S29Clonal evolution and drug resistance in the blood of patients with metastatic solid tumors responding to targeted therapies - THE CORNUCOPIA STUDY

Background: When metastatic cancers are challenged with targeted drugs a subset of resistant cells invariably emerges. As a result targeted therapies are only transiently effective. Strategies to overcome resistance are essential and require a deeper understanding of the evolutive nature of cancer. There is no currently effective way to monitor the emergence of resistant clones in solid tumors patients (PTS). Trials often include exploratory biopsies at progression (PD) to identify the molecular determinants of resistance. However, single-lesion biopsies vastly underrepresent molecular heterogeneity and might fail to detect resistant alleles impacting on further treatment responses. Contrariwise, molecular profiles of circulating tumor DNA (liquid biopsies, LB) allow for a longitudinal tracking of the tumor dynamics and real time monitoring of secondary resistance. How serial LBs and lesion-specific radiographic responses can be integrated to delineate mechanisms of drug resistance and guide further rounds of therapies is presently unknown. To address this question we designed CORNUCOPIA. Materials and methods: CORNUCOPIA is a translational study in PTS with metastatic colorectal, gastric, and breast cancer, responding to targeted therapy against known actionable oncogenes. PTS are LB-sampled at baseline, longitudinally and at PD using a purposely designed next generation sequencing panel for DNA aberrations in >200 loci associated with sensitivity and resistance to targeted agents. Concomitantly the original paraffin diagnostic sample, serial CT scans and on therapy bioptic tissue specimens are collected. Conclusions: Clonal evolution maps for individual patients will be generated by integrating molecular profiles from LB with lesion-specific radiographic responses. A sample size of 250 PTS will allow detecting a representative sample of low prevalence (< 10%) biomarkers of resistance in each subgroup. So far, 87 PTS ahve been enrolled in the trial. Based on these findings, a joined clinical-molecular review board will propose further lines of therapies. Funded by 5 X 1000 2011, Italian Min. of Health & FPRC-Candiolo. EudraCT 2016-000491-16.