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.