EXPERT ANALYSIS FROM SABCS 2014
SAN ANTONIO– Oncologists are split over the use of platinum compounds as adjuvant or neoadjuvant therapy for triple-negative breast cancer patients, a rift likely to continue until definitive outcome data become available several years from now.
“In the U.S., I would say that about half of all medical oncologists are now in a fairly routine manner giving carboplatin in this setting,” Dr. Eric P. Winer estimated at the San Antonio Breast Cancer Symposium.
He’s not among them.
“Is carboplatin ready for prime time use in the adjuvant or neoadjuvant setting in triple-negative breast cancer? I personally feel we first need a definitive study showing improvement in disease-free survival and/or overall survival, or something close to that,” said Dr. Winer, chief of the division of women’s cancers at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, Boston.
Proponents of platinum salts cite two positive phase II randomized trials – GeparSixto and CALGB 40603 – which demonstrated significantly higher pathologic complete response (pCR) rates in patients with stage II or III triple-negative breast cancer (TNBC) with the addition of carboplatin to neoadjuvant chemotherapy.
The pro-platinum camp points to evidence suggesting a pCR in women with TNBC appears to be a good surrogate endpoint for event-free survival and overall survival, as shown in a recent meta-analysis by Dr. Patricia Cortazar of the Food and Drug Administration and her coworkers. The investigators concluded that pCR in response to neoadjuvant therapy with various regimens was associated with a 76% improvement in event-free survival and an 84% improvement in overall survival in 557 women with TNBC (Lancet 2014;384:164-72).
“The two phase II studies are going in the same direction,” observed Dr. Gunter von Minckwitz of the German Breast Group and principal investigator in the GeparSixto trial. “We have surveyed our group of investigators, and they are all using platinum in triple-negative breast cancer. The German guidelines say you can, but you don’t have to.”
But Dr. Winer, and by his estimate roughly half of all American medical oncologists, remain unconvinced.
“I think we should all keep in mind that pCR is a marker of better outcome, it’s not necessarily a required step in the process,” he said.
He’s leery of relying upon pCR as a surrogate endpoint in light of the deeply disappointing BEATRICE experience. The phase III BEATRICE trial included nearly 2,600 women with TNBC who were randomized to adjuvant chemotherapy alone or in combination with bevacizumab. The bevacizumab group had a higher pCR, but no improvement in disease-free survival or overall survival (Lancet Oncol. 2013;14:933-42).
“I would hate to see us all indiscriminately adding platinum to standard regimens, increasing toxicity, particularly if it is not associated with long-term benefit,” Dr. Winer said. “And even if it is associated with long-term benefit, I want to tease out who really benefits and which triple-negative patients are most sensitive to these agents.”
Progress is occurring in this area, he added. In GeparSixto, the addition of neoadjuvant carboplatin to paclitaxel and nonpegylated liposomal doxorubicin was associated with a 66.7% pCR rate in the subgroup of TNBC patients with a BRCA 1 or 2 germline mutation and a 43.5% rate in those without such mutations (Lancet Oncol. 2014;15:747-56).
Moreover, in the phase III Triple Negative Breast Cancer Trial (TNT) presented at this year’s San Antonio symposium, Dr. Andrew N.J. Tutt reported that in a prespecified analysis of the small subgroup comprising 43 BRCA mutation-positive patients, the objective response rate was 68% in those randomized to carboplatin, compared with 33% in those assigned to docetaxel. Moreover, mean progression-free survival was 6.8 months with carboplatin, significantly better than the 4.8 months with docetaxel or the 3.1 months in carboplatin-treated patients without a BRCA 1/2 mutation.
The TNT trial included 376 patients with metastatic or recurrent locally advanced TNBC randomized to single agent therapy. While the study provides no evidence of a superior response to carboplatin, compared with docetaxel in unselected patients with metastatic TNBC, it does support BRCA 1/2 mutation genotyping as part of decision making regarding therapy in metastatic TNBC and familial breast cancer, according to Dr. Tutt, professor of breast oncology at the Institute of Cancer Research, London.
The trial also tested the utility of Myriad Genetics’ novel Homologous Recombination Deficiency (HRD) score as a predictor of platinum-responsiveness of TNBC and concluded it was without benefit.
Dr. Winer noted that TNBC accounts for only about 15% of breast cancers. Still, that’s roughly 35,000 new cases per year in the United States alone – and TNBC is responsible for a disproportionate degree of breast cancer mortality.
“Perhaps in patients with BRCA 1 or 2 mutations, we’re getting close to thinking that platinum may be a standard, but even here I would await the completion of ongoing trials before we embrace that concept,” he said.
Among these studies is the 12-258 INFORM trial, a multicenter study in which 166 newly diagnosed breast cancer patients with BRCA1 or 2 mutations are being randomized to preoperative cisplatin or doxorubicin/cyclophosphamide.
Dr. William M. Sikov, principal investigator for the CALGB 40603 trial (J. Clin. Oncol. 2015;33:13-21), predicted there will be little crossover between the platinum-user and nonuser camps until definitive trials report whether the therapy improves relapse-free or overall survival.
“One group will say, ‘There’s an absolute increase in pathologic complete response with carboplatin in these two studies, and I’m convinced it’s a beneficial drug in these patients.’ It’s inexpensive, it’s available, although not approved for triple negative breast cancer, and it has some hematologic toxicities. But we have no long-term outcomes yet. I don’t think the TNT results will change anyone’s mind,” according to Dr. Sikov of Women and Infants Hospital in Providence, R.I.
Dr. Winer reported receiving research funding from Genentech. Dr. Sikov serves as a consultant to AbbVie and Celgene. Dr. Tutt reported having no financial conflicts.