Abstract LB-231: Genomic profiling in serial metastatic colorectal tumors identifies copy number alterations and spatio temporal intra-patient heterogeneity profiles associated with clinical response. Q-CROC-01: NCT00984048

Introduction: Colorectal cancer (CRC) is the third leading cause of cancer related deaths primarily due to its resistance to current treatments. Studies aiming at understanding mechanisms of resistance have largely investigated the genomic landscape of primary tumors at diagnosis. However, selective pressures during therapy can lead to the expansion of resistant clones and tumor heterogeneity. This highlights the need to characterize the molecular changes of metastasis over time of treatment and response to decipher tumor evolution and therapeutic resistance mechanisms. Methods: Metastatic liver tissue samples were collected at baseline (pre-biopsies) and at the time of resistance (post-biopsies) in responder and non-responder CRC patients undergoing the same first-line treatment. Paired pre/post biopsies were collected from 14 patients including 4 patients with multiple post-biopsies to assess temporal and spatio-temporal tumor heterogeneity following treatment exposure. Biopsies were profiled using exome and transcriptome sequencing as well as high-density Single-Nucleotide Polymorphism (SNP) array analysis to capture chromosomal anomalies, loss of heterozygosity and copy number (CN) variations. Results: Profiling of 45 samples with both high-density SNP array and exome sequencing revealed 97.4% similarity between both technologies in the identification of genes targeted by copy number changes. Using chemo-naïve biopsies, we identified 120 CN gains and 47 CN loss that were significantly associated with patient progression free survival. Integrative analysis with transcriptome data revealed that only 10% of the genomic CN gains and 17% of the CN loss correlated with their gene expression levels. Based on CN variants comparison between paired pre/post treatment samples, we found high temporal intra-patient heterogeneity over time of treatment. Interestingly, we observed a relationship between heterogeneity and tumor response; showing that acquired resistant tumors have the highest temporal variations. Conclusion: This study, using a multi-omic approach to profile serial liver metastatic samples in CRC patients, highlights the genomic changes in tumor composition after treatment exposure and constitutes an innovative approach to identify clinical biomarkers and molecular signatures of resistance. Citation Format: Mathilde Couetoux du Tertre, Maud Marques, Karen Gambaro, Michael Witcher, Benoit Samson, Bernard Lespérance, Yoo-Joung Ko, Richard Dalfen, Eve St-Hilaire, Lucas Sidéris, Félix Couture, Sabine Tejpar, Ronald Burkes, Mohammed Harb, Errol Camlioglu, Adrian Gologan, Vincent Pelsser, André Constantin, Suzan McNamara, Petr Kavan, Claudia Kleinman, Gerald Batist. Genomic profiling in serial metastatic colorectal tumors identifies copy number alterations and spatio temporal intra-patient heterogeneity profiles associated with clinical response. Q-CROC-01: NCT00984048 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-231.