Circulating Tumor DNA in Patients with Early-Onset Systemic Sclerosis and Dermatomyositis

Background

Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune diseases that have been proposed as models of cancer immunoediting. Autoantibody-defined subsets show divergent cancer risks, yet malignancy often remains clinically occult. We tested whether circulating tumor DNA (ctDNA) can reveal subclinical cancer in new-onset SSc and DM.

Methods

We prospectively recruited adults with recent SSc or DM onset. Plasma ctDNA was assessed using a targeted next-generation sequencing panel covering commonly mutated cancer genes. Patients were followed for 18–24 months on average. ctDNA positivity was correlated with subsequent cancer diagnoses.

Findings

Among 134 patients (69 SSc, 65 DM), cancer was diagnosed in six (4·5%; three SSc, three DM). ctDNA was detected in four of these six patients (67%) a median of 13 months (range 1·4–17) before clinical diagnosis; in three of four patients, mutations detected in plasma matched those subsequently identified in the same patients’ primary tumors. ctDNA was also detected in 16 of 128 patients without a cancer diagnosis. ctDNA positivity conferred an 11·4-fold higher risk of malignancy relative to ctDNA negativity and yielded a negative predictive value of 98% and a positive predictive value of 20% for cancer within the observation window.

Interpretation

ctDNA testing identified most cancers that emerged within 18 months in new-onset SSc and DM and stratified near-term cancer risk. These findings support larger, interventional trials to determine whether ctDNA-guided surveillance improves timeliness of cancer detection, optimizes imaging and biopsy strategies, and enhances outcomes in patients with SSc and DM.

Funding

NIH, Scleroderma Research Foundation, Stabler Foundation, Chresanthe Staurulakis Memorial Fund, Sara and Alex Othon Research Fund, Bechtle Precision Medicine Fund for Scleroderma, Zhang Discovery Fund, Dr. Peter Buck Fund, Jerome L. Greene Foundation, Lustgarten Foundation for Pancreatic Cancer Research, Sol Goldman Sequencing Facility, Virginia and D.K. Ludwig Fund for Cancer Research.

RESEARCH IN CONTEXT

1. Evidence before this study: Patients with new onset systemic sclerosis (SSc) and dermatomyositis (DM) have an increased risk of contemporaneous cancer in distinct autoantibody subgroups, and mechanistic studies suggest that these patients may have cancer-induced autoimmunity. The optimal approach to cancer detection, and whether subclinical malignancy may be present in patients with new onset rheumatic disease, remains unknown.

2. Added value of this study: We show that circulating tumor DNA (ctDNA) is present in ∼15% of patients with new onset SSc and DM. Patients with ctDNA have a higher risk of subsequent malignancy, with data suggesting that it can detect cancer earlier than conventional methods in this patient population.

3. Implications of all the available evidence: These findings suggest that subclinical malignancy may be present in a subset of patients with new onset SSc and DM and that ctDNA may be a valuable tool to risk stratify patients for cancer.