Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.

Publication Title

Clinical chemistry

Authors

• 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

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.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology

Specialty/Research Institute

Surgery