Why pharmacogenomic biomarkers for chemotherapy-induced peripheral neuropathy fail: a systematic review of genetic associations, replication, and clinical translation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting toxicity of cancer treatment, yet reliable biomarkers to predict individual susceptibility remain lacking. Germline genetic variation has been widely investigated as a potential contributor to CIPN risk; however, the consistency and clinical utility of these associations remain unclear. We performed a systematic review of genetic association studies evaluating CIPN across neurotoxic chemotherapies. PubMed, Embase, Web of Science, and the Cochrane Library were searched (April 2025) for human studies assessing germline variants in relation to clinician- or patient-reported CIPN. Eligible studies were identified in four major drug classes: vincristine, taxanes, platinum agents, and bortezomib. Study characteristics, phenotyping approaches, ancestry, and variant-level data were extracted, and study quality was assessed using Q-Genie. Meta-analysis was not performed due to substantial heterogeneity in study design and outcome measures. 72 studies were included, predominantly involving cohorts of European ancestry. The most consistently replicated loci were CEP72 and ETAA1 for vincristine-induced neuropathy; EPHA5, FGD4, and FZD3 for taxane-induced neuropathy; and ABC transporter genes and GSTP1 for platinum-induced neuropathy. For bortezomib, associations involving TRPV1, DNA repair pathways, and inflammatory signalling showed emerging but largely non-replicated evidence. Across studies, marked heterogeneity in CIPN definitions, phenotyping instruments, statistical approaches, and effect allele reporting limited comparability and reproducibility. Collectively, these findings indicate that current pharmacogenomic approaches to CIPN are constrained by poor replication, population bias, and inconsistent methodology, which hinder translation into clinically actionable biomarkers. Future progress will require harmonised phenotyping, multi-ancestry genome-wide studies, and integration of functional validation to enable robust risk stratification and precision oncology approaches to CIPN. Systematic Review Registration: Identifier PROSPERO [CRD42025635757].