TY - JOUR

T1 - Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma

AU - Fan, Kaiji

AU - Ritter, Cathrin

AU - Nghiem, Paul

AU - Blom, Astrid

AU - Verhaegen, Monique E.

AU - Dlugosz, Andrzej

AU - Dum, Niels

AU - Woetmann, Anders

AU - Tothill, Richard W.

AU - Hicks, Rodney J.

AU - Sand, Michael

AU - Schrama, David

AU - Schadendorf, Dirk

AU - Ugurel, Selma

AU - Becker, Jurgen C.

PY - 2018

Y1 - 2018

N2 - Purpose: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. Experimental Design: Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375–specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. Results: miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P < 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P ¼ 0.037) but not in tumor-free (P ¼ 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions. Conclusions: Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.

AB - Purpose: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. Experimental Design: Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375–specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. Results: miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P < 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P ¼ 0.037) but not in tumor-free (P ¼ 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC ¼ 0.954 and 0.800) as well as in the prospective cohorts (AUC ¼ 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions. Conclusions: Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.

U2 - 10.1158/1078-0432.CCR-18-1184

DO - 10.1158/1078-0432.CCR-18-1184

M3 - Journal article

C2 - 30061360

AN - SCOPUS:85057197183

VL - 24

SP - 5873

EP - 5882

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 23

ER -