Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms

作者：Costanza Paoletti, Andi K. Cani, Jose Maciel Larios, Daniel H. Hovelson, Kimberly Aung, Elizabeth P. Darga, Emily M. Cannell, Paul J. Baratta, Chia‐Jen Liu, David T. W. Chu, Maryam Yazdani, Allen R. Blevins, Valeria Sero, Nahomi Tokudome, Dafydd G. Thomas, Christina L. Gersch, Anne F. Schott, Yi-Mi Wu, Robert J. Lonigro, Dan R. Robinson, Arul M. Chinnaiyan, Farideh Zamaniyan Bischoff, Michael D. Johnson, Ben Ho Park, Daniel F.C. Hayes, James Michael Rae, Scott Arthur Tomlins · 发表于：Cancer Research · 年份：2017 · 被引用次数：109 · 研究领域：Cancer Genomics and Diagnostics、Cancer Cells and Metastasis、Lung Cancer Treatments and Mutations

Abstract 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 CTCs 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 CTCs isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTCs and metastatic tissues. In 76 individual and pooled informative CTCs from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTCs and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTCs, and vice versa. CTC profiling identified diverse intra- and interpatient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity in individual CTCs. For example, in one patient, we observed CTCs that were either wild type for ESR1 (n = 5/32), harbored the known activating ESR1 p.Y537S mutation (n = 26/32), or harbored a ...