Estimating metabolic pathway overlap in precision oncology: integrating pharmacogenetics and polypharmacy

Introduction While metabolic pathway overlap is frequent in polypharmacy patients, the modification of genotype-predicted metabolic phenotypes by other substrates is not well established yet, and its relevance for pharmacogenetic implementation in gastrointestinal oncology has not been systematically assessed. We aimed to quantify the overlap between pharmacogenetically relevant treatment pathways and concomitant medications in routine gastrointestinal cancer care. Methods Guideline-recommended drugs for gastrointestinal malignancies were evaluated regarding their dependence on pharmacogenetically relevant enzymes. In parallel, real-world co-medication profiles were analyzed to assess the prevalence of inhibitors and inducers of these identified enzymes, as well as the substrate-mediated pathway sharing. Results Only a minority of systemic anticancer drugs recommended in treatment guidelines were directly affected by established pharmacogenetic polymorphisms, mainly involving CYP2D6, CYP2C19, CYP2C9, and related pathways. In contrast, co-medication profiles with medications sharing common metabolic pathways were highly prevalent whereas recognized moderate or strong inhibitors were much less frequent (<10%). Conclusion Although relatively few anticancer therapies are directly affected by actionable pharmacogenetic variants, the potential for metabolic pathway overlap may increase the clinical relevance of pharmacogenetics in gastrointestinal oncology. By systematically quantifying the coexistence of inhibiting co-medication as well as substrate-mediated pathway sharing, this study provides descriptive explorative estimates of the metabolic pathway-overlap burden. These findings suggest that pharmacogenetic implementation strategies should consider both genotype and medication-related pathway overlap to better inform estimates of drug exposure and support precision oncology.