Integrative genomic analysis reveals pharmacogenomic determinants of chemotherapy response

Background: Pharmacogenomic (PGx)markers are critical in understanding patient responses to chemotherapeutic agents. They influence how patients metabolize popular chemotherapeutic agents like fluoropyrimidines and irinotecan, thereby impacting efficacy and risk of severe toxicity. Although PGx testing significance is well established, their genomic profiling and clinical interpretation involves challenges including limited clinical evidence for many variants, incomplete capture of pharmacogenomic-relevant regions, tumor heterogeneity and sampling bias, and variant interpretation. Many cohort studies among the Uzbek population have also highlighted the challenges including the one among 99 Uzbek cancer patients (breast, gastric, colorectal) identified the clinically significant DPYD IVS14+1G>A splice-site variant, also known as the DPYD *2A allele in a significant fraction of individuals indicating that DPD-related 5-FU risk is present in the population and merits pretreatment consideration. Our current study presents the significance of a comprehensive genomic profiling (CGP) and interpretation of pharmacogenomic markers for effective chemotherapeutic performance in clinical scenario. Methods: A total of 124 patients who were genomically profiled using our CGP assay was retrospectively investigated for pharmacogenomic variants. The cohort included cancer types including breast, colon, lung, melanoma, pancreatic, stomach, ovarian, rectal, and hepatobiliary tract. CGP was performed on these patients using next-generation sequencing (NGS) with the OncoIndx® panel. Results: From the CGP results of the 124 profiled patients, three critical pharmacogenomic markers were detected. The DPYD wildtype genotype was detected in 92% (n=114) of patients which was interpreted to be associated with reduced risk of adverse events when treated with 5-FU/ fluoropyrimidine-based chemotherapy. Another 2.4% (n=3) of patients were detected with DPYD c.1129-5923C (HapB3) variant which was interpreted to impact DPYD function and can affect treatment outcomes leading to increased toxicity when treated with standard dosage of 5- FU / fluoropyrimidine-based- based chemotherapy. Further, 4% (n=5) were detected with wildtype genotype of TYMS, and 0.8% (n=1) heterozygous, and 4.8% (n=6) patients detected with 6bp deletion interpreted to cause increased toxicity/ADR. In addition, 9.7% (n=12) of patients were detected with UGT1A1 wildtype which determines response o irinotecan-based chemotherapy. Conclusion: This study, highlights the significance of profiling and effective interpretation of a patient's PGx phenotype from the profiled genotype as a critical measure to lower risk of debilitating adverse events and guide towards safer, more effective dosing of chemotherapy.