Uso di marcatori farmacogenetici per migliorare la sicurezza e l'efficacia dei trattamenti antiblastici all'interno dello studio di implementazione delle linee guida PGx PREPARE

Despite the scientific and clinical advances in pharmacogenomics (PGx) to date, its application in clinical practice is still limited, although numerous studies and implementation programs have been launched in recent years. The Experimental and Clinical Pharmacology of Centro di Riferimento Oncologico (CRO) has been investigating and supporting the use of pharmacogenetic markers in oncology for over 20 years to improve patient outcomes in terms of both toxicity and efficacy. However, there are still several obstacles to overcome in order to recognize the clinical utility of PGx. The U-PGx consortium (Ubiquitous Pharmacogenomics), which includes CRO Experimental and Clinical Pharmacology, was formed with the aim of filling these gaps by designing a prospective randomized controlled clinical trial called PREPARE: "PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions", funded by a grant from the Horizon 2020 program of European Commission (Grant Agreement N°668353). Our structure has been particularly involved in the design of this project and represents a national reference point for the implementation of this new model of personalized medicine in a unique program for its multi-gene, multi-drug and multi-ethnic approach in different European health contexts. This aspect is particularly relevant in oncology treatments, where drugs such as fluoropyrimidines and irinotecan have a narrow therapeutic index and the patient is exposed to toxic effects that are sometimes severe or even fatal. Therefore, the use of PGx guidelines in cancer clinical practice can be a powerful tool to improve and personalize cancer therapies. The main objective of this work was to implement PGx guidelines in the clinical practice of cancer patients in order to personalize their therapy. Specifically, our work focused on the implementation of clinical recommendations related to genetic variants in the DPYD, UGT1A and CYP2D6 genes following the prescription of fluoropyrimidines, irinotecan and tamoxifen, respectively. The secondary objective of this work was to demonstrate that PGx testing prior to administration of therapy has a positive impact on cancer patient outcomes in terms of toxicity and efficacy. Following this implementation project, a PGx diagnostic procedure was developed at our institute and integrated into the patient's clinical journey. Through the U-PGx experience, which has allowed health professionals to increase their awareness of PGx, requests from oncologists for PGx analysis prior to treatment have increased exponentially. A preliminary analysis of a subset of 563 patients showed that in the control arm, patients with actionable genotype had a higher risk of developing G ≥ 3 toxicity than patients with non-actionable genotype (p = 0.0317). This difference was not significant in the study arm in which patients received genotype-based dose reduction from the start of therapy (p = 0.746). Treatment discontinuation due to adverse events was also examined. This showed that patients with actionable genotype in the control arm discontinued therapy at a higher rate than wild-type patients (p = 0.0002). This trend was not significant in the study arm (p= 0.9999). Evaluation of treatment delays due to toxicity revealed a significant difference between patients with actionable and non-actionable genotype in the control arm (p = 0.0018). In the study arm, this difference did not reach statistical significance (p = 0.5492). Interesting data emerged from the evaluation of the Relative Dose Intensity (RDI) of patients with actionable genotype included in both arms. Patients with actionable genotype in the control arm had similar DI to patients with actionable genotype in the study arm who received PGx-based dose reduction prior to initiation of therapy (p = 0.3571). These data suggest that PGx approach is an easily implementable model in clinical oncology practice and improves patient outcome.