National Cancer Institute
Posted Date: Jan 26, 2016
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:
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:
Incidence and Mortality
Estimated new cases and deaths from breast cancer (women only) in the United States in 2015:
- New cases: 231,840.
- Deaths: 40,290.
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 60,290 cases of in situ disease, 231,840 new cases of invasive disease, and 40,290 deaths expected in 2015. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,660 American women will die of lung cancer in 2015. Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).
Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal Carcinoma In Situ 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 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 BRCA1 and BRCA2, 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).
- Personal history of breast cancer.
- Personal history of proliferative forms of benign breast disease.
- 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 BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year. Male BRCA2 mutation carriers also have an increased risk of breast cancer.
Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer or other primary cancers. Once a BRCA1 or BRCA2 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).
- 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.)
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.)
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:
- Breast magnetic resonance imaging (MRI), if clinically indicated.
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 BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.
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.
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):
- The menopausal status of the patient.
- The stage of the disease.
- The grade of the primary tumor.
- The estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.
- Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or amplification.
- The histologic type. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. For example, 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 these results, breast cancer is classified as:
- Hormone-receptor positive.
- HER2 positive.
- Triple negative (ER, PR, and Her2/neu negative).
Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting; these women are at greater risk of developing contralateral breast cancer.
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
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:
Table 1. Tumor Location and Related Histologic Subtype
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:
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:
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.
Selection of a local therapeutic approach depends on the following:
- Location and size of the lesion.
- Analysis of the mammogram.
- Breast size.
- Patientâs 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 in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.
- More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.
- There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.
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%.[Level of evidence: 3iiiA]
The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-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 6â10), while reducing morbidity from the procedure.
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.
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 nodeânegative 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 (P = .044),[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).[Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.
- 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, â2.5 to 3.5).[Level of evidence: 1iiDiiSimilarly, 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 (pT1â3a, pN0â1, 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.[Level of evidence: 1iiDii] Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.
- 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, â2.5 to 3.5).[Level of evidence: 1iiDii
- Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1â3a, pN0â1, 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.[Level of evidence: 1iiDii]
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.
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.[Level of evidence: 1iiA]
In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu-positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab. 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 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.[Level of evidence: 3iii]
- Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer. 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 Instituteâs Surveillance, Epidemiology, and End Results Program 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.[Level of evidence: 3iB]
- Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy. (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)âpositive 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 individualâs 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.
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, 0.68â0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72â0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78â0.91), which translated into an absolute survival gain of 5%.
Treatment options for HER2-positive early breast cancer:
Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.
Much of the evidence presented in the following sections on therapy for women with hormone receptorâpositive disease has been considered in an ASCO guideline that describes several options for the management of these patients.
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):
These three studies, plus several others, have been included in three meta-analyses addressing the question of whether the use of zoledronic acid in the adjuvant setting prolongs survival. The results of these meta-analyses are conflicting. One study found no significant impact on survival (relative risk [RR], .90; 95% CI, 0.61â1.33; P = .61). A second study found a significant effect on survival (HR, .81; 95% CI, .70â.94; P = .007). The third study found a borderline significant effect on survival (RR, .88; 95% CI, 0.77â 1.01; P = .06).[Level of evidence: 1iiA]
Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) 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.[Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[Level of evidence: 1iiDiv]
A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation, and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains. 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.
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 hormoneâreceptor 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.[Level of evidence: 2Div]; [Level of evidence: 3iiD]; [Level of evidence: 3iiDiv] 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 receptorâpositive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.
- For premenopausal women with hormoneâresponsive 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 nonâcross-resistant regimen or proceed to surgery, if feasible. Although switching to a nonâcross-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.
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):
The incorporation of many additional cytotoxic agents to anthracycline- and taxane-based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[Level of evidence: 1iiDiv]
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., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.
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.[Level of evidence: 1iiDiv] This has been confirmed in phase III studies.
Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptorâpositive 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%â8%) are far lower than have been reported with chemotherapy in unselected populations.[Level of Evidence: 1iDiv]
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%, P-value for trend < .04).[Level of Evidence: 1iiDiv]
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.
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 or during/after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptorâpositive disease and adjuvant trastuzumab for those with HER2-positive disease.
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
Multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.
The standard treatment option for locally advanced or inflammatory breast cancer is multimodality therapy that may include the following:
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.
The standard chemotherapy regimen for initial treatment is anthracycline-based chemotherapy and/or taxane-based therapy. 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):
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 receptorâpositive 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:
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.
- Five-year DFS was 69% in the chemotherapy arm versus 57% in the no-chemotherapy arm (HR, 0.59; 95% confidence interval, 0.35â0.99; P = .046), with most benefit seen in the subgroup with hormone receptorânegative disease.
- This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer.
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.[Level of evidence: 3iiDiii]
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 Receptorâ??Positive or Hormone Receptorâ??Unknown Breast Cancer
Endocrine therapy is recommended for patients with metastatic hormone receptorâpositive 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):
Hormone Receptorâ??Negative Breast Cancer
The treatment for hormone receptorânegative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)
HER2/neuâ??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.
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.
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 receptorânegative 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.[Level of evidence: 1iiA];
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.[Level of evidence: 1iiA]
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 treatment duration 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.[Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies, 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.[Level of evidence: 1iiA] 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.[Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.
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.
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/m2 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.[Level of evidence: 1iiA] Because of the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this should b
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