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.
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 melanomapatients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAFV600E 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 melanomapatients.
Authors: Sojun Hoshimoto; Mark B Faries; Donald L Morton; Tatsushi Shingai; Christine Kuo; He-Jing Wang; Robert Elashoff; Nicola Mozzillo; Mark C Kelley; John F Thompson; Jeffrey E Lee; Dave S B Hoon Journal: Ann Surg Date: 2012-02 Impact factor: 12.969
Authors: Yuuki Iida; Aaron Ciechanover; Diego M Marzese; Keisuke Hata; Matias Bustos; Shigeshi Ono; Jinhua Wang; Matthew P Salomon; Kevin Tran; Stella Lam; Sandy Hsu; Nellie Nelson; Yelena Kravtsova-Ivantsiv; Gordon B Mills; Michael A Davies; Dave S B Hoon Journal: Clin Cancer Res Date: 2017-04-07 Impact factor: 12.531
Authors: Daniela Massi; Emanuela Romano; Eliana Rulli; Barbara Merelli; Romina Nassini; Francesco De Logu; Ivan Bieche; Gianna Baroni; Laura Cattaneo; Gongda Xue; Mario Mandalà Journal: Eur J Cancer Date: 2017-04-14 Impact factor: 9.162
Authors: K J Busam; Y T Chen; L J Old; E Stockert; K Iversen; K A Coplan; J Rosai; R L Barnhill; A A Jungbluth Journal: Am J Surg Pathol Date: 1998-08 Impact factor: 6.394
Authors: Joyce N Barlin; Qin Zhou; Caryn M St Clair; Alexia Iasonos; Robert A Soslow; Kaled M Alektiar; Martee L Hensley; Mario M Leitao; Richard R Barakat; Nadeem R Abu-Rustum Journal: Gynecol Oncol Date: 2013-06-14 Impact factor: 5.482
Authors: Nikolaus B Wagner; Andrea Forschner; Ulrike Leiter; Claus Garbe; Thomas K Eigentler Journal: Br J Cancer Date: 2018-06-28 Impact factor: 7.640
Authors: Shadma Fatima; Yafeng Ma; Azadeh Safrachi; Sana Haider; Kevin J Spring; Fatemeh Vafaee; Kieran F Scott; Tara L Roberts; Therese M Becker; Paul de Souza Journal: Cancers (Basel) Date: 2022-03-25 Impact factor: 6.639