Systemic Sclerosis and Cancer Risk: What Do We Know?
Maria Suarez-Almazor, MD, PhD
Chief, Section of Rheumatology and Clinical Immunology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
Maryam Buni, MD
Assistant Professor, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
Suarez-Almazor M, Buni M. Systemic sclerosis and cancer risk: what do we know? [published online March 16, 2020]. Rheumatology Consultant.
Patients with systemic sclerosis (SSc) have an increased incidence of cancer compared with the general population.1-3 A 2013 systematic review and meta-analysis of 16 original studies—involving more than 7000 patients with SSc from various countries—showed a 75% increased risk of patients with SSc developing cancer compared with the general population.3 The risk was highest for lung cancer (relative risk [RR], 4.3) and to a lesser extent for hematopoietic cancers (RR, 2.2). No significant correlation was observed between SSc and breast cancer, an association that has been previously suggested in other studies.
A recent study conducted in Australia4 ascertained the incidence of cancer in patients with SSc enrolled in the Australian Scleroderma Cohort Study. Findings of the study showed a 2-fold increase in cancer risk among patients with SSc compared with a matched population. The risk for lung cancer in patients with SSc was 3-fold despite disease duration and was independent of traditional risk factors such as smoking. Additionally, patients with interstitial lung disease (ILD) significantly increased the risk of lung cancer by close to 3-fold. Breast cancer, on the whole, was not significantly increased in patients with SSc compared with the matched population; however, early breast cancer occurring within 5 years of onset of SSc had a 3-fold increase compared with controls. Similarly, melanoma incidence rates were not higher than in the general population but were increased for melanoma occurring within 5 years of SSc onset. Of interest, treatment with calcium channel blockers was significantly associated with a higher risk of any cancer (odds ratio [OR], 1.47; P = .016), breast cancer, and melanoma. An association between the use of calcium channel blockers and cancer has been reported for the general population but not consistently across all studies. The reason for this association is unknown but could relate to an effect in regulatory intracellular calcium pathways affecting cell apoptosis. In this study, because many patients received long-term treatment with calcium channel blockers, the potential confounding relationship between disease duration and calcium channel blocker treatment on the incidence of cancer could not be properly adjusted for.
Close or concurrent onset of scleroderma and cancer has been previously documented, raising the hypothesis that specific malignancies may trigger an autoimmune disease process in a subset of patients. This tight temporal association is most striking for breast cancer, with some patients developing SSc within months of a cancer diagnosis. A study by Shah et al initially reported the presence of autoantibodies in 23 patients with scleroderma and cancer, most of them with breast cancer.5 Patients with antibodies to RNA polymerase I/III had a close temporal relationship between the onset of scleroderma and cancer compared with patients with other autoantibodies, which suggested that malignancy may initiate a specific immune response resulting in SSc. In the Australian study,4 the presence of RNA polymerase III autoantibodies was also associated with increased risk of cancer (OR, 2.9; P = .044), diagnosed within 5 years of SSc disease onset. This association was primarily seen in patients with breast cancer. In contrast, the presence of anticentromere antibodies decreased the risk of lung cancer.4 These findings are similar to those reported in a recent study that found an increased risk of cancer within 3 years of SSc onset in patients who tested positive for RNA polymerase III antibodies.6 An increased association with cancer was also observed in those lacking the triad of centromere, type I topoisomerase, and RNA polymerase III antibodies, suggesting that other autoantibodies triggered by cancer may also play a role in the pathogenesis of SSc. The risk associated with different autoantibody profiles also varied according to the disease phenotype (diffuse vs limited).
The Australian study adds to the evidence for an increased risk of cancer in patients with SSc, especially within the first few years after SSc diagnosis, conceivably supporting the premise that in some patients, SSc is triggered by an autoimmune reaction to the tumor. The increased prevalence of RNA polymerase autoantibodies in patients who develop cancer also supports this hypothesis. Because the risk of lung cancer in SSc appeared to be sustained throughout the course of the disease, it is conceivable that in these patients, lung cancer might be an effect of SSc or its treatment. Of interest, an increased risk for melanoma was found in this study. Australia has among the highest incidence rates for melanoma, which could have contributed to this difference in risk compared with other populations. This increased incidence in the Australian population has been attributed to its geographic location, reduced ozone layer, and racial background of mostly fair-skinned people.
Several issues relevant to clinical practice need to be considered given the consistency of evidence across studies, and include the following:
- There is an increased risk of cancer within 3 to 5 years of SSc onset, and patients should undergo a comprehensive clinical examination and physical examination to identify any signs or symptoms of potential cancer, especially breast cancer.
- Age- and gender-appropriate guideline-based cancer screening should be performed among all patients. Regular skin cancer checks should be performed among patients with SSc with fair skin.
- The risk of lung cancer appears to be increased throughout the course of SSc, especially among patients with ILD. Careful monitoring of these patients with imaging may be needed.
- Prompt cancer diagnosis and treatment in patients with SSc is of special relevance, since these patients may not be able to receive effective cancer therapy, including radiation, certain chemotherapeutic agents, or immunotherapy. Treatment at earlier stages with less-complex regimens (eg, surgical procedure) can significantly improve their tolerance of treatment and outcomes.
- Categorization of SSc specific autoantibodies is important for cancer risk stratification and should be recommended for most patients with SSc.
Finally, no studies to date have evaluated the effectiveness and performance of additional cancer screening in patients with SSc beyond what is recommended for the general population. Additional research is needed to determine the benefit-risk profile of different cancer screening alternatives according to patient risk stratification, with the goal of proposing best practices that ensure prompt diagnosis and treatment of concomitant malignancies.
- Onishi A, Sugiyama D, Kumagai S, Morinobu A. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis Rheum. 2013;65(7):1913-1921. doi:10.1002/art.37969.
- Nevskaya T, Chandran S, Roos AM, et al. Epidemiology of cancer in systemic sclerosis—systematic review and meta-analysis of cancer incidence, predictors and mortality. Open J Rheumatol Autoimmune Dis. 2013;3(4):231-245. doi:10.4236/ojra.2013.34037.
- Bonifazi M, Tramacere I, Pomponio G, et al. Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2013;52(1):143-154. doi:10.1093/rheumatology/kes303.
- Morrisroe K, Hansen D, Huq M, et al. Incidence, risk factors and outcomes of cancer in systemic sclerosis [published online September 20, 2019]. Arthritis Care Res (Hoboken). doi:10.1002/acr.24076.
- Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum. 2010;62(9):2787-2795. doi:10.1002/art.27549.
- Igusa T, Hummers LK, Visvanathan K, et al. Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer. Ann Rheum Dis. 2018;77(8):1179-1186. doi:10.1136/annrheumdis-2018-212999.