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Clinical Trial
. 2019 Jan 9;17(1):8.
doi: 10.1186/s12916-018-1233-1.

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  1 , Mafalda Oliveira  2 , Tomás Pascual  3   4   5 , Jose Perez-Garcia  2   6 , Xavier Gonzàlez  5   7 , Jordi Canes  5 , Laia Paré  3 , Isabel Calvo  8 , Eva Ciruelos  9 , Montserrat Muñoz  3   4 , Juan A Virizuela  10 , Isabel Ruiz  11 , Raquel Andrés  12 , Antonia Perelló  13 , Jerónimo Martínez  14 , Serafín Morales  15 , Mercedes Marín-Aguilera  3 , Débora Martínez  3 , Juan C Quero  16 , Antonio Llombart-Cussac  17 , Aleix Prat  18   19   20
Affiliations
Clinical Trial

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 et al. BMC Med. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: clinicaltrials.gov, NCT01669239, Registered 20 August 2012.

Keywords: Breast cancer; HER2; HER2-enriched; PAM50; cardiac safety; intrinsic subtypes; neoadjuvant.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Hospital Vall d’Hebron (Barcelona) AC/R(AG)143/2012(3455). All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

Advisory role of AP for Nanostring Technologies. Advisory Role of JG for Roche. The other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CONSORT diagram
Fig. 2
Fig. 2
Left ventricular ejection fraction (LVEF) changes during neoadjuvant treatment and adjuvant period: from global population in red and from each of six patients who had > 10% drop in LVEF during the study period
Fig. 3
Fig. 3
Molecular heterogeneity of HER2-positive breast cancer. Intrinsic subtype distribution in baseline tumors (a), according to hormonal receptor status (b, c), and in surgical tumors (d). e Pathological complete response (pCR) rates of the intrinsic subtypes identified at baseline
Fig. 4
Fig. 4
Six differentially expressed genes between baseline and surgical specimens. a ESR1, b PGR, c ERBB2, d CD8A, e MKI67, f CCNB1
Fig. 5
Fig. 5
Rates of pathological complete response (pCR) according to the type of chemotherapy and anti-HER2 therapy using data from 15 neoadjuvant clinical trials in HER2-positive breast cancer. Bars denote 95% CIs. T taxane, L lapatinib, H herceptin (trastuzumab), A/T anthracycline/taxane based
See this image and copyright information in PMC

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