Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study.

Abstract

Carriers of germline pathogenic variants of theBRCA1gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predictgBRCA1pathogenic variants. The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouringgBRCA1pathogenic variants among patients presenting agranulocytosis during C1. Three hundred seven BC patients were included: 32 (10.4%)gBRCA1, 27 (8.8%)gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes,gBRCA1heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive forgBRCA1pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predictinggBRCA1were 45.8% (25.6-67.2%), 82.8% (77.5-87.3%), 22.9% (6.1-37.3%), and 93.4% (88.9-96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used forgBRCA1evaluation. Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1detection in non-metastatic BC patients.