Abstract 5548: Genotype-phenotype discordance of the hepatic drug metabolism enzyme CYP2C19 in gastrointestinal cancer patients

Abstract

Abstract CYP2C19 is a hepatic drug metabolizing enzyme that contributes to the metabolism of chemotherapeutic agents such as cyclophosphamide, thalidomide, bortezomib, icotinib, tivantinib and indisulam. CYP2C19 null function genotype strongly predicts phenotype in healthy populations. However we have previously shown an additional acquired loss of CYP2C19 metabolic function in up to one third of patients with advanced solid-tumor cancers. It is not known whether this effect also occurs in earlier stage disease. The aim of this study was to investigate whether this acquired loss of CYP2C19 function was detectable in patients with stage III-IV and resected disease. Patients undergoing treatment for gastro-intestinal tumors (n=50) with either no evaluable disease (resected) or stage III-IV disease were recruited following informed consent and probed for CYP2C19 activity (200 mg proguanil p.o.) on three test occasions. CYP2C19 metabolic activity was assessed using HPLC analysis of the 3h post dose plasma drug and metabolite concentrations. The log metabolic ratio (drug/metabolite ≤ 1 ≥) was used to categorize individuals as either extensive or poor metabolizers. CYP2C19 genotype was determined by PCR-RFLP to identify individuals homozygous for null function mutations (CYP2C19*2 and CYP2C19*3). One patient had a poor metabolizer genotype (CYP2C19*2*2) and was excluded. An acquired loss of CYP2C19 activity was observed in 23% (n=6) stage III-IV and 13% (n=3) of resected patients at the first test. This genotype-phenotype discordance was a significant in both groups (p<0.0001). Notably, hepatic CYP2C19 function was not stable over time in a number of study participants. CYP2C19 phenotype categories were altered in 7 stage III-IV patients and 5 resected patients over the period of testing. In the majority of these subjects CYP2C19 activity declined over at least one additional testing occasion. This study demonstrated that an acquired loss of CYP2C19 activity was present in patients with stage III-IV disease as well as in those subjects who had undergone resection. This work confirms our previous finding of a significant level of CYP2C19 genotype-phenotype discordance in patients with advanced end-stage cancer. This discordance is unlikely to be due to rare null mutations in this gene as dynamic changes in metabolic activity were observed in some individuals. While the use of genotyping is often suggested as a method to personalize treatment, this data indicates that this approach could significantly underestimate the number of phenotypic CYP2C19 poor metabolizers. An acquired loss of function may have implications for the safety and efficacy of chemotherapeutic agents metabolized by CYP2C19. Further work is required to elucidate the mechanisms behind this down-regulation of drug metabolism in cancer and to determine whether this phenomenon adversely affects therapeutic outcomes. Citation Format: Kathryn E. Burns, Wing-Yee Lo, Michael P. Findlay, George Laking, Nuala A. Helsby. Genotype-phenotype discordance of the hepatic drug metabolism enzyme CYP2C19 in gastrointestinal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5548. doi:10.1158/1538-7445.AM2014-5548