Integrating Somatic and Germline Pharmacogenomics for Therapeutic Decisions in Precision Oncology

PURPOSE: Clinical genomic profiling of tumors identifies therapeutic targets, while germline pharmacogenomics (PGx) guides drug dosing and toxicity avoidance. However, the combined clinical landscape of both somatic and germline actionable variants across cancers has not been comprehensively defined. METHODS: Tumor and matched germline whole-exome sequencing data were analyzed for 10,302 patients in The Cancer Genome Atlas. Somatic mutations with therapeutic relevance were mapped to US Food and Drug Administration (FDA)-approved targeted drugs using the Oncology Knowledge Base database (levels 1-4). Germline PGx variants were identified using PyPGx and cross-referenced with drug-gene interactions in PharmGKB (levels of clinical annotation 1-2). This enabled construction of an integrated germline-somatic PGx profile per patient. RESULTS: ). Across the cohort, 5,275 (51%) patients had more actionable germline variants than somatic mutations, whereas 1,988 (19%) had more actionable somatic mutations. CONCLUSION: Integrating germline PGx with somatic profiling reveals that actionable germline variants are nearly universal among patients with cancer in our cohort, extending beyond tumor-specific therapy to encompass toxicity and supportive care management. Routine implementation of combined germline and somatic sequencing in oncology could enhance therapeutic precision, minimize adverse effects, and inform individualized treatment decisions.