Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation

Toboni, Michael D.; Wu, Sharon; Farrell, Alex; Xiu, Joanne; Ribeiro, Jennifer R.; Oberley, Matthew J.; Arend, Rebecca; Erickson, Britt K.; Herzog, Thomas J.; Thaker, Premal H.; Powell, Matthew A.

doi:10.1016/j.ygyno.2023.08.015

Cited by 4 publications

(7 citation statements)

References 40 publications

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“…Our methodology included only patients exhibiting loss of MLH1 protein expression via IHC as an inclusion criterion, as this subgroup is considered more valid for methylation analysis in assessing tumor MSI. Bruegl [31][32][33]. Our findings align with these results exhibiting loss of MLH1 expression via IHC, 90% displayed methylation of the MLH1 gene.…”

Section: Discussionsupporting

confidence: 88%

Insights into MLH1 Methylation in Endometrial Adenocarcinoma through Pyrosequencing Analysis: A Retrospective Observational Study

Silva,

Ballini,

Caponio

et al. 2024

Cancers

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Background: In cancer care, the MLH1 gene is crucial for DNA mismatch repair (MMR), serving as a vital tumor suppressor. Evaluating MLH1 protein expression status, followed by analysis of MLH1 promoter methylation, has become a key diagnostic and prognostic approach. Our study investigates the complex link between MLH1 methylation and prognosis in endometrial adenocarcinoma (EA) patients. Methodology: MLH1 methylation status was accessed by a Pyrosequencing (PSQ) assay. Qualitative positivity for methylation was established if it exceeded the 11% cut-off; as well, a quantitative methylation analysis was conducted to establish correlations with clinicopathological data, relapse-free survival, and disease-free survival. Results: Our study revealed that 33.3% of patients without MLH1 methylation experienced relapses, surpassing the 23.3% in patients with methylation. Furthermore, 16.7% of patients without methylation succumbed to death, with a slightly higher rate of 17.6% in methylated patients. Qualitative comparisons highlighted that the mean methylation rate in patients experiencing relapse was 35.8%, whereas in those without relapse, it was 42.2%. This pattern persisted in disease-specific survival (DSS), where deceased patients exhibited a higher mean methylation level of 49.1% compared to living patients with 38.8%. Conclusions: Our findings emphasize the efficacy of PSQ for evaluating MLH1 methylation. While unmethylation appears to be associated with a higher relapse rate, the survival rate does not seem to be influenced by methylation. Quantitative percentages suggest that elevated MLH1 methylation is linked to relapse and mortality, though a study with a larger sample size would be essential for statistically significant results.

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Section: Discussionsupporting

confidence: 88%

Insights into MLH1 Methylation in Endometrial Adenocarcinoma through Pyrosequencing Analysis: A Retrospective Observational Study

Silva,

Ballini,

Caponio

et al. 2024

Cancers

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“…In addition, they observed an enrichment of JAK1 mutations in MLH1 hypermethylated ECs. 79 Other studies have also observed differences in the intratumoral immune infiltrate as well as interactions between JAK1 mutations and the interferon-γ pathway. 89 In an abstract of the 2022 Society of Gynecologic Oncology (SGO) Annual Meeting, Borden and colleagues 90 described a retrospective study of 18 recurrent EC treated with single-agent pembrolizumab and found that that recurrence-free survival and OS was significantly decreased in patients with epigenetic MMR-…”

Section: Heterogeneity By Mmr Mechanism In Ecmentioning

confidence: 98%

“…Subsequently, Toboni et al 79 reported on 1673 patients with MMR-D EC associated with alterations in MLH1 (89% with promoter hypermethylation and 11% MLH1-mutated) and found that epigenetic MMR-D ECs had decreased rates of PD-L1 positivity, immune cell infiltration, T-cell inflamed scores, and interferon-γ scores along with worse OS. In addition, they observed an enrichment of JAK1 mutations in MLH1 hypermethylated ECs.…”

Section: Heterogeneity By Mmr Mechanism In Ecmentioning

confidence: 99%

A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers

Liu,

Weigelt

2024

Cancer

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The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR‐deficiency (MMR‐D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. This is particularly relevant in endometrial cancer (EC) as 25%–30% of tumors are of MMR‐D/MSI‐high (MSI‐H) phenotype. Comprehensive assessment using immunohistochemistry (IHC) and sequencing‐based techniques are necessary to fully evaluate ECs given the importance of molecular subtyping in staging and prognosis. This also influences treatment selection as clinical trials have demonstrated survival benefits for immune checkpoint inhibitors (ICIs) alone and in combination with chemotherapy for MMR‐D/MSI‐H EC patients in various treatment settings. As a portion of MMR‐D/MSI‐H ECs are driven by Lynch syndrome, an inherited cancer predisposition syndrome that is also associated with colorectal cancer, this molecular subtype also prompts germline assessment that can affect at‐risk family members. Additionally, heterogeneity in the tumor immune microenvironment and tumor mutation burden (TMB) have been described by MMR mechanism, meaning MLH1 promoter hypermethylation versus germline/somatic MMR gene mutation, and this may affect response to ICI therapies. Variations by ancestry in prevalence and mechanism of MMR‐D/MSI‐H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR‐D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC.

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“…37 ECs differ according to the mechanism underpinning MSI instability. [39][40][41] MLH1-hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations. 39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic).…”

Section: Therapeutic Implications Of the Ec Molecular Subtypesmentioning

confidence: 99%

“…39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic). [39][40][41] CN-low ECs, also referred to as of NSMP, is a heterogeneous group of ECs classified by exclusion and encompassing tumors that do not display any of the other three defining molecular subtype features (i.e., POLE mutation, MSI, p53/TP53 alteration). 8,42 Several studies have focused on this NSMP group and showed that based on PTEN/PIK3CA mutation status, histology/grade, chromosome 1q gain/amplification, ER status or chromosomal instability, subgroups with distinct outcomes could be identified.…”

Section: Therapeutic Implications Of the Ec Molecular Subtypesmentioning

confidence: 99%

Moving into the modern era of molecular classification for endometrial cancer

Dagher,

Liu,

Mueller

et al. 2023

Journal of Surgical Oncology

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The molecular subtypes of endometrial carcinoma (EC) were first described by The Cancer Genome Atlas (TCGA) a decade ago. Using surrogate approaches, the molecular classification has been demonstrated to be prognostic across EC patients and to have predictive implications. Starting in 2020, the molecular classification has been incorporated into multiple guidelines as part of the risk assessment and most recently into the International Federation of Gynecology and Obstetrics (FIGO) staging. This review article discusses the implementation of the EC molecular classification into clinical practice, the therapeutic implications, and the molecular and clinical heterogeneity of the EC molecular subtypes.

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Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation

Cited by 4 publications

References 40 publications

Insights into MLH1 Methylation in Endometrial Adenocarcinoma through Pyrosequencing Analysis: A Retrospective Observational Study

Insights into MLH1 Methylation in Endometrial Adenocarcinoma through Pyrosequencing Analysis: A Retrospective Observational Study

A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers

Moving into the modern era of molecular classification for endometrial cancer

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