Influence of CYP2D6 polymorphisms on tamoxifen side effects in patients with breast cancer

CYP2D6 is a key enzyme involved in converting tamoxifen into its active metabolites. However, polymorphisms in CYP2D6 lead to variable enzymatic capacities. We aimed to examine the impact of CYP2D6 polymorphisms on tamoxifen-derived side effects in breast cancer patients.

Eighty-six patients with hormone receptor-positive breast cancer who received tamoxifen were classified as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM) metabolizers according to Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. All patients received 20 mg/day tamoxifen for 5 years, except PM, who were dose-escalated (20 mg/day for 4 months, 40 mg/day for 4 months, 60 mg/day for 4 months, then back to 20 mg/day). Adverse events-osteoarticular pain, hot flashes, asthenia, and uterine changes-were analyzed by Kaplan-Meier and Cox regression. A propensity score-matched (PSM) subgroup was also examined.

Rapid metabolizers (RM: NM + UM) consistently showed fewer uterine changes compared to slow metabolizers (SM: PM + IM) in both the entire cohort (HR 0.20, p = 0.001) and the PSM subgroup (HR 0.07, p = 0.011). Excluding PM and UM, comparison of IM vs. NM showed similar differences (complete group: HR 0.20, p = 0.002; PSM subgroup: HR 0.23, p = 0.068). Other side effects (joint pain, hot flashes, asthenia) were not significantly associated with CYP2D6 phenotype.

Uterine alterations in breast cancer patients treated with tamoxifen appear linked to decreased CYP2D6 activity, although we observed no association between CYP2D6 and other toxicities. These findings suggest closer monitoring for uterine toxicity in individuals with impaired CYP2D6 metabolism.