Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer

Abstract

Endometrial cancer is common, and a subset recurs and requires additional treatment.• Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). • However, this clinical trial highlights which cases are more likely to respond well: those containing mutations in genes known as Lynch genes and also some with mutations in POLE/POLD1 ("ultra-hypermutation" genes).• In contrast, the majority of dMMR endometrial cancers have silencing or DNA methylation of one of these genes, MLH1, and do not seem to be as responsive to single-agent immune therapy.• The availability of combination therapies may be important to consider for these women.Endometrial cancer (EC), the most common gynecological cancer affecting women in developed countries, is rising in incidence, partly because of increasing obesity and our aging population. 1 On the basis of genomic, proteomic, and epigenomic evaluations, 4 distinct molecular subtypes of EC have been defined: polymerase ε (POLE)-hypermutated, microsatellite instability, copy number-low/p53 wild type, and copy number-high/p53-mutated. 2 Up to 30% of all ECs are associated with DNA mismatch repair deficiency (dMMR). 3 As for other tumor types, dMMR in EC may be either acquired or due to inherited defects in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) or in EPCAM (causing downstream silencing of MSH2). [4][5][6][7][8][9] The majority of dMMR in ECs (~75% of dMMR and ~20% of all ECs) is caused by acquired hypermethylation of the MLH1 gene promoter. 3 The remaining causes of dMMR in ECs are attributed to either double somatic MMR mutations or germline MMR pathogenic variants. 10 Cancers with dMMR typically have a microsatellite instability-high (MSI-H) phenotype due to uncorrected errors that occur in repetitive DNA sequence during DNA replication, which results in a high somatic mutation frequency. When these dMMR-related mutational events occur in coding regions, the generation of high levels of novel frameshift peptide antigens occurs. The abundance and "foreign" nature of these frameshift peptide neoantigens in dMMR cancers likely explain the strong CD3+ and CD8+ T-cell responses, which are predictive of sensitivity to immune checkpoint inhibitor (ICI) therapy. 11 Most patients are diagnosed at an early stage and cured with surgery and/or local therapies. Chemotherapy (carboplatin combined with paclitaxel) has remained the first-line systemic therapy beyond endocrine therapy for women with advanced or recurrent EC. Therapeutic options after this are associated with poor outcomes with response rates of 20% or less. 12 Chemotherapy resistance has been reported in dMMR tumors, and this may explain the worse prognosis in the advanced setting in comparison with MMR-proficient tumors. 3,12,13 Immunotherapy using a single-agent ICI may be a highly effective treatment for dMMR/MSI-H ECs with reported overall tumor response rates (ORRs) between 27% and 57%. 12 However, these studies are small and include single...

Efficacy and Safety of PD-1/PD-L1 Inhibitor as Single-Agent Immunotherapy in Endometrial Cancer: A Systematic Review and Meta-Analysis

“…The use of ICIs as a single-agent immunotherapy appears to be a highly effective treatment for patients with dMMR or MSI-high endometrial cancers (ECs). The reported overall tumor response rates (ORRs) in this context ranged from 27% to 57% [ 27 ].…”

Immune Checkpoint Inhibitors and Mismatch Repair Status in Advanced Endometrial Cancer: Elective Affinities

“…Conversely, dMMR ECs may present DNA methylation or silencing of one of these genes, and frequently do not respond to ICIs. At the same time, since some pMMRs have also been reported to benefit from ICIs, additional predictive biomarkers should be considered for patient selection [35][36][37]. Thus, candidates for PD-1 blockade may extend beyond POLEm and dMMR ECs; additional factors such as tumor grade and combination of TIL levels and expression of checkpoint proteins may need to be considered for the optimization of treatment.…”

Novel Molecular Targets in Endometrial Cancer: Mechanisms and Perspectives for Therapy

“…The majority of cases of MMRd (75%) are caused by acquired promoter hypermethylation and the rest due to mutations. 23 The MMR pathway comprises specific repair enzymes which are dependent on four main genes: MLH1, PMS2, MSH2 and MSH6 . If one of the genes has a mutation, this results in the accumulation of multiple defects within the genome leading to tumorigenesis.…”