The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer, and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for millions of women with early-stage and advanced HER2-positive breast cancer. This review discusses the treatment of primary, nonmetastatic HER2-positive breast cancer in the adjuvant and neoadjuvant settings—settings in which tremendous progress has been made. Novel approaches, including the use of combinations of HER2-targeted therapies, are examined. Future challenges include refining such treatments, reducing toxicity in those who have low-risk disease, and simultaneously developing innovative therapies for patients who remain at high risk for relapse with existing treatment options.
Breast cancer is a model disease for the development of both targeted therapies and associated prognostic and predictive biomarkers. Targeted therapies have potentially greater anticancer activity and fewer side effects compared with the traditional cytotoxic chemotherapies that are used to treat breast cancer. The discovery of human epidermal growth factor receptor 2 (HER2) and its role in breast cancer, and the subsequent development of anti-HER2 therapies, have revolutionized the treatment of women with HER2-positive breast cancer and constitute a modern success story in oncology.
HER2 is a transmembrane receptor that belongs to the ErbB/HER family of receptor tyrosine kinases. In 20% to 30% of breast cancers, HER2 is amplified and the HER2 protein is overexpressed—patterns that, until the discovery of effective anti-HER2 therapies, were associated with more aggressive disease and worse outcomes. In this review, we discuss treatments for early-stage HER2-positive breast cancer in the adjuvant and neoadjuvant settings.
Defining HER2-Positive Breast Cancer
Because of its prognostic and predictive value, HER2 protein expression should be evaluated in the tumors of all patients with newly diagnosed primary invasive breast cancer either by immunohistochemistry (IHC) or in situ hybridization (ISH). The current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, updated in 2013, define HER2 positivity as 3+ on IHC (defined as uniform intense membrane staining of > 10% of invasive tumor cells) or amplified on ISH (a HER2:chromosome enumeration probe [CEP]17 ratio of > 2.0, or < 2.0 plus average HER2 copy number > 6 signals/cell).
Although a detailed discussion of HER2 testing is beyond the scope of this paper, we would like to note that if a patient’s HER2 expression is ultimately deemed to be equivocal on both IHC and ISH, the oncologist can still consider HER2-targeted therapy, based on the patient’s history, prognosis, and comorbidities.
The monoclonal antibody trastuzumab is the first and only targeted agent that has been approved for the adjuvant treatment of early-stage HER2-positive breast cancer. Trastuzumab binds to the extracellular domain of HER2, suppressing its signaling activity and inducing antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab was first approved for use in patients with metastatic HER2-positive disease, as monotherapy and in combination with paclitaxel or docetaxel.[2-4]
Two major North American Cooperative Group trials, published as a joint analysis in 2005, established the benefit of trastuzumab in the adjuvant setting. In both studies, patients were treated with a backbone of doxorubicin plus cyclophosphamide (AC) every 3 weeks for 4 cycles, but subsequent therapies differed slightly between the two trials. The first trial, National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP B-31), randomized women with HER2-positive, node-positive breast cancer to 4 cycles of single-agent paclitaxel, given every 3 weeks, with or without weekly trastuzumab (initial loading dose of 4 mg/kg, then 2 mg/kg weekly for 1 year), beginning with the first dose of paclitaxel. The second trial, North Central Cancer Treatment Group (NCCTG) N9831, randomized women with HER2-positive, node-positive or high-risk, node-negative disease to one of three regimens: weekly paclitaxel for 12 weeks, followed by no further treatment; weekly paclitaxel, followed by sequential trastuzumab for 52 weeks; or weekly paclitaxel with concurrent trastuzumab for 12 weeks, followed by trastuzumab alone for 40 weeks.
The combined analysis compared patients who were treated with paclitaxel that was administered concurrently with trastuzumab and those who received paclitaxel alone. The primary endpoint of both trials was disease-free survival (DFS). At the first joint interim efficacy analysis, it was recommended that the trials end enrollment and that the results be released. When initially published, at a median follow-up of 2 years, the hazard ratio (HR) for a first event in the trastuzumab group (compared with the control group) was 0.48 (95% confidence interval [CI] = 0.39–0.59; P < .0001). At 3 years, the absolute difference in DFS was 11.8% (95% CI = 8.1%–15.4%; P < .0001), and the absolute difference in overall survival (OS) was 2.5% (95% CI = 0.1%–5.0%; P < .015). An updated analysis confirmed that chemotherapy plus adjuvant trastuzumab resulted in superior DFS (85.7% vs 73.7%; HR = 0.52) and OS (93.0% vs 85.6%; HR = 0.61) at 4 years.
The results of NCCTG N9831 and NSABP B-31 established the benefit of trastuzumab in addition to anthracycline-/taxane-based adjuvant chemotherapy in women with early-stage breast cancer. These findings were reconfirmed in a recent Cochrane review that evaluated the use of adjuvant trastuzumab-containing regimens in eight studies of 11,991 women with early-stage breast cancer, in which the combined HRs for OS and DFS favored the trastuzumab-containing regimens (OS: HR = 0.66; 95% CI = 0.57–0.77; P < .00001 and DFS: HR = 0.60; 95% CI = 0.50–0.71; P < .00001).
In HER2-negative breast cancer, AC is often given on a dose-dense schedule with granulocyte colony-stimulating factor support, based on improved outcome data, particularly in patients with hormone receptor–negative breast cancer. Morris et al, in a phase II trial, assessed the feasibility and cardiac safety of incorporating trastuzumab into a dose-dense AC regimen. At a median follow-up of 84 months, the cumulative incidence of congestive heart failure (CHF) was 1.4% (95% CI = 1.36%–7.7%), which is comparable to rates seen in other major adjuvant trastuzumab trials (Table 1). Outcome results were similarly favorable. However, there are no data to suggest that a dose-dense AC regimen is superior in this setting, and the additional toxicity and cost that are associated with granulocyte colony-stimulating factor support should be considered. National Comprehensive Cancer Center (NCCN) guidelines do suggest that dose-dense AC is an acceptable option as part of trastuzumab-based adjuvant therapy.
Data on non–anthracycline-based adjuvant therapy in combination with trastuzumab come from the Breast Cancer International Research Group 006 (BCIRG-006) trial, in which women with HER2-positive, node-positive or high-risk, node-negative breast cancer were randomized to one of three regimens: A) AC every 3 weeks for 4 cycles, followed by docetaxel every 3 weeks for 4 cycles (AC-T); B) AC-T plus trastuzumab for 1 year (weekly beginning with the first dose of docetaxel, then every 3 weeks) (AC-TH); and C) docetaxel plus carboplatin every 3 weeks for 6 cycles, with concurrent weekly trastuzumab during chemotherapy, then every 3 weeks for 1 year of total trastuzumab therapy (TCH).
At a median follow-up of 65 months, both trastuzumab-containing arms experienced a significant improvement in estimated 5-year DFS (81% with TCH and 84% with AC-TH vs 75% with AC-T) and OS (91% with TCH and 92% with AC-TH vs 87% with AC-T). The differences in DFS and OS between AC-TH and TCH were not statistically significant, although the study was not powered to detect equivalence. Compared with AC-TH, TCH resulted in significantly lower rates of severe (grade 3/4) neutropenia and leukopenia, CHF, and sensory neuropathy but significantly higher rates of severe anemia and thrombocytopenia. TCH is the most common non–anthracycline-based adjuvant chemotherapy regimen in the United States for patients with HER2-positive breast cancer.
Because of the increased risk of cardiotoxicity (see Table 1), the decision of whether to treat with an anthracycline-containing or a non–anthracycline-containing regimen should be based on clinical stage, hormone receptor status, and comorbid conditions. It is our practice to administer anthracycline-based therapy in patients without cardiac risk factors, particularly in the setting of node-positive or hormone receptor–negative disease (Figure). The presence of cardiac risk factors alone (hypertension, known baseline cardiac dysfunction, age > 50 years) should not exclude patients from receiving HER2-directed therapy if otherwise indicated. However, such patients should be monitored closely.
Cardiac function should be assessed in all patients prior to starting trastuzumab. In the adjuvant setting, when administration of trastuzumab follows the use of an anthracycline, left ventricular ejection fraction (LVEF) should be measured after completion of the anthracycline and prior to the initiation of trastuzumab. The optimal surveillance schedule for trastuzumab-related cardiotoxicity has not been defined. At a minimum, patients should undergo a baseline evaluation for cardiac function, with a repeat study at 6 months. Early adjuvant trials employed more frequent monitoring—with evaluation of cardiac function at baseline; on completion of AC; and at 6, 9, and 18 months following initiation of trastuzumab.[12,13] In addition, new signs or symptoms that are suggestive of CHF warrant further evaluation.
In patients who experience cardiotoxicity while taking trastuzumab, it is reasonable to follow the dose adjustment guidelines from NSABP B-31 and NCCTG N9831. If the LVEF declines 16 percentage points or more from baseline, or 10 to 15 percentage points from baseline, yet to below the lower limits of normal, trastuzumab should be held for 4 weeks and cardiac function should be re-evaluated. If the LVEF remains below these levels at the 4-week re-evaluation or if the patient has signs or symptoms of CHF, trastuzumab should be discontinued permanently and standard therapy for heart failure should be initiated. Similarly, trastuzumab should be permanently discontinued if it is held for three nonconsecutive doses because of declines in LVEF.
The recommended duration of adjuvant trastuzumab treatment remains a total of 12 months. This is based on the studies above, plus the results of the HERA trial, which found no difference in DFS or OS between 12 and 24 months of trastuzumab, and the results of the PHARE trial, which demonstrated that 6 months of adjuvant trastuzumab resulted in worse DFS rates and increased the number of deaths and more distant recurrences compared with 12 months.[14,15] The use of concurrent cytotoxic chemotherapy and trastuzumab vs sequential trastuzumab following chemotherapy was evaluated in several trials, including HERA and NCCTG N9831.[14,16] While sequential therapy appears to have benefit compared with non–trastuzumab-containing regimens, better outcomes were observed with the concurrent approach (ie, trastuzumab combined with a taxane). Based on these findings, concurrent adjuvant trastuzumab in combination with chemotherapy is preferred.
In an attempt to improve outcomes further, novel agents have been combined with trastuzumab in the adjuvant setting. The results of the BETH trial were reported at the 2013 San Antonio Breast Cancer Symposium. In this trial, the anti–vascular endothelial growth factor monoclonal antibody bevacizumab was combined with chemotherapy plus trastuzumab in approximately 3,000 women with node-positive and high-risk, node-negative HER2-positive breast cancer. After a median follow-up of 38 months, there was no improvement in invasive disease–free survival (primary endpoint) with the addition of bevacizumab (HR = 0.99; 95% CI = 0.79–1.25; P = .96).
Other agents that target HER2 have been developed since the introduction of trastuzumab, including lapatinib, pertuzumab, and ado-trastuzumab emtansine, all of which are under investigation in the adjuvant setting. To date, trastuzumab remains the only agent that has a known survival benefit in the adjuvant setting.
The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial is evaluating the combination of trastuzumab plus lapatinib in early-stage breast cancer in more than 8,000 patients (clinicaltrials.gov identifier, NCT00490139). A planned interim analysis of early data from ALTTO has resulted in the closing of the lapatinib-only arm; the data monitoring committee has indicated that this arm is unlikely to meet the prespecified criteria of noninferiority to trastuzumab. This trial is the second study to suggest a lack of benefit from lapatinib alone in the adjuvant setting. The other three trial arms are continuing without modification. The APHINITY trial is a phase III study enrolling over 4,000 patients that is comparing 1 year of adjuvant trastuzumab plus placebo with trastuzumab plus pertuzumab following the investigators’ choice of chemotherapy (clinicaltrials.gov identifier, NCT01358877). The first patients were enrolled in 2011.
To date, HER2 overexpression is the only predictive marker for HER2-targeted therapy. However, the tremendous improvement in outcomes seen with anti-HER2 therapy in both early-stage and metastatic breast cancer has led to interest in identifying patients who are HER2-negative by conventional IHC/ISH but who might still benefit from anti-HER2 therapy. For example, in a study of patients with hormone receptor–positive metastatic breast cancer who were treated with letrozole plus lapatinib, on initial analysis, only patients with centrally confirmed HER2 amplification seemed to benefit from the addition of lapatinib. However, a subsequent retrospective analysis demonstrated that among HER2-negative patients, those with low estrogen receptor (ER) expression experienced significant improvement in progression-free survival, suggesting an interaction between hormone receptor signaling and HER family signaling.
Additional prospective studies are underway. NSABP B-47 is a randomized phase III trial that is currently recruiting patients and is comparing adjuvant chemotherapy alone vs adjuvant chemotherapy plus trastuzumab in women with node-positive or high-risk, node-negative, HER2-low invasive breast cancer (clinicaltrials.gov identifier, NCT01275677). Several correlative studies are planned, including an evaluation of HER2 mRNA levels; these hope to identify predictive markers for improved outcomes in women who have been diagnosed with HER2-negative breast cancer per ASCO/CAP guidelines.
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