دورية أكاديمية
Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation.
| العنوان: | Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation. |
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| المؤلفون: | Toboni MD; University of Alabama at Birmingham, Division of Gynecologic Oncology, Birmingham, AL, USA. Electronic address: MDToboni@uabmc.edu., Wu S; Caris Life Sciences, Phoenix, AZ, USA., Farrell A; Caris Life Sciences, Phoenix, AZ, USA., Xiu J; Caris Life Sciences, Phoenix, AZ, USA., Ribeiro JR; Caris Life Sciences, Phoenix, AZ, USA., Oberley MJ; Caris Life Sciences, Phoenix, AZ, USA., Arend R; UAB Comprehensive Cancer Center Experimental Therapeutics Program, Birmingham, AL, USA., Erickson BK; University of Minnesota, Division of Gynecologic Oncology, Minneapolis, MN, USA., Herzog TJ; University of Cincinnati Cancer Center, Cincinnati, OH, USA., Thaker PH; Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, MO, USA., Powell MA; Washington University School of Medicine, Division of Gynecologic Oncology, St. Louis, MO, USA. |
| المصدر: | Gynecologic oncology [Gynecol Oncol] 2023 Oct; Vol. 177, pp. 132-141. Date of Electronic Publication: 2023 Sep 08. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 0365304 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-6859 (Electronic) Linking ISSN: 00908258 NLM ISO Abbreviation: Gynecol Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, Academic Press. |
| مستخلص: | Objectives: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. Methods: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. Results: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity. Conclusions: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors. Competing Interests: Declaration of Competing Interest SW, JRR, AF, JX, MJO: Caris Life Sciences (employee salary, stock/stock options). PHT: DSM or Advisory Board: Iovance, AstraZeneca, GlaxoSmithKline, Clovis Oncology, Zentalis, Novocure, Seagen, Immunogen, R-Pharm, Aadi Pharmaceuticals, Caris Life Sciences, Merck, Immunon; Stock/Stock Options: Immunon. TJH: Consulting Fees: AstraZeneca, Caris Life Sciences, Clovis Oncology, Eisai, Genelux, Genentech, GlaskoSmithKline, Immunogen, J&J, Merck, Mersana, Seagen; Meeting Support: Alkermes; DSM or Advisory Board: Corcept; Leadership or Fiduciary Role: GOG-Foundation. MAP: Consulting Fees: GlaxoSmithKline/Tesaro, Merck, AstraZeneca, Clovis Oncology, Seagen, Eisai. BKE: Consulting Fees: GlaskoSmithKline, Merck, Signatera. RA: Consulting Fees: GlaskoSmithKline, Merck, Sutro, Seagen. (Copyright © 2023 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Endometrial cancer; Hormonal therapy; Immune microenvironment; Immunotherapy; MLH1 hypermethylation; MLH1 mutation; Mismatch repair deficiency; Molecular profiling; Precision oncology |
| تواريخ الأحداث: | Date Created: 20230908 Latest Revision: 20231012 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.ygyno.2023.08.015 |
| PMID: | 37683549 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1095-6859 |
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| DOI: | 10.1016/j.ygyno.2023.08.015 |