CME Author: Vicki Brower
Study Authors: Xiaoyun Xu, Lebin Song, et al.
Target Audience and Goal Statement:
Rheumatologists, oncologists, internists
To understand the suggested association of SLE with the development of various cancers.
Questions Addressed By This Study:
What is the association between lupus and specific cancers? How does this study compare with other studies, some of which have shown a positive association between certain cancers and lupus, and others which did not?
Study Synopsis and Perspective:
The true incidence of cancer in SLE has remained unclear, as previous studies found conflicting and incomplete results on the association between certain cancers and lupus.
Here researchers conducted systemic review and meta-analysis of 3 online databases, which included 24 eligible studies in which they found elevated overall risk of 16 cancer types among patients with SLE — both women and men — with a pooled standardized incidence rate (SIR) of 1.28 (95% CI 1.16-1.42), according to Xiaoyun Xu, MD, and colleagues from Nanjing Medical University in China.
Specifically, researchers found epidemiological evidence that SLE was associated with 16 cancer types in both genders, and a decreased risk for prostate cancer and cutaneous melanoma. They grouped 24 cancer types into 6 systemic groups: lymphatic and hematopoietic cancers, reproductive cancers, urinary cancers, digestive cancers, respiratory cancers, and others. In the first group, researchers found the most prominent associations among non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, multiple myeloma, and leukemia. Reproductive cancers included breast, uterus, cervical, ovarian, and vaginal/vulvar cancers. The urinary group included renal, prostate, and bladder cancers. Digestive cancers included esophageal, gastric, hepatobiliary, pancreatic, and colorectal cancers. Respiratory cancers included lung, oropharynx, and larynx cancers. In the miscellaneous group there were cutaneous melanoma, non-melanoma skin cancer, brain, and thyroid cancers.
For the lymphatic/hematopoietic group of malignancies, they found that in 11 studies there was an increased risk of non-Hodgkin’s lymphoma (SIR 4.93, 95% CI 3.81-6.36) and also for Hodgkin’s lymphoma (SIR 2.60, 95% CI 2.14-3.17). Substantial increases were also found in 10 studies of leukemia (SIR 2.01, 95% CI 1.64-2.47) and in four studies of multiple myeloma (SIR 1.48, 95% CI 1.02-2.14).
In the reproductive cancer category, there were 19 studies of SLE and breast cancer. “Remarkably,” the researchers commented, there was no association for breast cancer (SIR 0.89, 95% CI 0.77-1.04), nor was there an association for uterine cancer (SIR 0.70, 95% CI 0.46-1.07) or ovarian cancer (SIR 0.92, 95% CI 0.74-1.33).
Increased risks were seen, however, for cervical cancer (SIR 1.56, 95% CI 1.29-1.88) and cancer of the vagina/vulva (SIR 3.48, 95% CI 2.69-4.50).
For urinary cancers, there was a decreased risk for prostate cancer (SIR 0.78, 95% CI 0.70-0.88), but increased risks for renal cancer (SIR 2.10, 95% CI 1.11-3.96) and bladder cancer (SIR 1.86, 95% CI 1.16-2.99).
Among digestive tract cancers, significant associations were seen for esophageal (SIR 1.64, 95% CI 1.43-1.87), gastric (SIR 1.31, 95% CI 1.04-1.63), and hepatobiliary cancers (SIR 2.37, 95% CI 1.67-3.38), though not for pancreatic (SIR 1.24, 95% CI 0.97-1.60) or colorectal cancer (SIR 0.97, 95% CI 0.85-1.09).
For cancers of the respiratory tract, significant associations were observed between SLE and lung cancer (SIR 1.62, 95% CI 1.40-1.87), oropharyngeal cancer (SIR 1.52, 95% CI 1-2.30), and laryngeal cancer (SIR 2.90, 95% CI 1.82-4.62).
The “other cancers” group included cutaneous melanoma, which showed a decreased risk (SIR 0.72, 95% CI 0.56-0.93), while increased risks were found for nonmelanoma skin cancers (SIR 1.41, 95% CI 1.07-1.87) and thyroid cancer (SIR 1.80, 95% CI 1.46-2.23). No association was seen for brain cancer.
While researchers cited a number of studies with alternate findings, they also mentioned other studies which found similar results to their own. For example, some studies found SLE to be significantly associated with higher risks of thyroid, cervical, and hematologic cancers. Another study, with more than 25 years of follow-up, confirmed that lupus patients had particularly increased risks of non-Hodgkin’s lymphoma and kidney cancer. Another researcher found decreased risks of prostate and bladder cancer in a large group (11,763) of patients in Taiwan. Other studies confirmed that no direct associations were found between lupus and breast cancer risk
Arthritis Research & Therapy, Dec 6, 2018; DOI: 10.1186/s1307-018-1760-3
Study Highlights and Explanation of Findings:
Despite considerable progress in diagnosis and treatment that has led to increased survival among SLE patients, their mortality risks remain two-fivefold higher than the general population — not only for all-cause mortality, but also for cancer deaths, the team wrote.
Therefore, to more clearly determine the rates of various cancers in SLE patients, Xu and co-authors searched the literature for studies published through May 2018, identifying 24 eligible studies. Malignancies were classified as lymphatic and hematopoietic, reproductive, urinary, digestive, respiratory, and “other.” They believe that their current study represents “the first and largest systemic evaluation to reveal the relationship between SLE and the development of cancer risk.”
The team found that the highest risk of cancer was (in descending order) in lymphomas, leukemia, multiple myeloma, cervix, vagina/vulva, renal, bladder, esophagus, gastric, hepatobiliary, lung, oropharynx, larynx, nonmelanoma skin, and thyroid cancers. They found decreased risks of prostate cancer and cutaneous melanoma, and no significant association between lupus and breast, uterine, ovarian, pancreatic, colorectal, or brain cancers.
“Several potential mechanisms could account for cancer development in SLE patients. These patients, by virtue of their disease, have basic defects in immune cell function, resulting in immune dysregulation, which might prevent aberrant cells from being removed and eventually contributing to increased cancer risk,” the authors noted.
They emphasized that in particular, smoking is “regarded as a significant etiologic agent for cancer development in SLE. They cited that in comparison with patients who do not smoke, the risk of lung cancer in this population was increased almost 4-fold (adjusted hazard ratio [HR] = 3.6, 95% CI = 1.32-9.83). While other authors suggested that SLE might influence breast cancer risk, this study did not find any positive or negative association between the two diseases. Regarding the strong association between SLE and non-Hodgkin’s lymphoma, they cited a theory by other researchers that abnormal beta-cell function and the use of immunosuppressive drugs could lead to lymphoma by direct mutagenesis or by perturbing immune surveillance.
They also mentioned genetic and environmental factors as potential triggers for the development of cancer in these patients.
There have also been reports of potential roles for co-stimulatory molecules such as CTLA4 and OX40L that may participate in the pathogenesis of SLE and that have been linked with carcinogenesis, Song and team wrote. They cited other studies that reported the existence of “several important co-stimulatory molecules, including OX40L and CTLA4, which may play a crucial role in both the pathogenesis of SLE and in carcinogenesis.” CTLA-4 is a checkpoint molecule that downregulates the immune response. Song and colleagues hypothesized that CTLA-4 may predispose SLE patients to tumor growth and/or progression, and the development of inflammatory autoimmune diseases “under compromised expression,” they wrote.
These findings, they wrote, “could be used to drive public policies and to help guide personalized medicine to better manage SLE and reduce associated cancer morbidity and mortality.”
“Future high-quality research is required to verify our findings and this should pay more attention to the underlying mechanisms between SLE and cancer risks,” they concluded. Strengths of the new research include low-to moderate heterogeneity and design of the meta-analysis.
One limitation of the study, the team said, was incomplete or limited data from the studies they reviewed about potential confounding factors such as age, sex, ethnicity, and environmental triggers. Subgroup analyses were not conducted on criteria such as ethnicity, alcohol use, and smoking because of insufficient primary study data.
Nancy Walsh originally wrote this story for MedPage Today
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner