Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study

Abstract

BackgroundAnti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.Patients and methodsBERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive.ResultsSafety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively).ConclusionTreatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab.Clinical Trial InformationNCT02132949

Optimal treatment of early stage HER2‐positive breast cancer

“…The cardiac safety profile observed and high pCR rates achieved in both cohorts supported the use of pertuzumab and trastuzumab with a taxane after doxorubicin‐based or epirubicin‐based chemotherapy in this scenario. Most patients in the study had HER2‐enriched tumors, and the highest pCR rate (75%) was observed in that subgroup . To date, dual blockade with trastuzumab and pertuzumab plus chemotherapy should be considered the standard of care for patients with HER2‐positive breast cancer who meet criteria for neoadjuvant treatment.…”

“…The addition of pertuzumab to a taxane and trastuzumab as first‐line treatment in advanced, HER2‐positive breast cancer improved OS by almost 16 months . The activity of pertuzumab also has been studied in the neoadjuvant setting in several phase 2 trials (Table ) . The NeoSphere trial demonstrated that dual‐blockade with pertuzumab and trastuzumab plus chemotherapy produced a significantly improved pCR rate in the breast compared with chemotherapy and trastuzumab alone (46% vs 29%, respectively).…”

“…This pCR rate is the highest ever reported and compares favorably with the rates reported is studies with longer and more aggressive chemotherapy regimens. The BERENICE study evaluated 2 anthracycline‐containing chemotherapy regimens followed by paclitaxel or docetaxel with pertuzumab and trastuzumab in the neoadjuvant setting. The cardiac safety profile observed and high pCR rates achieved in both cohorts supported the use of pertuzumab and trastuzumab with a taxane after doxorubicin‐based or epirubicin‐based chemotherapy in this scenario.…”

“…To date, dual blockade with trastuzumab and pertuzumab plus chemotherapy should be considered the standard of care for patients with HER2‐positive breast cancer who meet criteria for neoadjuvant treatment. In patients who have tumors measuring <2 cm and no lymph node involvement (ie, clinical T1N0 disease), there are no data to recommend neoadjuvant treatment with pertuzumab . Moreover, considering the excellent outcomes of patients with small HER2‐positive breast cancers who received adjuvant paclitaxel and trastuzumab (the APT trial), as described below, in most of these patients, adjuvant treatment should be recommended (see Fig.…”

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

“…pCR rates were 61.8% in cohort A and 60.7% in cohort B. Of note, the highest pCR rates were found in the HER2-enriched PAM50 subtype (75 and 73.7%, respectively) [69]. Another trial, the TRAIN-2 study, compared 6 cycles of weekly paclitaxel, trastuzumab, carboplatin (PTC) plus pertuzumab preceded either by 3 cycles of FEC, trastuzumab plus pertuzumab or by 3 cycles of PTC plus pertuzumab.…”