scholarly journals O002/#43 Randomized phase 3 study of lenvatinib plus pembrolizumab for advanced endometrial cancer (aec): subgroup analysis of patients with DNA mismatch repair deficient (DMMR) tumors

2021 ◽  
Author(s):  
V Makker ◽  
N Colombo ◽  
A Casado Herráez ◽  
A Santin ◽  
E Colomba ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Subgroup Analysis ◽  
Dna Mismatch Repair ◽  
Phase 3 ◽  
Dna Mismatch

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.

DNA mismatch repair protein defects and endometrial cancer in women age 40 and younger

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5579-5579
Author(s):  
K. K. Shih ◽  
K. Garg ◽  
D. A. Levine ◽  
N. Kauff ◽  
N. R. Abu-Rustum ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Young Women ◽  
Dna Mismatch Repair ◽  
High Grade ◽  
Advanced Stage ◽  
Dna Mismatch ◽  
Repair Protein ◽  
Mismatch Repair Protein

5579 Background: The significance of the hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to describe the incidence and prognostic implications of DNA mismatch repair protein defects in a series of patients age 40 years and younger with endometrial cancer. Methods: We performed a retrospective cohort study of patients age 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry (IHC) was performed. Cases were analyzed according to presence of DNA MMR protein defects. Standard two-sided statistical tests were performed. Results: Of the 71 identified patients, the median age was 37 years (range, 24–40), with a median follow-up of 47 months (range, 1–178). The majority were of endometrioid histology (94%), stage I (73%), and FIGO grade 1 (61%). IHC was performed with available blocks (n = 56), and loss of DNA MMR was found in 9 cases (16%). Cases with loss of DNA MMR were more likely to have high-grade (FIGO 2 or 3) tumors (p < 0.001), be advanced stage (III or IV) at the time of diagnosis (p < 0.001), and have a family history suggestive of hereditary non-polyposis colorectal cancer (p = 0.01). There was no difference between the groups in histology, obesity (BMI>30), parity, or history of infertility. Analysis of clinical outcomes revealed that cases with loss of DNA MMR had significantly worse overall survival (median survival not reached, log rank p = 0.018). At the time of last follow-up, 2 (22%) patients with loss of DNA MMR were dead of disease compared with 2 (4%) patients with retained DNA MMR. Conclusions: Endometrial cancer is rare in young women age 40 years or less. In these patients, loss of DNA MMR was associated with worse clinicopathologic factors (high-grade and advanced-stage tumors) and worse outcome. Other clinical risk factors associated with endometrial cancer were not associated with loss of DNA MMR. The data suggest that MMR testing in women 40 years of age or younger with endometrial cancer may have clinically useful prognostic information. No significant financial relationships to disclose.

Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer

2009 ◽  
Vol 114 (3) ◽  
pp. 486-490 ◽  
Author(s):  
Floor J. Backes ◽  
Marino E. Leon ◽  
Iouri Ivanov ◽  
Adrian Suarez ◽  
Wendy L. Frankel ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Protein Expression ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Prospective Evaluation ◽  
Dna Mismatch ◽  
Repair Protein ◽  
Mismatch Repair Protein
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