Association of germline ABCB1 and ERCC1 polymorphisms with CDK4/6 inhibitor-induced neutropenia in patients with breast cancer: a systematic review and meta-analysis.

ABCB1

Germline ABCB1 variants, encoding P-glycoprotein, altering CDK4/6 inhibitor efflux and bone marrow exposure.

Grade 3 or 4 neutropenia affects up to 60% of patients treated with CDK4/6 inhibitors for HR+/HER2- advanced breast cancer, and data on predictive germline polymorphisms have been conflicting. This PROSPERO-registered meta-analysis searched PubMed, Scopus and Web of Science and retained four studies totalling 1,138 patients, covering four variants: ABCB1 rs1128503 and rs1045642, ERCC1 rs11615 and rs3212986. No variant was associated with neutropenia overall, but ancestry-dependent heterogeneity emerged for ABCB1: rs1045642 T-carrier status increased risk in European patients (pooled OR 1.62; 95% CI 1.05-2.52) and decreased it in East Asians (OR 0.31; 95% CI 0.13-0.74; subgroup difference p = 0.0009). The signal previously reported for ERCC1 rs11615 disappeared on independent replication.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An effect-direction reversal between populations, based on only four studies with some ancestry subgroups resting on a single study, is far more often explained by differential linkage disequilibrium or chance than by distinct biology. The most instructive result here is negative: ERCC1 rs11615, a borderline signal from a single study, does not survive replication — a useful reminder of how fragile isolated pharmacogenetic associations are. None of these variants belongs in a work-up before CDK4/6 inhibitor therapy today.

Analysis by Dr Thibaut Benquey