Pre-emptive pharmacogenetic testing implementation for chemotherapy dosage optimization: the translational experience at CRO of Aviano

Abstract

Background: Pharmacogenomics (PGx) is one of the first clinical applications of the postgenomic era and allows personalized medicine rather than the established 'one size fits all' approach. A pre-emptive PGx testing shouldreduce 'trial and error' prescribing and lead to more efficacious, safer and cost-effective drug therapy. Its application in routine patient care is still limited, despite national and international guidelines. We have recently completed a retrospective genotyping of 603 cancer patients, treated with fluoropyrimidines (FL), demonstrating that the test specificity for the prediction of early G >= 3 toxicity based on the analysis of DPYD-rs3918290, -rs55886062, and -rs67376798 was 99%. rs3918290 and rs67376798 were associated to G >= 3 toxicity after bootstrap and Bonferroni correction (P = 0.003,P = 0.048). rs55886062 was not significant likely due to its low allelic frequency, but one out of two heterozygous patients (compound heterozygous with rs3918290) died from toxicity after one cycle. Our data on the role of UGT1A1*28 in predicting the occurrence of early severe (G >= 3) toxicity after an irinotecan (IRI) based treatment have been published. Method(s): Based on these data, current literature, and SIF-AIOM guidelines, the Experimental and Clinical Pharmacology Unit of CRO (Aviano) has set up during 2014, a clinical PGx service accessible to Medical and Radiotherapic Oncology Units. Result(s): Up to date 233 cancer patients candidate to a therapy with either FL or IRI were referred to the Pgx service prior to treatment. Based on the genotype data for DPYD (rs3918290, rs55886062, rs67376798), or UGT1A1*28 a starting dose adjustment was suggested for 18 patients, possibly preventing an early and potentially life-threatening toxicity in 7 cases (3%), roughly estimated on our previous data. A PGx electronic report is embedded in the patient clinical record. A further result of this experimental service was a progressive sensitization of the oncologists on PGx, demonstrated by the increasing rate by time of patients referred for pre-treatment genotyping. Cost-effectiveness and HTA studies are ongoing to assess the clinical utility of a pre-emptive PGx approach in oncology. Conclusion(s): Based on this successful experience and according to the international CPIC and DPWG guidelines we have planned to increase the drugs to be tested in our Institute for PGx based dose adjustment and move another step toward a safer and more efficacious personalized medicine.