Elsevier

The Lancet Oncology

Volume 15, Issue 7, June 2014, Pages 747-756
The Lancet Oncology

Articles
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial

https://doi.org/10.1016/S1470-2045(14)70160-3Get rights and content

Summary

Background

Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.

Methods

Patients with previously untreated, non-metastatic, stage II–III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m2 once a week) and non-pegylated liposomal doxorubicin (20 mg/m2 once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880.

Findings

296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1–49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3–42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96–1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4–60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4–44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0–40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7–44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5.

Interpretation

The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.

Funding

GlaxoSmithKline, Roche, and Teva.

Introduction

A six to nine times higher risk for relapse has been reported for patients with triple-negative breast cancer or with HER2-positive breast cancer who do not achieve a pathological complete response with neoadjuvant treatment.1, 2, 3 Because of this strong prognostic effect, pathological complete response was proposed as a surrogate for survival in these two breast cancer subtypes, although outcome improvements at surgery did not correlate with improvements of survival.4, 5

Patients with triple-negative breast cancer, compared with other subtypes, showed high pathological complete responses with neoadjuvant treatment with anthracyclines, cyclophosphamide, and taxanes.6 Recently, an even higher proportion of patients achieving a pathological complete response was reported when bevacizumab was given simultaneously with these cytotoxic agents.7, 8 The introduction of a dual blockade of the HER2 pathway by either two antibodies or by an antibody and a tyrosine-kinase inhibitor, given simultaneously with a taxane-based chemotherapy, induced the highest rates of pathological complete response noted in patients with HER2-positive breast cancer so far.9, 10, 11

Carboplatin potentially adds further activity to these treatments. Preclinical data suggest that triple-negative breast cancers are more sensitive to interstrand crosslinking agents that damage the DNA such as platinum, because of deficiencies in the BRCA-associated DNA repair mechanism.12 Non-randomised cohort studies suggested higher rates of pathological complete response in triple-negative breast cancer and especially in the subset of BRCA-mutation carriers compared with non-triple negative breast cancer in non-BRCA-mutation carriers.11, 13, 14, 15 A strong synergistic treatment effect was postulated in HER2-positive disease for the combination of a taxane, trastuzumab, and a platinum salt.16 Subsequently, two phase 2 trials examined carboplatin in HER2-positive metastatic breast cancer. One trial showed superior outcome for patients receiving paclitaxel and trastuzumab in combination with carboplatin compared with patients receiving paclitaxel and trastuzumab alone at the same dose.17 The other study did not show a similar effect when carboplatin was added to docetaxel and trastuzumab;18 however, this study used a lower dose of docetaxel (75 mg/m2) in the carboplatin arm.

Several cohort studies reported on the neoadjuvant use of carboplatin in combination with docetaxel and trastuzumab, but until recently no randomised trial has shown the additive effect of platinum to standard type of treatment in the neoadjuvant setting.19

The aim of the randomised GeparSixto study was to assess the additional effect of neoadjuvant carboplatin to a regimen containing an anthracycline, a taxane, and targeted therapy (trastuzumab/lapatinib or bevacizumab) on pathological complete response in patients with stage II–III triple-negative breast cancer and HER2-positive breast cancer.

Section snippets

Patients

Women with previously untreated, unilateral or bilateral, non-metastatic primary invasive triple-negative or HER2-positive breast carcinoma were enrolled into our study if they provided written informed consent. Triple-negative status was defined as oestrogen and progesterone receptor levels of less than 1% and HER2-negative (HercepTest [Dako] score 0 or 1+ or gene amplification ratio <2·2 by in-situ hybridisation). Patients older than 18 years, having a Karnofsky performance status index 80 or

Results

Between Aug 29, 2011, and Dec 12, 2012, we screened 728 patients at 54 centres in Germany for eligibility. 68 patients did not have their biological subtype centrally confirmed and 65 patients did not meet other eligibility criteria. Of the remaining 595 patients, seven did not start treatment (four because of investigator decisions and three because of patient's decision) and were not included in the intention-to-treat analysis. Thus, 588 patients (295 with carboplatin, 293 without) were

Discussion

The findings of the GeparSixto phase 2 study show that, at a prespecified α level of 0·2, a significantly greater proportion of patients achieved a pathological complete response with the addition of carboplatin to a combination regimen including a taxane, non-pegylated liposomal doxorubicin, and dual HER2-receptor blockade in patients with HER2-positive breast cancer or inhibition of neoangiogenesis in patients with triple-negative disease. An absolute increase in the proportion of patients

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