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
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.
Lin, Selena Y; Chang, Shu-Ching; Lam, Stella; Ramos, Romela Irene; Tran, Kevin; Ohe, Shuichi; Salomon, Matthew P; Bhagat, Ali Asgar S; Teck Lim, Chwee; Fischer, Trevan D; Foshag, Leland J; Boley, Christine L; O'Day, Steven J; and Hoon, Dave, "Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy." (2020). Articles, Abstracts, and Reports. 3588.