National Cancer Institute


Expert-reviewed information summary about the treatment of ductal carcinoma in situ, lobular carcinoma in situ, and invasive breast cancer.

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.

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).

Breast Cancer Treatment

General Information About Breast Cancer

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

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

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

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

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2016:

  • New cases: 246,660.
  • Deaths: 40,450.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 61,000 cases of disease, 246,660 cases of invasive disease, and 40,450 deaths expected in 2016. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 72,160 American women will die of lung cancer in 2016. 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 (DCIS). (Refer to the Ductal Carcinoma In Situ section in the Breast Cancer Diagnosis and Pathology section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States and the United Kingdom 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.

Anatomy

Drawing of female breast anatomy showing  the lymph nodes, nipple, areola, chest wall, ribs, muscle, fatty tissue, lobe, ducts, and lobules.Anatomy of the female breast. The nipple and areola are shown on the outside of the breast. The lymph nodes, lobes, lobules, ducts, and other parts of the inside of the breast are also shown.

Risk and Protective Factors

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

  • Family health history.
  • Major inheritance susceptibility.
    • Germline mutation of the genes and , and other breast cancer susceptibility genes.
  • Alcohol intake.
  • Breast tissue density (mammographic).
  • Estrogen (endogenous):
    • Menstrual history (early menarche/late menopause).
    • Nulliparity.
    • Older age at first birth.
  • Hormone therapy history:
    • Combination estrogen plus progestin hormone replacement therapy (HRT).
  • Obesity.
  • Personal history of breast cancer.
  • Personal history of proliferative forms of benign breast disease.
  • Race.
  • Radiation exposure to the breast/chest.

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

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes and . Specific mutations of and are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with and 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. Male mutation carriers also have an increased risk of breast cancer.

Mutations in either the or the gene also confer an increased risk of ovarian cancer or other primary cancers. Once a or mutation has been identified, other family members can be referred for genetic counseling and testing. (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 and interventions to reduce the risk of female breast cancer include the following:

  • Estrogen use (after hysterectomy).
  • Exercise.
  • Early pregnancy.
  • Breast feeding.
  • Selective estrogen receptor modulators (SERMs).
  • Aromatase inhibitors or inactivators.
  • Risk-reducing mastectomy.
  • Risk-reducing oophorectomy or ovarian ablation.

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

Screening

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

Diagnosis

Patient evaluation

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

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

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

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

Contralateral disease

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

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

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

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):

  • 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.

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

  • 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 hybridization.

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. Its prognostic utility primarily targets adjuvant therapy−decision making in women aged 61 years and younger with stage I/II lymph node–negative breast cancer 5 cm or smaller. The MINDACT trial (NCT00433589) will help determine if the assay should be used to decide whether adjuvant chemotherapy may benefit a patient.
  • Oncotype DX: The Oncotype DX 21 gene assay is the gene profile test with the most extensive clinical validation thus far, albeit in a prospective–retrospective fashion. A 21-gene recurrence score (RS) is generated based on the level of expression of each of the 21 genes:
    • RS <18: low risk.
    • RS ≥18 and <31: intermediate-risk.
    • RS ≥31: high risk.

The following trials describe the prognostic and predictive value of multigene assays:

Results from the trial (NCT01272037) 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 RS 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 and predispose women to develop breast cancer, prognostic data on / mutation carriers who have developed breast cancer are conflicting. These women are at greater risk of developing contralateral breast cancer. (Refer to the Prognosis of BRCA1- and BRCA2-related breast cancer section of the PDQ Genetics of Breast and Gynecologic Cancers summary for more information.)

Posttherapy Considerations

Hormone replacement therapy

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

  • Breast Cancer Prevention
  • Hot Flashes and Night Sweats

Related Summaries

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

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

Histopathologic Classification of Breast Cancer

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

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

  • Phyllodes tumor.
  • Angiosarcoma.
  • Primary lymphoma.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to the following:

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

Definitions of TNM and AJCC Stage Groupings

The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer. When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III. As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.

Early/Localized/Operable Breast Cancer

Treatment Option Overview for Early/Localized/Operable Breast Cancer

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

Surgery

Stage 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.

Locoregional treatment

Selection of a local therapeutic approach depends on the following:

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

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

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

Surgical staging of the axilla should also be performed.

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

The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated. However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:

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

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

Axillary lymph node management

Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%. Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[]

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.

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

Evidence (SLN biopsy):

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

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

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

Breast reconstruction

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

  • Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA's website] for more information on breast implants.)
  • Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

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

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.

Post–breast-conserving surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women. Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death. Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

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

With regard to radiation dosing and schedule, the following has been noted:

  • Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.
  • Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years ( = .044),[] and from 7.3% to 4.3% at 5 years ( < .001).[] Results were similar after a median follow-up of 17.2 years.[] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.
  • Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.
    • A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule. The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).[
    • Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.[]

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

Regional nodal irradiation

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

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

Postmastectomy

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

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

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

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

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

Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.

Timing of postoperative radiation therapy

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

Evidence (timing of postoperative radiation therapy):

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

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

Late toxic effects of radiation

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

  • Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months. The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[]
  • Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer. This was probably caused by the radiation received by the left myocardium.

    Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.

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

  • Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy. (Refer to the PDQ summary on Lymphedema for more information.)
  • Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were monitored for 5.5 years to assess the rate of brachial plexus injury. The diagnosis of such injury was made clinically with computerized tomography (CT) to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.
  • Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy. No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy. Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.
  • Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years. In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.

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. This classification, with some modification, is described below:

The selection of therapy is most appropriately based upon 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 particular situation. The treatment options described below should be modified based upon both patient and tumor characteristics.

Chemotherapy

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

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

Evidence (anthracycline-based regimens):

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

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

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

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

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

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

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

Chemotherapy schedule: Dose-density

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

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

Docetaxel and cyclophosphamide

Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):

Timing of postoperative chemotherapy

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

Toxic effects of chemotherapy

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

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

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

  • Heart failure (if an anthracycline is used).
  • Thromboembolic events.
  • Premature menopause.
  • Second malignancy (leukemia).

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

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

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

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer. This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.

HER2/neu-negative breast cancer

For HER2/neu-negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.

Triple-negative breast cancer (TNBC)

TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Combination chemotherapy

Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.

Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):

Platinum agents

Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[] A randomized clinical trial, (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.

Poly (ADP-ribose) polymerase (PARP) inhibitor agents

The PARP inhibitors are being evaluated in clinical trials for patients with mutations and in TNBC. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with -mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.

HER2/neu-positive breast cancer

Treatment options for HER2-positive early breast cancer:

Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.

Trastuzumab

Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.

Evidence (duration of trastuzumab therapy):

A number of studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.

Cardiac toxic effects with adjuvant trastuzumab

Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:

  • In the HERA () trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab. Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.
  • In the (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm. The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).
  • In the trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).
  • In the (BCIRG 006) (NCT00021255) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm. There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.
  • In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.

Lapatinib

Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu-positive breast cancer.

Evidence (against the use of lapatinib for HER2 positive early breast cancer):

Hormone receptor–positive breast cancer

Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients.

Tamoxifen

Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

Evidence (tamoxifen for hormone receptor–positive early breast cancer):

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials. Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.

Evidence (duration of tamoxifen therapy):

Tamoxifen and chemotherapy

Based on the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy. However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies. Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.

Evidence (tamoxifen plus ovarian suppression):

Aromatase inhibitors (AI)

Premenopausal women

AI have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Evidence (comparison of an AI with tamoxifen in premenopausal women):

Postmenopausal women

In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.

Initial therapy

Evidence (AI vs. tamoxifen as initial therapy in postmenopausal women):

Sequential tamoxifen and AI versus 5 years of tamoxifen

Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen. The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.

Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):

In the meta-analysis, which included 11,798 patients from six trials, the 10-year recurrence rate was reduced from 19% to 17% in the AI-containing groups (RR, 0.82; 95% CI, 0.75–0.91; = .0001). The overall 10-year mortality was 17.5% in the tamoxifen group and 14.6% in the AI-containing group (RR, 0.82; 95% CI, 0.73–0.91; = .0002).[]

Sequential tamoxifen and AI for 5 years versus 5 years of an AI

The evidence indicates that there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.

Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):

In the meta-analysis, which included 12,779 patients from the trials, the 7-year recurrence rate was slightly reduced from 14.5% to 13.8% in the groups that received 5 years of an AI (RR, 0.90; 95% CI, 0.81–0.99; = .045). Overall mortality at 7 years was 9.3% in the tamoxifen-followed-by-AI groups and 8.2% in the AI-alone groups (RR, 0.89; 95% CI, 0.78–1.03; = .11).[]

One AI versus another for 5 years

Switching to an AI after 5 years of tamoxifen

The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.

Duration of AI therapy

Evidence (additional 5 years of letrozole vs. placebo):

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.

Evidence (bisphosphonates in the treatment of early breast cancer):

An ongoing phase III trial () is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.

Preoperative Systemic Therapy

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer in an attempt 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.[] 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).[]

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 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). pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.[] However, on the basis 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.

Patient selection, staging, treatment, and follow-up

Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

  • Patient selection.
  • Choice of systemic therapy.
  • Management of the axilla and surgical approach.
  • Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone–receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:

  • CT scan of the chest and abdomen and a bone scan.
  • Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.

The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:

  • If suspicious nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.[]; []; [] Alternatively, it is acceptable in this circumstance to perform ALND, based on the possibility of undetected positive nodes.
  • In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy. If the SLN biopsy is negative, ALND can be omitted.
  • If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.

When considering preoperative therapy, treatment options include the following:

  • For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.
  • For HER2-positive disease, chemotherapy and HER2-targeted therapy.
  • Ideally, the entire treatment regimen is administered before surgery.
  • For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.
  • For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.

Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible. Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

HER2/neu-negative breast cancer

Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Evidence (preoperative anthracycline-based regimen):

In an effort to improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.

Evidence (anthracycline/taxane-based chemotherapy regimen):

Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Evidence (adding carboplatin to an anthracycline-taxane based chemotherapy regimen in patients with TNBC):

Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., [NCT00408408] and [NCT00567554]).[] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.

HER2/neu-positive breast cancer

After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline- and taxane-based regimens.[] This has been confirmed in phase III studies.

Trastuzumab

Evidence (trastuzumab):

A phase III ( [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to preoperative chemotherapy (anthracycline/taxane-based), concurrent with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.

An ongoing trial, (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.

Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials in an attempt to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):

On the basis of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive. The FDA approved no more than three to six cycles of pertuzumab. Thus, a pertuzumab-based regimen as outlined above is a new treatment option for patients with HER2-positive breast cancer who are candidates for preoperative therapy. There is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.

The ongoing (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval. Results are expected in 2016.

Lapatinib

Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Evidence (lapatinib):

More definitive efficacy data were provided by the phase III ALLTO () trial that randomly assigned women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting. The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.

Cardiac toxic effects with pertuzumab and lapatinib

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[]

  • Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a nonanthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5).
  • Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[]

  • LVEF decline was observed in 3.1% of the patients who received monotherapy (95% CI, 2.2%–4.4%) and 2.9% of the patients who received dual therapy (95% CI, 2.1%–4.1%).
  • Symptomatic heart failure was observed in 0.88% of the patients who received monotherapy (95% CI, 0.47%–1.64%) and 1.49% of the patients who received dual therapy (95% CI, 0.98%–2.23%).

Preoperative endocrine therapy

Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor–positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[]

Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients. A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, -value for trend < .04).[]

The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women or comparable to tamoxifen-associated outcomes. An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy

There is currently no clear role for adjuvant chemotherapy in cases in which pCR is not obtained after receipt of an anthracycline/taxane combination chemotherapy regimen. Clinical trials of novel therapies should be considered in these individuals (after neoadjuvant or preoperative trials).

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor–positive disease and adjuvant trastuzumab for those with HER2-positive disease. (Refer to the Hormone receptor–positive breast cancer subsection in the Early/Localized/Operable Breast Cancer section of this summary for more information.)

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. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage IIIC breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

Based on 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:

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.

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. 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):

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

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

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer and inflammatory breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Locoregional Recurrent Breast Cancer

Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.

The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy. The rates are somewhat higher (up to 10%) for those treated with mastectomy. Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.

Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.

ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence. Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.

Treatment options for locoregional recurrent breast cancer include the following:

Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.

Treatment options also depend on the site of recurrence, as follows:

  • Cutaneous: A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[]
  • Chest wall: Local chest wall recurrence after mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative. Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater-than-2-year disease-free interval before recurrence have the best chance for prolonged survival. The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%. The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.
  • Breast: In the CALOR trial (NCT00074152), patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[]
    • Five-year DFS was 69% in the chemotherapy arm versus 57% in the no-chemotherapy arm (HR, 0.59; 95% confidence interval, 0.35–0.99; = .046), with most benefit seen in the subgroup with hormone receptor–negative disease.
    • This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer.

Refer to the Metastatic (systemic) disease section of this summary for information about treatment for recurrent metastatic breast cancer. All patients with recurrent breast cancer are considered candidates for ongoing clinical trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Metastatic Breast Cancer

Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months, some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[]

Treatment options for metastatic breast cancer include the following:

Cytologic or histologic documentation of metastatic disease is obtained whenever possible.

Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Hormone Receptor–Positive or Hormone Receptor–Unknown Breast Cancer

Tamoxifen and aromatase inhibitor (AI) therapy

Initial hormone therapy

Initial hormone therapy depends, in part, on the patient's menopausal status.

For postmenopausal patients with newly diagnosed metastatic disease and estrogen receptor (ER)–positive tumors, progesterone receptor (PR)–positive tumors, or ER/PR-unknown tumors, hormone therapy is generally used as initial treatment. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient either has not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year.

While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER-positive, PR-positive, or ER/PR-unknown, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the AI compared with tamoxifen.[]

Evidence (initial hormone therapy in postmenopausal women):

Another initial treatment option for postmenopausal women is AI therapy combined with cyclin-dependent kinase inhibitor therapy (refer to the Cyclin-dependent kinase inhibitor therapy section of this summary for more information).

In premenopausal women, several randomized but underpowered trials have tried to determine whether combined hormone therapy (luteinizing hormone–releasing hormone [LH-RH] agonists plus tamoxifen) is superior to either approach alone. Results have been inconsistent.

Evidence (initial hormone therapy in premenopausal women):

Second-line hormone therapy

Women whose tumors are ER-positive or ER-unknown, with bone or soft tissue metastases only, and who have been treated with tamoxifen, may be offered second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AI, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens; and fulvestrant, an ER down-regulator.

Evidence (second-line hormone therapy):

Mammalian target of rapamycin (mTOR) inhibitor therapy

Endocrine therapy is recommended for patients with metastatic hormone receptor–positive disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mTOR inhibitors might enhance the efficacy of endocrine therapies.

Evidence (mTOR inhibitor therapy):

Cyclin-dependent kinase inhibitor therapy

Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in the first-line setting. Palbociclib is an orally available CDK4/6 inhibitor that has been shown in two trials to enhance the efficacy of endocrine therapy.

Evidence (cyclin-dependent kinase inhibitor therapy):

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. A number of HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab

Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[]

Evidence (trastuzumab):

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.

Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.

  • In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone.[]
  • However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial ( [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.[]

Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.

Evidence (pertuzumab):

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.

Evidence (T-DM1):

Tyrosine kinase inhibitor therapy

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.

Evidence (lapatinib):

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.

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

  • Anthracyclines.
    • Doxorubicin.
    • Epirubicin.
    • Liposomal doxorubicin.
    • Mitoxantrone.
  • Taxanes.
    • Paclitaxel.
    • Docetaxel.
    • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).
  • Alkylating agents.
    • Cyclophosphamide.
  • Fluoropyrimidines.
    • Capecitabine.
    • 5-Fluorouracil (5-FU).
  • Antimetabolites.
    • Methotrexate.
  • Vinca alkaloids.
    • Vinorelbine.
    • Vinblastine.
    • Vincristine.
  • Platinum.
    • Carboplatin.
    • Cisplatin.
  • Other.
    • Gemcitabine.
    • Mitomycin C.
    • Eribulin mesylate.
    • Ixabepilone.

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

  • AC: Doxorubicin and cyclophosphamide.
  • EC: Epirubicin and cyclophosphamide.
  • Docetaxel and doxorubicin.
  • CAF: Cyclophosphamide, doxorubicin, and 5-FU.
  • CMF: Cyclophosphamide, methotrexate, and 5-FU.
  • Doxorubicin and paclitaxel.
  • Docetaxel and capecitabine.
  • Vinorelbine and epirubicin.
  • Capecitabine and ixabepilone.
  • Carboplatin and gemcitabine.
  • Gemcitabine and paclitaxel.

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. Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[];

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.

At this time, 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. 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.[]

Decisions regarding the duration of chemotherapy may take into account 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.[] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies, 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 or a different chemotherapy regimen given at higher versus lower doses.[] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy versus 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.[] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Cardiac toxic effects with anthracyclines

The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:

  • Advanced age.
  • Previous chest-wall radiation therapy.
  • Previous anthracycline exposure.
  • Hypertension and known underlying heart disease.
  • Diabetes.

The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin. The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion. The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m or more when further treatment with an anthracycline is likely to be of benefit. Dexrazoxane has a similar protective effect in patients receiving epirubicin.

High-dose Chemotherapy With Stem Cell Support

Studies comparing high-dose chemotherapy with stem cell support versus conventional chemotherapy in patients with metastatic disease indicate no OS or relapse-free survival benefit for patients receiving high-dose chemotherapy with stem cell support.[] Because of the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this should be considered only as part of a clinical trial.

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. 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 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.

Bone Modifier Therapy

The use of bone modifier therapy to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[] Zoledronate has been at least as effective as pamidronate.

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

(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):

In November 2011, on the basis 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with metastatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Ductal Carcinoma In Situ

Introduction

Ductal carcinoma (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. 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.

DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily on the basis 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.

Treatment Options for Patients With DCIS

Treatment options for DCIS include the following:

In the past, the customary treatment for DCIS was mastectomy. 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. 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 either breast radiation therapy (50 Gy) or no further therapy.

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

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; < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; = .03).[] 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.

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.

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. 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. 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.

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):

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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Changes to This Summary (10/21/2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Early/Localized/Operable Breast Cancer

Added text to state that a European Organization for Research and Treatment of Cancer trial reported that women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Statistical data about the study population and the varying overall and disease-free survival outcomes per random assignment were included (cited Poortmans et al. as reference 51 and level of evidence 1iiA).

Revised text to state that in two unblinded studies, TEXT and SOFT, exemestane was also compared with tamoxifen in 4,690 premenopausal women who underwent ovarian ablation (cited level of evidence 1iDii). Added statistics to support that there was no difference in overall survival and cited level of evidence 1iiA. Also added observations from a follow-up report on the differences in quality-of-life for the exemestane-ovarian suppression group versus the tamoxifen-ovarian suppression group, noting that the differences were all significant at <.001 and occurred in patients who did and did not receive chemotherapy (cited Bernhard et al. as reference 140 and level of evidence 1iC).

Metastatic Breast Cancer

Added text to include CDK4/6 inhibitors to the targeted therapies that are treatment options for metastatic breast cancer.

Revised text to state that in the final analysis of the Paloma3 trial, a median progression-free survival of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm was shown (cited Cristofanilli et al. as reference 34 and level of evidence 1iC). Also revised the statistic about uncommon febrile neurtopenia that was found in both groups. Added that tumor PIK3CA mutational status did not significantly affect the magnitude of benefit associated with fulvestrant plus palbociclib.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Breast Cancer Treatment are:

  • Roisin Connolly, MB, BCh (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins)
  • Beverly Moy, MD, MPH (Massachusetts General Hospital)
  • Joseph L. Pater, MD (NCIC-Clinical Trials Group)

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

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

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.


A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
X
Y
Z
#
 
A
B
C
E
F
G
H
K
L
M
N
O
P
R
S
T
U
V
 
 
Manténgase informado con las últimas informaciones de OncoLink!   Suscribirse a OncoLink eNews
Ver nuestros archivos de boletines