Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial

Joaquín Gavilá,Raquel Andrés,Mercedes Marín-Aguilera,Débora Martínez,Laia Paré,Serafín Morales,Jerónimo Martínez,Antonia Perelló,Montserrat Muñoz,Tomás Pascual,Eva Ciruelos,Mafalda Oliveira,Jordi Canes,Xavier González ,José Manuel Pérez-García ,Juan Antonio Virizuela ,Isabel Ruíz ,Antonio Llombart-Cussac,Isabel Calvo,Juan C Quero,Aleix Prat

doi:10.1186/s12916-018-1233-1

Abstract

The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. clinicaltrials.gov, NCT01669239 , Registered 20 August 2012.

Highlights

The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2positive early breast cancer
The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pathological complete response (pCR) rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% confidence interval (CI) 1.71–19.42)
The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events

Summary

Introduction

The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2positive early breast cancer. The addition of 1 year of adjuvant pertuzumab to standard chemotherapy plus trastuzumab led to a 19% relative risk reduction in invasive disease-free survival [6] Based on this data, dual HER2 blockade in combination with chemotherapy is the standard of care in first-line advanced disease and will become more widely used in early BC. In the pivotal first-line metastatic trial that led to the approval of trastuzumab, a New York Heart Association class III– IV cardiac toxicity of 13% and 27% was observed with trastuzumab in combination with paclitaxel or doxorubicin/cyclophosphamide, respectively [8] According to this data, concomitant administration of trastuzumab and anthracyclines is not recommended. Concomitant administration of neoadjuvant trastuzumab with a conventional anthracycline [18] or trastuzumab/pertuzumab with an anthracycline/taxane combination [4] in early BC was found to be associated with a reduction in left ventricular ejection fraction (LVEF) in 4.6% and 5.6% of patients, respectively

Methods

Results

Discussion

Conclusion