Cancer in Systemic Sclerosis: Clinical Associations and Prognostic Impact From the EUSTAR Registry

Cancer represents a major cause of death in systemic sclerosis (SSc). Established risk factors are limited to specific subsets, particularly early diffuse anti-RNA polymerase III (POLR3)-positive disease, needing further exploration.

We performed a nested case-control study within the European Scleroderma Trials and Research group: "cases" were defined as patients with SSc who developed cancer at any time point; controls were patients with SSc who were cancer free, matched for age and disease duration. Malignancies were classified as "synchronous" to SSc onset (±3 years), "subsequent" (more than three years after), or "previous" (more than three years before). Clinical, serologic, and treatment associations, as well as survival rates, were analyzed.

A total of 454 patients with SSc with cancer (29% synchronous, 51% subsequent, 20% previous) and 454 controls were identified. Mean age was 55 ± 13 years, disease duration was 5 ± 2 years; 88% were female, and 27.5% had diffuse SSc; 30.5% had interstitial lung disease (ILD), 32% had anti-topoisomerase, and 10% had anti-POLR3. Synchronous cancers were associated with anti-POLR3 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.13-3.69), U1RNP (OR 3.56, 95% CI 1.03-12.3), and smoking (OR 1.57, 95% CI 1.01-2.44), but they were negatively associated with digital ulcers (OR 0.55, 95% CI 0.31-0.93). Calcinosis was inversely associated with subsequent cancers (OR 0.42, 95% CI 0.17-0.93). Breast cancer showed time-dependent associations with anti-POLR3 and anti-PM/Scl; lung cancer was mainly subsequent and associated with ILD (OR 2.00, 95% CI 1.12-3.54), anti-topoisomerase (OR 2.61, 95% CI 1.38-5.04), and smoking. Cancers occurred more frequently in patients treated with cyclophosphamide. Malignancy worsened overall survival, particularly when subsequent. Radiation therapy did not impact mortality rate or new-onset ILD.

Cancer timing and site identify distinct clinical-serologic associations in SSc, with different prognostic implications. As cancers diagnosed during follow-up are major determinants of death, our findings inform the implementation of stratified cancer surveillance in SSc.