Innovative strategies for tailoring therapy in cancer patient pharmacogenetics and therapy personalization in metastatic colorectal cancer patients treated with irinotecan
Pharmacogenetics focuses on inter-subject variation in drug therapeutic effects and toxicity depending on genetic polymorphisms. Irinotecan and fluoropyrimidine, currently used in cancer chemotherapy, are characterized by a sometimes unpredictably severe toxicity. Pharmacogenomics was largely applied in the last years to the irinotecan-based colorectal cancer (CRC) treatment personalization with limited data regarding validated marker of severe toxicity.
In the first part of my thesis, I have been focusing on the investigation of innovative pharmacogenetic markers of neutropenia or gastrointestinal toxicity irinotecan-related using the “tagging polymorphisms (SNPs)” (TagSNPs) approach. Since therapeutic implications of cancer-related inflammation have gained great attention in recent years, innovative prospects for the optimization of tailored therapy arose. Two hundred and fifty metastatic CRC patients, homogeneously treated with an irinotecan-including regimen (FOLFIRI), have been collected retrospectively for this study. Clinical parameters of toxicity (by NCI-CTC scale) and response to the therapy (by WHO criteria) were monitored all along the study. They were genotyped for 246 htSNPs characterizing 22 transcriptional regulators and cytokines inflammation-related genes; positive findings were replicated in a cohort of 167 metastatic CRC patients receiving FOLFIRI-based therapy. One polymorphism (rs1053004) in STAT-3 gene resulted predictive of severe GI toxicity in both discovery and replication cohort with a protective effect toward the risk of developing grade 3-4 events (OR=0.51 CI=0.27-0.99 p=0.045; OR=0.38 CI=0.15-0.95 p=0.038, respectively). Additional variants in NRs genes, especially HNF4α and VDR, although not validated, were suggested to contribute to determining the risk of developing neutropenia and GI toxicity. Preliminary pharmacokinetic data supported the observed genotype/phenotype clinical associations. A validated contribution of STAT-3 rs1053004 in determining GI toxicity risk after FOLFIRI therapy was pointed out. Further potential predictive markers of irinotecan-related toxicity were suggested. These findings could represent a further step towards personalized FOLFIRI therapy.
UGT1A1*28 polymorphism has been demonstrated in the last years to have an impact on irinotecan pharmacokinetics and toxicity to the treatment. Although, the adoption of a pre-emptive UGT1A1*28 genotyping to increase irinotecan safety and to better characterize patient “Diagnosis Related Groups”, for therapy reimbursement purposes in clinical practice, is still limited. The second part of my thesis aimed to estimate the effect of UGT1A1*28 on the costs associated with irinotecan-related toxicity. A retrospective analysis of the costs of toxicity management was conducted on a subset of the aforementioned population of 250 mCRC patients. 243 mCRC patients treated with FOLFIRI have been genotyped for UGT1A1*28. The mean predicted cost per patient was higher for *1/*28 (1,119€) and *28/*28 (4,886€), as compared to *1/*1 (812€) (P<0.001). This is consistent with a different grade 4 toxicity profile among the three groups of patients, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele.
The aim of the third part of my thesis consisted of evaluating the implementation of the routine application of prospective DPYD risk variants and UGT1A1*28 screening at the National Cancer Center CRO of Aviano. A Pharmacogenetic implementation infrastructure has been set-up starting from January 2014 for the prevention of irinotecan (UGT1A1*28 rs8175347) and/or fluoropyrimidine (DPYD rs3918290, rs55886062, rs67376798)-associated toxicity in the clinical routine of the National Cancer Center CRO of Aviano. Genotyping was performed by PCR-based methods, such as pyrosequencing, Sanger sequencing, and fragment analysis. A digital Pharmacogenomic report including the dose-adjustment recommended according to the published pharmacogenetics guidelines will finally be embedded in patients’ clinical record and ultimately made available to the medical personnel. From September 2011 to September 2016, a total of 393 patients were genotyped for such variants at CRO-Aviano. Three hundred and eighty-six out of 393 patients were screened for at least one DPYD variants and 40 for UGT1A1*28. Of these patients, 9 patients (2.58%) were found to carry at least one DPYD variants, and two patients (5.00%) were found to carry two *28 risk alleles for UGT1A1. Moreover, twenty-three patients out of 393 (5.85%) were referred for toxicity from the CRO-Aviano oncologists.
In conclusion, in this work of thesis, interesting molecular markers with a predictive value on pharmacokinetics and pharmacodynamics of irinotecan were described. A possible application of these parameters in the clinical practice will be useful to design a tailored irinotecan dosing based on peculiar characteristics of each patient. In addition to the prevention of severe toxicity, pre-treatment UGT1A1*28 genotyping should be considered to save economic resources related to the management of irinotecan-related toxicities and for innovative reimbursement strategies. Plus, the implementation of pre-emptive pharmacogenetics tests is now part of a European Project (U-PGx) with the aim of providing the final proof of pharmacogenetics efficacy in increasing drug safety when fully integrated into the clinical practice
