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

Abstract

BackgroundThe 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.MethodsPatients 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.ResultsEighty-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.ConclusionsThe 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 registrationclinicaltrials.gov, NCT01669239, Registered 20 August 2012.

Combination of pegylated liposomal doxorubicin and docetaxel as neoadjuvant therapy for breast cancer with axillary lymph node metastasis

“…A number of studies reported clinical RRs of 58% to 91% and pCRs of 3% to 41% after NAC in patients with BC. 8 – 21 , 26 Although there is no consensus concerning the optimal protocol for treating BC, it is generally agreed that anthracyclines and taxanes are among the best options. Phase II and III trials have been conducted to examine different combinations of these agents.…”

“…Phase II and III trials have been conducted to examine different combinations of these agents. 8 – 21 , 26 The clinical RR of doxorubicin and docetaxel as NAC for BC was 70%. 10 Regarding the use of the combination of epirubicin, cyclophosphamide, and paclitaxel as NAC for patients with stage II–III BC, the ORR and pCR rate were 83.7 and 15.1% respectively.…”

“…It was assumed that the investigational regimen would be of no interest if the pCR rate was ≤8% and of interest if the pCR rate was >8%. 6 – 20 Accordingly, a minimum total sample size of 90 patients was calculated. Assuming a 10% dropout rate, the target enrollment was 100 patients.…”

Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

“…The clinical value of the HER2-E subtype in HER2+ breast cancer is starting to be elucidated. From a therapeutic perspective, the HER2-E subtype has shown, across 14 clinical trials and ∼2,000 patients, higher sensitivity to anti-HER2-based therapies than the non-HER2-E subtypes [7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, not all HER2-E tumors achieve a complete response following anti-HER2-based therapies.…”

Review A meta-analysis of the efficacy and safety of additional anti-HER2-targeting drugs in HER2-positive advanced breast cancers

“…In the combination therapy with multiple anti-HER2-targeting drugs, that is, in the NeoSphere trial [15], compared with trastuzumab plus docetaxel, the new adjuvant trastuzumab plus docetaxel added pertuzumab (a HER2-directed monoclonal antibody) signi cantly increased the proportion of patients who achieved complete pathological remission. For most HER2-positive early breast cancer patients, multidrug chemotherapy and dual HER2 blockade should be considered [16,17]. Giordano et al [18] also suggested the combination of trastuzumab, pertuzumab, and taxanes for rst-line treatment.…”