P196 Improved progression-free survival in metastatic colorectal cancer patients carriers of the HNF1A coding variant p.I27L treated with irinotecan

Adrien Labriet , Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, QC, Canada
Elena Demattia , Clinical and Experimental Pharmacology, “Centro di Riferimento Oncologico”- National Cancer Institute, Aviano, Italy
Erika Cecchin , Clinical and Experimental Pharmacology, “Centro di Riferimento Oncologico”- National Cancer Institute, Aviano, Italy
Éric Lévesque , Medecine, CHU de Québec Research Center and Faculty of Medicine, Laval University, Québec, QC, Canada
Derek Jonker , Division of Medical Oncology, Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
Félix Couture , CHU de Québec Research Center and Faculty of Medicine, Laval University, Québec, QC, Canada
Angela Buonadonna , Medical Oncology Unit, “Centro di Riferimento Oncologico”- National Cancer Institute, Aviano, Italy
Mario D’Andrea , Medical Oncology Unit, “San Filippo Neri Hospital”, Rome, Italy
Lyne Villeneuve , Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, QC, Canada
Giuseppe Toffoli , Experimental and Clinical Pharmacology Unit, Clinical and Experimental Pharmacology, “Centro di Riferimento Oncologico”- National Cancer Institute, Aviano, Italy
Chantal Guillemette , Canada Research Chair in Pharmacogenomics, CHU de Québec Research Center, Québec, QC, Canada
Hepatocyte nuclear factor 1 alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic function including detoxification processes. We examined whether HNF1A polymorphisms are associated with clinical outcomes in metastatic colorectal cancer patients (mCRC) treated with irinotecan-based chemotherapy using a haplotype-tagging single nucleotide polymorphism approach. We studied 167 Canadian and 250 Italian mCRC patients comprising a total of 417 Caucasian cases. Cox regression and logistic regression analyses were performed to assess relationships with response rate, progression-free survival (PFS) and overall survival (OS), and toxicities, respectively. The association between marker and irinotecan pharmacokinetic parameters was also studied in 49 mCRC cases, and with mRNA expression in tissues of healthy donors using data from the GTEx project. The intronic rs2244608A>G marker was predictive of an improved PFS in the Canadian cohort and validated in Italians, with hazard ratios of 0.74 and 0.72, P=0.076 and 0.038, respectively. In individuals of European descent, rs2244608A>G was in strong linkage (r²=0.98) with the HNF1A coding variant rs1169288c.79A>C (p.I27L). In support of an altered HNF1A function, carriers of the rs2244608G minor allele displayed enhanced drug exposure by 45% (P=0.032) compared to non-carriers. In healthy donors, we observed an altered mRNA expression of genes in the liver (ABCC1, P=0.009, ABCC2, P=0.048 and CYP3A5, P=0.001; n=89) and the intestine (TOP1, P=0.004; n=75). Our findings suggest that the HNF1A rs2244608, or the tightly linked functional coding variant p.I27L, might be a potential prognostic marker with irinotecan-based regimens.