Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cells documents heterogeneous resistance mechanisms

Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer, to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTC and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTC isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTC and metastatic tissues. In 76 individual and pooled informative CTC from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTC and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTC, and vice versa. CTC profiling identified diverse intra- and inter-patient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity (LOH) in individual CTC. For example, in one patient, we observed CTC that were either wildtype for ESR1 (n=5/32), harbored the known activating ESR1 p.Y537S mutation (n=26/32), or harbored a novel ESR1 p.A569S (n=1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTC. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ykwoCB