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Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms.
Cancer Res 2018; 78(4):1110-1122CR

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 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 CTCs. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.Significance: These findings demonstrate the complementary nature of genomic profiling from paired tissue metastasis and circulating tumor cells from patients with metastatic breast cancer. Cancer Res; 78(4); 1110-22. ©2017 AACR.

Authors+Show Affiliations

Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan. Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan. Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine Department of Oncology, Baltimore, Maryland.Menarini Silicon Biosystems, Inc., San Diego, California.Menarini Silicon Biosystems, Inc., San Diego, California.Menarini Silicon Biosystems, Inc., San Diego, California.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Present address: Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan.Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan.Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan.Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.Menarini Silicon Biosystems, Inc., San Diego, California.Georgetown University, Washington, D.C.The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine Department of Oncology, Baltimore, Maryland.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Breast Oncology Program of the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Comphrehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. tomlinss@med.umich.edu. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29233927

Citation

Paoletti, Costanza, et al. "Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms." Cancer Research, vol. 78, no. 4, 2018, pp. 1110-1122.
Paoletti C, Cani AK, Larios JM, et al. Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms. Cancer Res. 2018;78(4):1110-1122.
Paoletti, C., Cani, A. K., Larios, J. M., Hovelson, D. H., Aung, K., Darga, E. P., ... Tomlins, S. A. (2018). Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms. Cancer Research, 78(4), pp. 1110-1122. doi:10.1158/0008-5472.CAN-17-2686.
Paoletti C, et al. Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms. Cancer Res. 2018 02 15;78(4):1110-1122. PubMed PMID: 29233927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms. AU - Paoletti,Costanza, AU - Cani,Andi K, AU - Larios,Jose M, AU - Hovelson,Daniel H, AU - Aung,Kimberly, AU - Darga,Elizabeth P, AU - Cannell,Emily M, AU - Baratta,Paul J, AU - Liu,Chia-Jen, AU - Chu,David, AU - Yazdani,Maryam, AU - Blevins,Allen R, AU - Sero,Valeria, AU - Tokudome,Nahomi, AU - Thomas,Dafydd G, AU - Gersch,Christina, AU - Schott,Anne F, AU - Wu,Yi-Mi, AU - Lonigro,Robert, AU - Robinson,Dan R, AU - Chinnaiyan,Arul M, AU - Bischoff,Farideh Z, AU - Johnson,Michael D, AU - Park,Ben H, AU - Hayes,Daniel F, AU - Rae,James M, AU - Tomlins,Scott A, Y1 - 2017/12/12/ PY - 2017/09/06/received PY - 2017/10/19/revised PY - 2017/12/07/accepted PY - 2017/12/14/pubmed PY - 2019/1/24/medline PY - 2017/12/14/entrez SP - 1110 EP - 1122 JF - Cancer research JO - Cancer Res. VL - 78 IS - 4 N2 - 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 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 CTCs. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.Significance: These findings demonstrate the complementary nature of genomic profiling from paired tissue metastasis and circulating tumor cells from patients with metastatic breast cancer. Cancer Res; 78(4); 1110-22. ©2017 AACR. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/29233927/Comprehensive_Mutation_and_Copy_Number_Profiling_in_Archived_Circulating_Breast_Cancer_Tumor_Cells_Documents_Heterogeneous_Resistance_Mechanisms_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=29233927 DB - PRIME DP - Unbound Medicine ER -