Clinical and Experimental Gastroenterology (May 2021)
An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome
Abstract
Christina Therkildsen,1,2 Lars Henrik Jensen,3 Maria Rasmussen,2 Inge Bernstein4,5 1Department of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen, Denmark; 2The Danish HNPCC Register, Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Copenhagen, Denmark; 3Department of Oncology, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark; 4Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark; 5Faculty of Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Inge BernsteinDepartment of Gastroenterology, Aalborg Hospital, Hobrovej 18-22, Aalborg, 9100, DenmarkTel +45 97666805Email [email protected]: During the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment—both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2, most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14– 100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.Keywords: hereditary colorectal cancer, HNPCC, Lynch syndrome, endometrial cancer, germline mismatch repair defect
