Clinicopathologic features associated with defective DNA mismatch repair (MMR): A GOG 0210 cohort study of 1041 endometrioid endometrial cancer cases

2015 ◽  
Vol 137 ◽  
pp. 20-21
Author(s):  
D.G. Mutch ◽  
M.A. Powell ◽  
A. Schmidt ◽  
R. Broaddus ◽  
N. Ramirez ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cohort Study ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Clinicopathologic Features ◽  
Dna Mismatch ◽  
Endometrioid Endometrial Cancer

Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population

2020 ◽  
Vol 51 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Azusa Yamamoto ◽  
Tatsuro Yamaguchi ◽  
Okihide Suzuki ◽  
Tetsuya Ito ◽  
Noriyasu Chika ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Molecular Characteristics ◽  
Variant Of Uncertain Significance ◽  
Dna Mismatch ◽  
Germline Variant ◽  
Uncertain Significance ◽  
Repair Genes

Abstract Background The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. Methods Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. Results Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). Conclusions This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

Clinical characterization of DNA mismatch repair deficiency (MMR-D) in endometrial cancer (EC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 1522-1522
Author(s):  
Karen Anne Cadoo ◽  
Christina Tran ◽  
Deborah DeLair ◽  
Angela G. Arnold ◽  
Asad Ashraf ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Dna Mismatch Repair Deficiency

A phase II trial of durvalumab (Medi 4736) in advanced endometrial cancer: PHAEDRA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5614-TPS5614 ◽  
Author(s):  
Yoland Catherine Antill ◽  
Martin R. Stockler ◽  
Peey Sei Kok ◽  
Kristy Pamela Robledo ◽  
Kim Gillies ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Unmet Need ◽  
Tumour Response ◽  
Survival Duration ◽  
Genetic Characteristics ◽  
Objective Tumour Response ◽  
Dna Mismatch

TPS5614 Background: Advanced endometrial cancer (EC) progressing after 1 or more lines of chemotherapy is an area of unmet need with objective tumour response rates to subsequent lines of chemotherapy of ≤20%. DNA mismatch repair (MMR) deficiency, seen in approximately 15% of EC, is associated with a high mutational load and in addition, up to 90% of ECs are reported to have PDL1/ PD1 expressions. These factors make immune check point inhibition an ideal target for treatment. Methods: DESIGN: Multicentre phase 2 trial in two cohorts. ELIGIBILITY: Advanced, unresectable endometrial cancer that is either MMR-proficient and progressing after 1-3 lines of chemotherapy, or MMR-deficient and progressing after 0-3 lines of chemotherapy. ENDPOINTS: Objective tumour response rate (OTRR) according to iRECIST (primary) and RECIST 1.1, disease control rates at 16 and 24 weeks, progression free survival, overall survival, duration of OTR and DC, adverse events, health related quality of life. Tertiary correlative objectives: Associations between immunologic (including PD-L1), DNA mismatch repair (MMR) and other genetic characteristics with clinical outcomes; and family history of cancer and referral to familial cancer services. INTERVENTION: Durvalumab 1500 mg intravenously every 28 days until disease progression or prohibitive toxicity. STATISTICS: Total of 70 participants in two cohorts (35 each) will have 90% power to distinguish a difference in observed OTRR of ≥20% versus ≤5% (uninteresting rate) using Simon’s 2-stage minimax design with 10% type 1 error rate and allowing 10% ineligibility and missing data. Durvalumab will be considered worthy of pursuit if 4 or more OTR are observed in the first 32 participants in each cohort (OTRR ≥12.5%). BIOSPECIMENS: Tumour tissue and serial bloods (5 time points) will be collected for translational research. PHAEDRA is an investigator-initiated, cooperative-group trial led by ANZGOG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney. Australian New Zealand Clinical Trials Registry: Clinical trial information: ACTRN12617000106336.

scholarly journals DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 279 ◽  
Author(s):  
Jisup Kim ◽  
Jin Kong ◽  
Wookyeom Yang ◽  
Hanbyoul Cho ◽  
Doo Chay ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Molecular Classification ◽  
Clinicopathologic Features ◽  
Immune Markers ◽  
Dna Mismatch ◽  
Sporadic Cancer ◽  
Mmr Deficiency

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer.

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