Abstract P5-08-01: Reconstructing the evolutionary paths of BIG 1-98

We are reconstructing the dynamics of tumour growth, treatment response, and origins of resistance of the Breast International Group (BIG) 1-98 study to determine the evolutionary paths of non-responders. We established the somatic alteration landscape of primary tumours collected at surgery from BIG 1-98 patients using targeted DNA sequencing of 287 genes of FFPE samples from 538 patients. Combined analysis of genetic and clinical data indicates increased genomic instability; TP53 mutations and copy number variations of 11q13 and 8p11 are associated with poor prognosis. We developed an in silico simulation framework to investigate if the non-responder outcome is due to (over)-treatment or intrinsic to evolutionary selection prior to diagnosis. To reconstruct the evolutionary history of tumours, we created a computational multitype branching process that tracks the expansion of diverse clonal lineages as they acquire driver and passenger mutations that alter their proliferation and mutation rates. To account for the heterogeneity between patients, we created a fitting procedure based on the Cramer-von Misses statistic to find the likelihood of parameters of our computational model that recreate the mutational landscape and clinicopathological factors observed in each patient. Once the fitting procedure is done, we simulate the course of treatment following the study arm scheme accounting for the cell-cycle action mechanism of Tamoxifen and Letrozole. Using our tool, we are characterising the range of tumour development scenarios covering different degrees of aggressiveness and genomic instability. Our computational model allows simulation of diverse adjuvant-schemes to predict optimised treatment regimes for validation in patient-derived tumour xenograft mouse models. Citation Format: Lara-Gonzalez LL, Loi S, Ferrari D, Papenfuss A, Goode DL. Reconstructing the evolutionary paths of BIG 1-98 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-08-01.