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

被引：23

作者：

Lin, Selena Y. ^{[1
]}

Chang, Shu-Ching ^{[2
]}

Lam, Stella ^{[1
]}

Ramos, Romela Irene ^{[1
]}

Tran, Kevin ^{[1
]}

Ohe, Shuichi ^{[1
]}

Salomon, Matthew P. ^{[1
]}

Bhagat, Ali Asgar S. ^{[3
,4
]}

Lim, Chwee Teck ^{[3
,4
]}

Fischer, Trevan D. ^{[5
]}

Foshag, Leland J. ^{[5
]}

Boley, Christine L. ^{[6
]}

O'Day, Steven J. ^{[6
]}

Hoon, Dave S. B. ^{[1
]}

机构：

[1] St Johns Hlth Ctr, John Wayne Canc Inst, Dept Translat Mol Med, PHS, Santa Monica, CA USA

[2] Providence St Joseph Hlth, Med Data Res Ctr, Portland, OR USA

[3] Natl Univ Singapore, Dept Biomed Engn, Singapore, Singapore

[4] Natl Univ Singapore, Dept Mech Engn, Singapore, Singapore

[5] John Wayne Canc Inst, Dept Surg Oncol, PHS, Santa Monica, CA 90404 USA

[6] John Wayne Canc Inst, Dept Immunooncol & Clin Res, PHS, Santa Monica, CA 90404 USA

来源：

CLINICAL CHEMISTRY | 2020年 / 66卷 / 01期

关键词：

STAGE-III MELANOMA; CUTANEOUS MELANOMA; NODE METASTASIS; BETA-CATENIN; EXPRESSION; DISEASE; BIOCHEMOTHERAPY; CLASSIFICATION; HETEROGENEITY; PREDICTION;

D O I：

10.1373/clinchem.2019.307140

中图分类号：

R446 [实验室诊断]; R-33 [实验医学、医学实验];

学科分类号：

1001 ;

摘要：

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 <0.01) compared to nondisease donor blood. CTC-CTNNB1 was associated with progressive disease/stable disease compared to complete-responder patient status (P = 0.02). Serial CTC profiling identified subclinical disease in patients who developed progressive disease during treatment/follow-up. CONCLUSIONS: CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients. (C) 2019 American Association for Clinical Chemistry

引用

页码：169 / 177

页数：9

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