In patients with triple-negative breast cancer, the addition of carboplatin significantly improved the rate of pathologic complete response after neoadjuvant chemotherapy in a study by the German Breast Group (GBG)/Gynecologic Oncology Working Group–Breast (AGO-B) reported at the 2013 ASCO Annual Meeting.1
“An absolute increase of more than 20% was observed in patients with triple-negative breast cancer, but the HER2-positive subgroup did not benefit,” reported Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group and Professor of Gynecology at the University of Frankfurt.
Several neoadjuvant studies have suggested that triple-negative patients are sensitive to cisplatin and carboplatin, especially those with BRCA mutations. However, randomized trials incorporating platinums have produced mixed results.
“The role of carboplatin in breast cancer is not yet fully understood, and its efficacy has not been determined,” he said.
The GeparSixto study evaluated the benefit of adding carboplatin to paclitaxel plus pegylated liposomal doxorubicin given as a weekly regimen for 18 weeks to 595 patients. Added to this backbone were three targeted agents corresponding to tumor subtype: trastuzumab (Herceptin) and lapatinib (Tykerb) for HER2-positive patients and bevacizumab (Avastin) for triple-negative patients. Halfway into the study, the carboplatin dose was reduced from AUC 2 to AUC 1.5 because of toxicity concerns at the interim safety analysis.
Investigators compared the rates of pathologic complete response (ypT0, ypN0, ie, invasive and no in situ residual disease) between paclitaxel/doxorubicin and paclitaxel/doxorubicin/carboplatin. The level of statistical significance was set at P < .2.
Of the 588 patients who started treatment, 31% of the control arm and 38% of the carboplatin arm discontinued due to adverse events. Six cycles were completed by 61% and 52%, respectively.
Forty percent of patients experienced at least one serious adverse event. The control arm had more pneumonia (17 vs 2 patients), but more hematologic toxicity was seen with carboplatin (49 vs 10 patients), and diarrhea was most likely in patients receiving lapatinib (15 vs 0–3 patients in other arms).
The addition of carboplatin significantly increased the pathologic complete response rate, which was 37.2% in the control arm and 46.7% in the carboplatin arm (P < .2). Using other, more liberal definitions of pathologic complete response, the same pattern was observed, with absolute differences of 8% to 10%, Dr. von Minckwitz reported.
The difference, however, was driven by the drug’s effect in the triple-negative subgroup, in which pathologic complete response was achieved by 37.9% of the control arm and 58.7% of the carboplatin arm (P < .05). “You can see there is a tremendous 20% difference between the arms in these patients,” he noted.
In HER2-positive patients, on the other hand, pathologic complete responses were achieved by 36.3% and 33.1%, respectively.
Clinical complete responses were consistent with the overall result, achieved by 36.9% of patients on the control arm and 43.1% of those on the carboplatin arm. Breast-conserving therapy rates, however, were no different between the two arms—76.7% and 72.4%, respectively, showing “very high efficacy for both arms,” he said.
Results in Context
Dr. von Minckwitz concluded that while the carboplatin-containing regimen increased pathologic complete response, “the observed high efficacy of this regimen has to be weighed against a high rate of treatment discontinuations,” which occurred for 39% of patients treated with chemotherapy plus a targeted agent and 48% of those receiving the same plus carboplatin.
“We have to further analyze the adverse events for the different regimens, to find out which of the components is most responsible,” he suggested.
A biomarker program aims to identify subgroups of patients with triple-negative breast cancer who may obtain the greatest benefit from carboplatin. The investigators are also analyzing the results according to BRCA mutation status.
“Finally, the results have to be set in context with the upcoming [Cancer and Leukemia Group B]/Alliance 40603 phase II study, which is adding bevacizumab and/or carboplatin to weekly paclitaxel followed by dose-dense anthracycline/cyclophosphamide,” he said. ■
Disclosure: Dr. Von Minckwitz has received honoraria from Roche and Sanofi and research funds from Roche, GlaxoSmithKline, and Teva.
1. Von Minckwitz G, Schneeweiss A, Salat C, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2012.
Judy Garber, MD, MPH, Professor of Medicine at Harvard Medical School and Director of the Cancer Risk and Prevention Center at Dana-Farber Cancer Institute, Boston, was the formal discussant of the GeparSixto paper.
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