Abstract B62: Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy

Response to neoadjuvant chemoradiotherapy (nCRT) varies substantially among patients with locally advanced rectal cancer, but key determinants of treatment response are not fully understood. Intratumoral genetic heterogeneity (ITGH) is a common feature of solid tumors and has been proposed to drive disease progression and treatment response. Others and we have recently demonstrated that primary nontreated rectal tumors exhibit significant ITGH, but the effect of nCRT in shaping the clonal architecture of rectal cancer has not yet been addressed. In the present work, we further expanded the analysis of ITGH in rectal cancer by analyzing whole-exome sequencing (WES) and clinical data from 79 primary nontreated rectal cancers obtained from The Cancer Genome Atlas. We show that primary rectal tumors exhibit a remarkable variability in the degree of ITH. We also analyzed the effect of nCRT on ITGH and monitored tumor cell subpopulation dynamics after treatment through WES of paired tumor samples collected at diagnosis (pretreatment) and at surgery following nCRT (post-treatment) from seven patients. We show that treatment exposure does not introduce novel somatic mutations or significantly alter tissue genetic heterogeneity. Instead, nCRT acts as a potent selective pressure, shaping the mutational landscape of rectal tumors and allowing the selection and expansion of tumor cell subpopulations, which are more prone to resist nCRT. Our results shed light on the highly heterogeneous and dynamic mutational landscape of rectal tumors and indicate that ITGH may directly affect response to nCRT. Citation Format: Cibele Masotti, Fabiana Bettoni, Bruna R. Correa, Angelita Habr-Gama, Joaquim Gama-Rodrigues, Maria Viana, Bruna B. Vailati, Guilherme P. Sao Juliao, Laura M. Fernandez, Pedro A. F. Galante, Rodrigo O. Perez, Anamaria A. Camargo. Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B62.