Clinical outcome and toxicity from taxanes in breast cancer patients with BRCA1 and BRCA2 pathogenic germline mutations

Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P = .0025) and leukopenia (P = .001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P = .001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P = .04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P = .04; P = .03; P = .06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.

Keywords: BRCA; breast cancer; chemotherapy toxicity; peripheral neuropathy; taxanes.