Circulating tumor DNA level is associated with time to clinical recurrence in Merkel cell carcinoma: Implications for patient management - 04/11/25

Doi : 10.1016/j.jaad.2025.10.032

Tomoko Akaike, MD ^a,^b, Manisha Thakuria, MD ^c,^d, Ann W. Silk, MD ^d, Daniel S. Hippe, MS ^b, Peter Y. Ch'en, MPH ^a,^e, Song Youn Park, MD ^a, Nicole M. Urman, MD ^f, Meliea W. Chiu, BS ^f, Hannah Kim, BS ^f, Emily Y. Kim, MD ^c,^g, Evan T. Hall, MD ^a,^b, Shailender Bhatia, MD ^a,^b, Sunil Reddy, MD ^f, Michael Krainock, MD ^h, Alexey Aleshin, MD ^h, Jacob S. Choi, MD, PhD ⁱ, Kenneth Y. Tsai, MD, PhD ^j, Sue S. Yom, MD ^k, Siegrid S. Yu, MD ^k, Jaehyuk Choi, MD, PhD ^l, Sunandana Chandra, MD ⁱ, Paul T. Nghiem, MD, PhD ^a,^b, Lisa C. Zaba, MD, PhD ^f,^⁎

^a University of Washington, Seattle, Washington

^b Fred Hutchinson Cancer Center, Seattle, Washington

^c Brigham and Women's Hospital, Boston, Massachusetts

^d Dana-Farber Cancer Institute, Boston, Massachusetts

^e Albert Einstein College of Medicine, Bronx, New York

^f Stanford University School of Medicine, Stanford, Palo Alto, California

^g University of Michigan Hospital, Ann Arbor, Michigan

^h Natera, Inc, Austin, Texas

ⁱ Northwestern University, Chicago, Illinois

^j Moffitt Cancer Center, Tampa, Florida

^k University of California San Francisco, San Francisco, California

^l University of Texas Southwestern, Dallas, Texas

^∗ Correspondence to: Lisa C. Zaba, MD, PhD, Department of Dermatology, Stanford University, 780 Welch Rd, Suite CJ CJ220I, Palo Alto, CA 94304. Department of Dermatology Stanford University 780 Welch Rd Suite CJ CJ220I Palo Alto CA 94304

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Abstract

Background

Merkel cell carcinoma (MCC) recurs in 40% of patients. Circulating tumor DNA (ctDNA) is an emerging blood-based biomarker for early MCC recurrence detection.

Objective

To evaluate the timing and prognostic significance of ctDNA levels relative to clinical recurrence.

Methods

This multicenter prospective study analyzed 669 tumor-informed ctDNA tests from 215 MCC patients (stage I-IV) without clinically evident disease after treatment.

Results

Patients with at least 1 positive ctDNA test were more likely to experience recurrence compared to ctDNA-negative patients (hazard ratio: 18.1, 95% CI: 8.9-36.7), with 77% developing clinically evident disease by 1 year. The median lead time between the first positive ctDNA and clinical recurrence was 2.7 months. Clinical recurrences usually occurred within 3 months for ctDNA levels above 10 molecules/mL, within 6 months for levels between 1-10 molecules/mL, and within 9 months for levels below 1 molecule/mL.

Limitations

In this real-world study, there was variability in timing and frequency of follow-up examinations, imaging, and ctDNA testing, although most patients were followed with both ctDNA and imaging.

Conclusions

A positive ctDNA test detects MCC recurrence approximately 3 months earlier than imaging. Negative ctDNA can help reduce imaging frequency through serial ctDNA monitoring, while positive ctDNA warrants closer patient follow-up.

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Key words : biomarker, circulating tumor DNA, ctDNA, lead time, Merkel cell carcinoma, recurrence

Abbreviations used : ctDNA, HR, MCC, MCPyV, MTM

Plan

Introduction

Materials and methods

Study design and patient cohort

Tumor-informed ctDNA assay

	Funding sources: Supported by funding from the Kuni Foundation Discovery Grant for Cancer Research: Advancing Innovation, and patient gift fund at Stanford University for LZ. Supported in part by the National Institutes of Health / National Cancer Institute, Maryland, USA, P01 CA225517 and P30 CA015704 , the MCC Patient Gift Fund at UW , Kelsey Dickson Team Science Courage Research Award: Advancing New Therapies for Merkel Cell Carcinoma (MCC) to PN. Andy Hill Cancer Research Endowment : Implementations and Outcomes Research Award #FY25-IOR-08 to PN and TA. Supported by the Dargie Family fund for AWS. Supported by patient gift fund at Brigham and Women's Hospital for MT.
	Patient consent: Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and included at the time of article submission to the journal stating that all patients gave consent with the understanding that this information may be publicly available.
	IRB approval status: The study protocol was reviewed and approved by the Institutional Review Board at Stanford IRB 61461, University of Washington/Fred Hutch Cancer IRB 6585, Dana-Farber/Harvard Cancer Center IRB 09-156, Northwestern University IRB STU00216228, University of California San Francisco IRB 21-35252, and Moffitt Cancer Center IRB 00000971, ensuring compliance with the Helsinki Declaration's ethical principles.