An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Abstract

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.

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort

“…The availability of counseling and testing for these two syndromes have made a significant contribution to cancer prevention and control. HBOC patients can benefit from personalized treatments, increased surveillance, chemo-prevention, and/or risk-reducing surgery, while LS carriers with colorectal cancer could consider subtotal colectomy or immune checkpoint therapy in advanced cases [ 5 , 6 ]. Carriers at reproductive age may also seek advice for prenatal diagnosis and assisted reproduction, including pre-implantation genetic testing.…”

Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study

“…Understanding the genetic and molecular genomic background of LS patients in the era of precision cancer medicine is of great importance in order to use MMR germline pathogenic variants as predictive biomarkers. MMR deficiency can be employed for the selection of Algerian LS patients for the treatment with immune checkpoint inhibitors (Therkildsen et al., 2021).…”

Vaccines for immunoprevention of DNA mismatch repair deficient cancers

“…[70][71][72] So far, however, no significant difference in immune therapy response rates between Lynch syndrome carriers and sporadic MMRd patients with cancer have been reported. 73 This counterintuitive observation may be explained by the fact that Lynch-associated MMRd cancer cells have evolved particularly effective strategies of evading attacks by the host's immune cells. This hypothesis is supported by several studies reporting an elevated frequency of immune evasion mechanisms in Lynchassociated compared with sporadic MMRd colorectal cancers.…”