Selena Y Lin, Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USAFollow
Shu-Ching Chang, Medical Data Research Center, Providence Health & Services, Portland, OR, USAFollow
Stella Lam, Department of Translational Molecular Medicine, John Wayne Cancer Institute, Saint John's Health Center, PHS, Santa Monica, CA.
Romela Irene Ramos, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USAFollow
Kevin Tran, Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow
Shuichi Ohe, Department of Translational Molecular Medicine, John Wayne Cancer Institute, Saint John's Health Center, PHS, Santa Monica, CA.
Matthew P Salomon, Center for Endocrine Tumors and Disorders, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Ali Asgar S Bhagat
Chwee Teck Lim
Trevan D Fischer, Department of Surgical Oncology, John Wayne Cancer Institute, PHS, Santa Monica, CA.Follow
Leland J Foshag, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USAFollow
Christine L Boley, Department of Immuno-Oncology and Clinical Research, John Wayne Cancer Institute, PHS, Santa Monica, CA.Follow
Steven J O'Day, The John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CAFollow
Dave Hoon, The John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CAFollow

Document Type

Article

Publication Date

1-1-2020

Publication Title

Clinical chemistry

Keywords

Aged; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Disease-Free Survival; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplastic Cells, Circulating; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins B-raf; RNA, Messenger; Risk Factors; Up-Regulation; beta Catenin

Abstract

BACKGROUND: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel.

METHODS: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed.

RESULTS: CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase, CTC-mRNA biomarkers, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients, whereby the latter had poor disease-free (P = 0.03) and overall survival (P = 0.02). Incorporation of a DNA biomarker with mRNA profiling increased overall CTC-detection capability by 57% compared to mRNA profiling only. RNA sequencing of isolated CTCs identified significant catenin beta 1 (CTNNB1) overexpression (P

CONCLUSIONS: CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients.

Clinical Institute

Cancer

Department

Oncology

Department

Surgery

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