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.
The rationale for studying platinum in triple-negative breast cancer is clear: The drugs are active in ovarian cancer, which has molecular similarities to basal-like breast cancer; BRCA-associated breast cancer is basal-like on microarrays; and response to platinum is associated with germline BRCA mutations, low BRCA expression or inactivation of BRCA by methylation, suggestive of a DNA repair theme, she said.
Clinically, however, the benefit of platinum is less clear. In a small ongoing neoadjuvant study of 38 patients with BRCA1 mutations, Polish investigators observed a pathologic complete response in 60.5% of patients receiving four cycles of cisplatin.1 In their phase II study in the metastatic setting, 20 patients with BRCA1 mutations received six cycles of cisplatin at 75 mg/m2 and 80% responded, with complete responses seen in 45%.2 However, in the phase II BALI‑1 study reported by Baselga et al, also in the metastatic setting, only 10% of patients unselected for BRCA status with triple-negative disease responded to cisplatin alone.3
Unanswered Questions
“Certainly, there is interest and concern about platinum agents, and therefore it is particularly important that the German Breast Group has taken on the evaluation of carboplatin in this setting, building upon their prior work,” Dr. Garber said.
“They showed very impressive results in the triple-negative group,” she noted, “but this came with significant adverse effects, and one wonders what simplifications might have made the regimen more tolerable.”
Dr. Garber would like to see further evaluation of various predictors of response, including germline BRCA mutation status. Follow-up for clinical outcomes beyond pathologic complete response will also be critical, she said. While data from collaborative trials show that risk of recurrence is reduced when patients achieve pathologic complete responses, “this is not the same as cure,” she noted, “and we need to ask whether [pathologic complete response] is enough to make decisions going forward.”
“We must figure out for whom the platinums work before we give them indiscriminately. They clearly have activity but also toxicity,” she concluded, adding that the optimal, least toxic platinum-containing regimen still remains unclear.
“Physicians who don’t like to change therapy based on a single study may want to wait for the results of the Alliance 40603 trial, the results of which are anticipated in December 2013,” she said. ■
Disclosure: Dr. Garber has been a consultant or advisor to Novartis, Pfizer, and Tesaro, and has received research funding from AstraZeneca, Myriad Genetics, Novartis, and Pfizer.
References
1. Byrski T, Gronwald J, Huzarski T, et al: Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Hered Cancer Clin Pract 9(suppl 2):A4, 2011.
2. Byrski T, Dent R, Blecharz P, et al: Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 14:R110, 2012.
3. Baselga J, Gomez P, Greil R, et al: Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 31:2586-2592, 2013.
