Published online Jan 24, 2022. doi: 10.5306/wjco.v13.i1.49
Peer-review started: April 9, 2021
First decision: July 27, 2021
Revised: August 11, 2021
Accepted: December 22, 2021
Article in press: December 22, 2021
Published online: January 24, 2022
Patients with Lynch Syndrome and hereditary non polyposis colorectal cancer (HNPCC) have an increased cumulative lifetime risk of developing colorectal, endometrial, ovarian, stomach, small bowel, hepatobiliary, urothelial, and brain cancers. These individuals may have co-existent systemic inflammatory conditions such as inflammatory bowel disease (IBD) and rheumatic diseases. Treatment of moderate to severe inflammatory disease generally involves modulating the immune system with systemic immunosuppressive medications, in particular monoclonal antibodies and immunomodulators alone or in combination. Interaction of the inflammatory disease and immunosuppressive medications in individuals at increased risk of malignancy due to baseline genetic diagnosis is unknown.
The immune system is known to protect against cancer by detecting neoantigens presented by cancer cells, so clinicians may be hesitant to prescribe these medications in patients with HNPCC due to concern of an elevated cancer risk. This leads to significant morbidity for these individuals. Moreover, treatment with immunosuppressive medications might theretically place them at higher risk for cancer. There is limited existing data to guide clinicians in this regards.
The primary aim was to compare the proportion of individuals with Lynch syndrome and HNPCC who develop cancer based on comorbid inflammatory disease status. Lynch syndrome and HNPCC individuals with comorbid inflammatory disease (cases) were matched to controls (Lynch syndrome and HNPCC without comorbid inflammatory disease) in a 1:2 ratio. Our secondary aim was to compare the proportion of comorbid inflammatory disease patients (n = 21) who developed cancer with and without exposure to a monoclonal antibody and/or immunomodulator therapy in Lynch syndrome and HNPCC population.
Lynch Syndrome and HNPCC individuals enrolled in the David G. Jagelman Hereditary Colorectal Cancer Registries at the Sanford R. M.D. Center for Hereditary Colorectal Neoplasia at the Cleveland Clinic from 1979 to 2019 who met inclusion criteria were included in the study. Individuals with comorbid IBD including ulcerative colitis (UC) and Crohn’s disease (CD), and rheumatic diseases were included. For our primary aim, controls were randomly chosen from the registry after matching for presence and type of mismatch repair gene pathogenic variant, age at last follow up, and gender. We compared the proportion of patients who had developed any cancer up to last follow up or death between the two groups. For our secondary aim, patients were divided into two groups based on any exposure to these medications. Duration of exposure was determined through the electronic medical record or paper chart review by duration of prescription length and provider notes. The proportion of individuals who developed a cancer was calculated from the year of diagnosis of comorbid disease until last follow up or death.
64 HNPCC patients including 21 cases with a comorbid inflammatory disease and 43 controls without comorbid inflammatory disease were analyzed. The proportion of patients who had developed cancer after diagnosis of comorbid inflammatory disease in cases was 57.1% with a 10 year (6.0-16.5) median duration of follow-up and 46.5% in controls (P = 0.42) when also followed for 10 years prior to last follow up or death. Approximately half of the cancers were HNPCC-specific: 52.4% of cases vs 44.2% of controls (P = 0.54). For the secondary aim, we compared the proportion of individuals who developed cancer after diagnosis of a comorbid inflammatory disease in the 9/21 (39.5%) individuals exposed to monoclonal antibodies and/or immunomodulators to the 12/21 (61.5%) unexposed. Seven of nine (77.8%) exposed compared to 5/12 (41.7%) unexposed patients developed any cancer after diagnosis of a CID (P = 0.18). The hazard ratio for cancer with medication exposure was calculated to be 1.59 (P = 0.43, 95%CI: 0.5-5.1). This is the first study of its kind, attempting to address the interaction between genetic predisposition to cancer, inflammatory disease and immunosuppression. It remains to be seen whether these results are reproduced in larger multicenter studies.
In our small cohort, comorbid inflammatory disease does not appear to add any additional cancer risk to patients with HNPCC regardless of MMRPV status. The decision to start a biologic or immunomodulator in this cohort is understandably complex and should be individualized with consideration given to any colonic inflammatory disease.
We propose collaborative research to assess the risk of malignancy in lynch syndrome and HNPCC individuals on immunosuppressive medications. The risk of colorectal cancer in IBD has historically been associated with severity and duration of the disease. From this standpoint, immunosuppressive medications can potentially decrease colorectal incidence in patients with IBD. However, there are no studies that directly address individuals with genetic predisposition to cancer. Genetic susceptibility to malignancy adds another layer of complexity given the intricacy of balancing immunosuppression which decreases malignancy risk in inflammation but may also theoretically decrease immune surveillance.