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