Retrospective Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jan 24, 2022; 13(1): 49-61
Published online Jan 24, 2022. doi: 10.5306/wjco.v13.i1.49
Association of cancer with comorbid inflammatory conditions and treatment in patients with Lynch syndrome
Muhammad S Faisal, Carol A Burke, David Liska, Amy L Lightner, Brandie Leach, Margaret O’Malley, Lisa LaGuardia, Benjamin Click, JP Achkar, Matthew Kalady, JM Church, Gautam Mankaney
Muhammad S Faisal, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
Carol A Burke, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, United States
David Liska, Amy L Lightner, Margaret O’Malley, Lisa LaGuardia, JM Church, Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH 44195, United States
Brandie Leach, Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland, OH 44195, United States
Benjamin Click, Department of Gastroenterology, Hepatology, & Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
JP Achkar, Center for Inflammatory Bowel Disease, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
Matthew Kalady, Department of Colorectal Surgery, Ohio State University, Columbus, OH 43210, United States
Gautam Mankaney, Department of Gastroenterology and Hepatology, Virginia Mason Franciscan Health, Seattle, WA 98101, United States
Author contributions: Burke CA, Liska D, Lightner A, Kalady M and Church J provided original data as well as reviewed and edited the manuscript; Faisal MS collected variables and analyzed data; Leach B, O'Malley M and LaGuardia L provided technical support, data variables, and reviewed the manuscript; Click B, Achkar JP, Burke CA and Mnakaney G designed the study, supervised and edited the final version; Faisal MS and Mankaney G envisioned the study, wrote the final manuscript.
Institutional review board statement: This study was approved by Cleveland Clinic Institutional Review Board (IRB 2884).
Informed consent statement: This study was exempt from signed consent form requirements.
Conflict-of-interest statement: Authors have no conflicts of interest to disclose.
Data sharing statement: Consent was not obtained but the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Gautam Mankaney, MD, Doctor, Department of Gastroenterology and Hepatology, Virginia Mason Franciscan Health, 1100 Ninth Avenue C3-GAS, Seattle, WA 98101, United States.
Received: April 9, 2021
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
Research background

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.

Research motivation

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.

Research objectives

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.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.