BRCA1/2 mutations may influence carboplatin outcomes in TNBC
Germline mutation status of BRCA1 and BRCA2 in patients with triple-negative breast cancer (TNBC) can affect treatment outcome, according to a secondary analysis of the GeparSixto* trial.
“It appears likely that BRCA1 and BRCA2 mutation carriers show superior response rates following standard neoadjuvant chemotherapy, while patients without BRCA1 and BRCA2 mutations may benefit from the addition of carboplatin,” said the researchers.
In patients with TNBC who harboured BRCA1 and BRCA2 germline mutations, rates of pathological complete response (pCR) to bevacizumab added on to a polychemotherapy regimen comprising paclitaxel and low-dose doxorubicin were higher than patients without the mutations (66.7 percent vs 36.4 percent, odds ratio [OR], 3.50; p=0.008). [JAMA Oncol 2017;doi:10.1001/jamaoncol.2017.1007]
However, the high pCR rate in BRCA1 and BRCA2 mutation carriers (66.7 percent) was not further increased by adding carboplatin to the regimen in a neoadjuvant setting (65.4 percent). In contrast, the addition of carboplatin benefitted patients without BRCA1 and BRCA2 mutations ─ by increasing rates of pCR (55 percent vs 36.4 percent, OR, 2.14; p=0.004) and disease-free survival (DFS) after a median follow-up of 35 months compared with noncarriers in the noncarboplatin arm (85.3 percent vs 73.5 percent, hazard ratio, 0.53; p=0.04).
“Because of the lack of additive effects observed in this study and the finding that elevated pCR rates translate into a clinical benefit [in terms of improved DFS], a less intense therapy regimen might be considered for BRCA1 and BRCA2 germline mutation carriers,” said the researchers, noting that carboplatin addition was shown to increase haematological and nonhaematological adverse effects previously. [Lancet Oncol 2014;15:747-756]
“Our findings may have implications for personalized therapy regimens that consider BRCA1 and BRCA2 germline mutation status.”
The secondary analysis was based on 291 women (mean age 48 years) out of 315 patients with TNBC enrolled in the multicentre prospective GeparSixto trial, who were randomized 1:1 to either a carboplatin or noncarboplatin arm in addition to a regimen of paclitaxel, bevacizumab, and low-dose doxorubicin.
“The GeparSixto trial was complicated by a nonstandard chemotherapy backbone with a lower intensity and nonstandard formulation of anthracycline … [Also,] caution should be exercised in drawing too many conclusions from small subsets [n=50 for BRCA1 and BRCA2 mutation carriers],” according to Drs Hope Rugo and Karen Gelmon from University of California-San Francisco Comprehensive Cancer Center in San Francisco, California, US and University of British Columbia in Vancouver, Canada, respectively in an editorial. [JAMA Oncol 2017;doi:10.1001/jamaoncol.2017.1954]
According to Rugo and Gelmon, the findings are not sufficient to change practice.
“[I]t remains unclear how and when [platinum] agents should be incorporated into neoadjuvant and adjuvant chemotherapy regimens. It also remains to be determined whether platinum can be used instead of anthracyclines, or if these agents should be used preferentially in those who do not achieve a pCR to standard neoadjuvant chemotherapy, and whether various methods of testing [homologous recombination deficiency] will help to define the subset of patients most likely to benefit.”
“Platinum agents improve response, but toxicity is increased and benefits on outcome remain uncertain,” they wrote. “Individualization of therapy is desperately needed.”