BRCA1 and BRCA2 proteins play a central role in DNA repair process. We hypothesize that BRCA1/BRCA2 germline mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy.
We included women with primary breast cancers treated with (neo)adjuvant chemotherapy and screened for BRCA1/BRCA2 germline mutations in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3-4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use, and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort).
Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. None of the patients received dose-dense (every 14 days) chemotherapy. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. Among patients with triple-negative breast cancers, febrile neutropenia (35% vs. 12%, p = 0.038), grade 3-4 neutropenia (73% vs. 28%, p = 0.003) and grade 4 neutropenia (60% vs. 13%, p = 0.001) were significantly more frequent in BRCA1 carriers compared to non-carriers. Among BRCA1 carriers, the majority of patients were likely to have grade 3-4 neutropenia (88%; p < 0.001), but none of those having mutations located in the RING domain (0%, p = 0.165) compared to non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the three groups.
BRCA1 germline mutations predispose breast cancer patients to greater acute hematological toxicity. This has implication for primary prophylaxis with G-CSF.
La Fondation Henriette Meyer.
All authors have declared no conflicts of interest.