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

Background: Anti-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 methods: BERENICE (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.

Results: Safety 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).

Conclusion: Treatment 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 information: NCT02132949.

Figure 1.

Study design. BC, breast cancer; ddAC, dose-dense doxorubicin plus cyclophosphamide; ECOG, Eastern Cooperative Oncology Group; FEC, fluorouracil, epirubicin, and cyclophosphamide; HR, hormone receptor; LVEF, left ventricular ejection fraction; q2w, every 2 weeks; q3w, every 3 weeks; qw, every week. Only one cohort was opened at a time at any given site, and was defined before any patients were enrolled at that site. Investigator choice of cohort was based on local/regional practice.

Figure 2.

pCR (ypT0/is ypN0) (A) in the intention-to-treat (ITT) population and (B) by intrinsic breast cancer subtype.^a D, docetaxel; ddAC, dose-dense doxorubicin plus cyclophosphamide; FEC, fluorouracil, epirubicin, and cyclophosphamide; H, trastuzumab; HR, hormone receptor; P, pertuzumab; pCR, pathologic complete response; T, paclitaxel. Six patients in cohort A and two in cohort B had missing central HR assessments. ^aPatients were classified by intrinsic BC subtype using gene expression analyses carried out by applying the Nanostring nCounter platform and the PAM50 subtype prediction used to describe the major intrinsic subtypes (see supplementary data, available at Annals of Oncology online). ^bThe statistical model applied did not allow categorization into any of the subgroups. ^cTechnical failure (assay failure or failure to extract RNA).