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Novel Pharmacogenomic Markers of Irinotecan-Induced Severe Toxicity in Metastatic Colorectal Cancer Patients

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Novel Pharmacogenomic Markers of Irinotecan-Induced Severe Toxicity in Metastatic Colorectal Cancer Patients Novel pharmacogenomic markers of irinotecan-induced severe toxicity in metastatic colorectal cancer patients Thèse Siwen Sylvialin Chen Doctorat en sciences pharmaceutiques Philosophiae doctor (Ph.D.) Québec, Canada © Siwen Sylvialin Chen, 2015 ii Résumé L’irinotécan est un agent de chimiothérapie largement utilisé pour le traitement de tumeurs solides, particulièrement pour le cancer colorectal métastatique (mCRC). Fréquemment, le traitement par l’irinotécan conduit à la neutropénie et la diarrhée, des effets secondaires sévères qui peuvent limiter la poursuite du traitement et la qualité de vie des patients. Plusieurs études pharmacogénomiques ont évalué les risques associés à la chimiothérapie à base d’irinotécan, en particulier en lien avec le gène UGT1A, alors que peu d’études ont examiné l’impact des gènes codant pour des transporteurs. Par exemple, le marqueur UGT1A1*28 a été associé à une augmentation de 2 fois du risque de neutropénie, mais ce marqueur ne permet pas de prédire la toxicité gastrointestinale ou l’issue clinique. L’objectif de cette étude était de découvrir de nouveaux marqueurs génétiques associés au risque de toxicité induite par l’irinotécan, en utilisant une stratégie d’haplotype/SNP-étiquette permettant de maximiser la couverture des loci génétiques ciblés. Nous avons analysé les associations génétiques des loci UGT1 et sept gènes codants pour des transporteurs ABC impliqués dans la pharmacocinétique de l’irinotécan, soient ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2 ainsi que SLCO1B1. Les profils de 167 patients canadiens atteints de mCRC sous traitement FOLFIRI (à base d’irinotécan) ont été examinés et les marqueurs significatifs ont par la suite été validés dans une cohorte indépendante de 250 patients italiens. Nous avons découvert dans la région intergénique en aval du gène UGT1, un nouveau marqueur (rs11563250G) associé à un moindre risque de neutropénie sévère (rapport des cotes (RC)=0.21; p=0.043 chez les canadiens, RC=0.27; p=0.036 chez les italiens, et RC=0.31 p=0.001 pour les deux cohortes combinées). De plus, le RC est demeuré significatif après correction pour multiples comparaisons (p=0.041). Par ailleurs, pour l’haplotype défini par les marqueurs rs11563250G et UGT1A1*1 (rs8175347 TA6), le RC était de 0.17 (p=0.0004). Un test génétique évaluant ces marqueurs permettrait d’identifier les patients susceptibles de bénéficier d’une augmentation de dose d’irinotécan. En revanche, une autre combinaison de marqueurs, ABCC5 rs3749438 et rs10937158 (T–C), a prédit un risque plus faible de diarrhée sévère dans les deux cohortes (RC = 0.43; p=0.001). La coexistence des marqueurs ABCG1 rs225440T et ABCC5 rs2292997A a prédit un risque accru de neutropénie (RC=5.93; p=0.0002), alors qu’une prédiction encore plus significative a été obtenue lorsque ces marqueurs sont combinés au marqueur de risque bien établi UGT1A1*28 rs8175347 (RC=7.68; p<0.0001). Enfin, les porteurs de l’allèle de protection iii UGT1 rs11563250G en absence d’allèles de risque, ont montré une incidence réduite de neutropénie sévère (8.2% vs. 34.0%; p<0.0001). Nous concluons que ces nouveaux marqueurs génétiques prédictifs pourraient permettre d’améliorer l’évaluation du risque de toxicité et personnaliser le traitement à base d’irinotécan pour les patients atteints du cancer colorectal métastatique. iv Abstract Irinotecan is a cytotoxic agent widely used for the treatment of solid tumors, most particularly for metastatic colorectal cancers (mCRC). Treatment with this drug frequently results in severe neutropenia and diarrhea that can seriously impact the course of treatment and patients’ quality of life. Pharmacogenomic tailoring of irinotecan-based chemotherapy has been the subject of several investigations, especially for the UGT1A1 gene, but with limited data regarding transporter genes. In this study, we sought to discover toxicity-associated markers using a haplotype-tagging SNP (htSNP) strategy to maximize gene coverage. We examined the genetic association across the UGT1 locus, and in seven transporter genes participating in irinotecan pharmacokinetics involving the ABC transporter genes ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2 and the solute carrier organic anion transporter gene SLCO1B1. The profiles of 167 mCRC Canadian patients treated with FOLFIRI-based regimens were examined and findings were replicated in an independent cohort of 250 Italian patients. We found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; p=0.043 and OR=0.27; p=0.036, respectively, and OR=0.31 when combined; p=0.001), which remained significant upon correction for multiple testing in the combined cohort (p=0.041). For the two-marker haplotype rs11563250G and UGT1A1*1 (rs8175347 TA6), the OR was of 0.17 (p=0.0004). Genetic testing of this marker may identify patients who might benefit from increased irinotecan dosing. In combined cohorts, a two-marker ABCC5 rs3749438 and rs10937158 haplotype (T–C) predicted a lower risk of severe diarrhea (odds ratio (OR) of 0.43; p=0.001). The co-occurrence of ABCG1 rs225440T and ABCC5 rs2292997A predicted an increased risk of severe neutropenia (OR=5.93; p=0.0002), which was further improved when incorporating the well-known risk marker UGT1A1*28 rs8175347 (OR=7.68; p<0.0001). In contrast, carriers of one protective marker (UGT1 rs11563250G) but none of these risk alleles experienced significantly less severe neutropenia (8.2% vs. 34.0%; p<0.0001). This combination of predictive genetic markers could lead to better risk assessment and may thus enhance personalized treatment. v vi Table of Contents Résumé ................................................................................................................. iii Abstract ................................................................................................................. v Table of Contents ................................................................................................ vii List of Tables ........................................................................................................ ix List of Figures ...................................................................................................... xi List of Abbreviations ......................................................................................... xiii Acknowledgements .......................................................................................... xvii Foreword ............................................................................................................. xix Chapter I Introduction ........................................................................................ 1 1. Colorectal cancer............................................................................................ 1 1.1 Disease Prevalence and Incidence ........................................................................ 1 1.2 An overview of treatment options ......................................................................... 2 2. Irinotecan, an antineoplastic agent used in first-line treatment of mCRC . 4 2.1 Mechanism of Action ........................................................................................... 6 2.2 Pharmacokinetic pathways of irinotecan: metabolism and transport ............. 7 2.3 Tissular & Cellular transport of irinotecan and its metabolites ...................... 12 2.4 Pharmacodynamic pathways of irinotecan ...................................................... 19 2.5 Toxicities induced by irinotecan ....................................................................... 22 3. Pharmacogenomics (PGx) ........................................................................... 25 3.1 Established pharmacogenomics tests : a few examples ................................... 26 3.1.1 Warfarin ........................................................................................................ 26 3.1.2 Clopidogrel .................................................................................................. 28 3.2 Irinotecan Pharmacogenomics ......................................................................... 29 3.2.1 Molecular and clinical impact of UGT1A1*28 ............................................ 29 3.2.2 Other UGT1A variants ................................................................................. 31 3.2.3 UGT1A1*28 genotyping test ....................................................................... 33 4. Hypothesis & Objectives ................................................................................ 39 4.1 Identify UGT1 markers to better predict risk of severe toxicity ..................... 39 4.2 Identify novel markers to help predict toxicity induced by irinotecan in drug transport pathways ................................................................................................. 40 5. Methodologies & Approaches ........................................................................ 41 5.1 Study cohorts: ...................................................................................................... 41 5.1.1 Discovery cohort ............................................................................................ 41 5.1.2 Validation cohort ............................................................................................ 42 5.2 Evaluation of toxicity outcomes ....................................................................... 43 vii 5.2.1
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