]
204. Carey LA, Berry DA, Cirrincione CT, et al.: Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 34 (6): 542-9, 2016. [PMC free article: PMC4980567] [PubMed: 26527775]
205. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15 (10): 1137-46, 2014. [PubMed: 25130998]
206. Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012. [PMC free article: PMC3331733] [PubMed: 21665955]
207. Valachis A, Nearchou A, Polyzos NP, et al.: Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer 133 (9): 2245-52, 2013. [PubMed: 23629633]
208. Eiermann W, Paepke S, Appfelstaedt J, et al.: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12 (11): 1527-32, 2001. [PubMed: 11822750]
209. Preece PE, Wood RA, Mackie CR, et al.: Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 284 (6319): 869-70, 1982. [PMC free article: PMC1496321] [PubMed: 6802332]
210. Masuda N, Lee SJ, Ohtani S, et al.: Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 376 (22): 2147-2159, 2017. [PubMed: 28564564]
211. Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994. [PubMed: 8182811]
212. Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994. [PubMed: 7848404]
213. Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006. [PubMed: 17033037]

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.

The standard 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 (refer to the Postoperative Systemic Therapy section of this summary for more information), although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy.[1]

For patients who 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 who 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: 3iiiDii]

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 or Hormone Receptor-Unknown Breast Cancer

Hormone Receptor-Negative Breast Cancer

The treatment for hormone receptor-negative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)

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, ado-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 (adenosine diphosphate-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.

Chemotherapy

Patients on 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.[59]

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

• Anthracyclines.

  -

  Doxorubicin.

  -

  Epirubicin.

  -

  Liposomal doxorubicin.[60-63]

  -

  Mitoxantrone.

• Taxanes.

  -

  Paclitaxel.[64,65]

  -

  Docetaxel.

  -

  Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[66,67]

• Alkylating agents.

  -

  Cyclophosphamide.

• Fluoropyrimidines.

  -

  Capecitabine.[68-70]

  -

  5-Fluorouracil (5-FU).

• Antimetabolites.

  -

  Methotrexate.

• Vinca alkaloids.

  -

  Vinorelbine.[71]

  -

  Vinblastine.

  -

  Vincristine.

• Platinum.

  -

  Carboplatin.

  -

  Cisplatin.

• Other.

  -

  Gemcitabine.[72]

  -

  Mitomycin C.

  -

  Eribulin mesylate.[73,74]

  -

  Ixabepilone.[75]

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

• AC: Doxorubicin and cyclophosphamide.[76]
• EC: Epirubicin and cyclophosphamide.[77]
• Docetaxel and doxorubicin.[78]
• CAF: Cyclophosphamide, doxorubicin, and 5-FU.[79]
• CMF: Cyclophosphamide, methotrexate, and 5-FU.[80]
• Doxorubicin and paclitaxel.[81,82]
• Docetaxel and capecitabine.[83]
• Vinorelbine and epirubicin.[84]
• Capecitabine and ixabepilone.[85]
• Carboplatin and gemcitabine.[86]
• Gemcitabine and paclitaxel.[87]

There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An Eastern Cooperative Oncology intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially.[88] Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[88][Level of evidence: 1iiA]; [89,90]

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.

Currently, no data support the superiority of any particular regimen. 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.[1,91] 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.[92][Level of evidence: 1iiA]

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.[93,94][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies,[94] 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 [95] or a different chemotherapy regimen given at higher versus lower doses.[96][Level of evidence: 1iiA] 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.[97][Level of evidence: 1iiA] 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.
• Pathologic (or impending) fractures.
• Pleural or pericardial effusions.

(Refer to the PDQ summary on Cancer Pain for more information; refer to the PDQ summary on Cardiopulmonary Syndromes for information about pleural and pericardial effusions.)

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases.[105] 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 pathologic fractures.

Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[106,107]

Bone Modifier Therapy

The use of bone modifier therapy to reduce skeletal morbidity in patients with bone metastases should be considered.[108] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[109-111][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[112]

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.[113] 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).[113][Level of evidence: 1iiD] 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.[114]

(Refer to the PDQ summary on Cancer Pain for more information on bisphosphonates.)

Bevacizumab

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor–A. Its role in the treatment of metastatic breast cancer remains controversial.

Evidence (bevacizumab for metastatic breast cancer):

1. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[115] The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.[115][Level of evidence: 1iiA]

   -

   The study failed to demonstrate a statistically significant effect on PFS (4.9 months with combination therapy vs. 4.2 months with capecitabine alone; HR, 0.98) or OS (15.1 months vs. 14.5 months).[115][Level of Evidence: 1iiA]

2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.[116][Level of evidence: 1iiA]

   • The trial demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P < .001).[116][Level of Evidence: 1iiA]
   • The addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months; P = .16).
   • Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.
3. The AVADO (NCT00333775) trial randomly assigned 736 patients to receive docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer.[117][Level of evidence: 1iiA]

   -

   The combination of docetaxel plus bevacizumab at 15 mg/kg, but not 7.5 mg/kg, modestly improved median PFS compared with placebo (10.1 mo vs. 8.1 mo) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[117][Level of Evidence: 1iiA]

   -

   More toxicity was seen in patients in the bevacizumab-containing arms, with significantly higher rates of bleeding and hypertension compared with patients in the placebo arms.

4. The RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[118][Level of evidence: 1iiA]

   -

   Median PFS was longer for each bevacizumab-containing combination (capecitabine cohort: increased from 5.7 months to 8.6 months; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and taxane-anthracycline cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[118][Level of Evidence: 1iiA]

   -

   No statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed.

   -

   Toxicities associated with bevacizumab were similar to those seen in previous bevacizumab clinical trials.

5. The RIBBON 2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[119][Level of evidence: 1iA]

   -

   Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64–0.93; P = .0072).

   -

   However, no statistically significant difference in OS was seen (16.4 months for chemotherapy plus placebo vs. 18.0 months for chemotherapy plus bevacizumab, P = .3741).[119][Level of evidence: 1iA]

   -

   Toxicities associated with bevacizumab were similar to those seen in previous clinical trials.

In November 2011, because of the consistent finding that bevacizumab improved PFS only modestly but did not improve OS, and given bevacizumab’s considerable toxicity profile, the FDA revoked approval of bevacizumab for the treatment of metastatic breast cancer.

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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102. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989. [PubMed: 2910423]
103. Hensley ML, Hagerty KL, Kewalramani T, et al.: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27 (1): 127-45, 2009. [PubMed: 19018081]
104. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996. [PubMed: 8955656]
105. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005. [PubMed: 15928300]
106. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993. [PubMed: 8478230]
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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 2015, 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 histopathologic 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: 1iiDii]

   • 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 pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
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: 1iiDii]

   • 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: 1iiD] 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 pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[14-17]

The Van Nuys Prognostic Index is one pathologic staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic 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, 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: 1iDii]
   • With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03).
   • Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01).
   • The benefit of tamoxifen extended to patients with positive or uncertain margins.[21] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
   • 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, 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: 1iDi]
4. The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) trial 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

1. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed September 21, 2018.
2. Siegel R, Ward E, Brawley O, et al.: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61 (4): 212-36, 2011 Jul-Aug. [PubMed: 21685461]
3. Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999. [PubMed: 10430251]
4. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997. [PubMed: 9412283]
5. Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982. [PubMed: 6286091]
6. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998. [PubMed: 9469327]
7. Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001. [PubMed: 11498833]
8. Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000. [PubMed: 10683002]
9. Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006. [PubMed: 16801628]
10. Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001. [PubMed: 11148554]
11. Correa C, McGale P, Taylor C, et al.: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010 (41): 162-77, 2010. [PMC free article: PMC5161078] [PubMed: 20956824]
12. McCormick B, Winter K, Hudis C, et al.: RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33 (7): 709-15, 2015. [PMC free article: PMC4334775] [PubMed: 25605856]
13. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev 11: CD000563, 2013. [PubMed: 24259251]
14. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995. [PubMed: 7882273]
15. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75 (6): 1223-1227, 1995.
16. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994. [PubMed: 7831528]
17. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996. [PubMed: 8635094]
18. Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999. [PubMed: 10320383]
19. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009. [PubMed: 19447038]
20. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999. [PubMed: 10376613]
21. Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003. [PubMed: 12867108]
22. Margolese RG, Cecchini RS, Julian TB, et al.: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 387 (10021): 849-56, 2016. [PMC free article: PMC4792688] [PubMed: 26686957]
23. Forbes JF, Sestak I, Howell A, et al.: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet 387 (10021): 866-73, 2016. [PMC free article: PMC4769326] [PubMed: 26686313]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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• be discussed at a meeting,
• be cited with text, or
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The lead reviewers for Breast Cancer Treatment are:

• Joseph L. Pater, MD (NCIC-Clinical Trials Group)
• Karen L. Smith, MD, MPH ( )

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389406]

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