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2022-RA-809-ESGO Underlying causes and prognosis of mismatch repair deficiency in endometrial cancer other than MLH1 promoter hypermethylation
  1. Merve Kaya1,
  2. Cathalijne Post2,
  3. Carli M Tops3,
  4. Ellen Stelloo4,
  5. Maartje Nielsen3,
  6. Melanie E Powell5,
  7. Alexandra Leary6,
  8. Linda R Mileshkin7,
  9. Paul Bessette8,
  10. Stephanie M de Boer2,
  11. Ina M Jürgenliemk-Schulz9,
  12. Ludy Lutgens10,
  13. Jan J Jobsen11,
  14. Elzbieta M van der Steen-Banasik12,
  15. Remi A Nout2,
  16. Nanda Horeweg2,
  17. Tom van Wezel4,
  18. Vincent Smit4,
  19. Carien L Creutzberg2 and
  20. Tjalling Bosse4
  1. 1Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
  2. 2Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands
  3. 3Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
  4. 4Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
  5. 5Department of Clinical Oncology, Barts Health NHS Trust, London, UK
  6. 6Department of Medical Oncology, Gustave Roussy, Villejuif, France
  7. 7Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
  8. 8Department of Obstetrics and Gynaecology, University of Sherbrooke, Sherbrooke, QC, Canada
  9. 9Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands
  10. 10Department of Radiation Oncology, MAASTRO Clinic, Maastricht, Netherlands
  11. 11Department of Radiation Oncology, Medical Spectrum Twente, Enschede, Netherlands
  12. 12Department of Radiation Oncology, Radiotherapy Group, Arnhem, Netherlands


Introduction/Background The vast majority of mismatch repair-deficient (MMRd) endometrial carcinomas (EC) are due MLH1 promoter hypermethylation. Here, we aimed to investigate the prevalence, prognosis and underlying causes (including Lynch syndrome (LS)) of MMRd EC other than MLH1 promoter hypermethylation.

Methodology From the 409 MMRd ECs that were identified by MMR-immunohistochemistry (IHC) in the PORTEC-1,-2 and -3 trials, 97 cases did not have MLH1 promoter hypermethylation. These 97 cases were analyzed by matched tumor-normal tissue targeted next-generation sequencing (NGS) for the presence of MMR and POLE mutations (class 4/5 variants). Furthermore, microsatellite instability (MSI) testing was performed. Differences in 5-year recurrence-free survival (RFS) were analysed using the Kaplan-Meier method and log-rank test. On a subset of cases NGS is pending and results will be added for the meeting.

Results In 34 cases (35%) a germline MMR mutation (LS-associated) was identified of which 8 (24%) had a second somatic hit. Upon excluding LS-associated ECs, a somatic alteration in MMR genes was observed in 52% (n=33), including double somatic hits in 35% (n=22). In the remaining 48% of cases (n=30) no MMR mutation was found of which the majority (n=22) was confirmed MSI. Rereview of all (discrepant) MMR-IHC did not reveal misinterpretation of MMRd status. Somatic POLE mutations were identified in 7/97 cases (7%). The 5-year RFS did not differ significantly between LS-associated and non-LS-associated MMRd EC (5-year RFS 94.1% [95% CI 86.5–100%] vs 93.5% [95% CI 87.5–99.9%], respectively; p=0.72; figure 1).

Abstract 2022-RA-809-ESGO Figure 1

Kaplan-Meier survival curves for recurrence-free survival for patients with LS-associated EC (germline mutation in MMR gene) and other non-LS-associated MMRd EC. All Cases with MMRd phenotype without MLH1 promoter hypermethylation are included in this analysis, including cases with a concurrent POLE mutation (POLEmut-MMRd EC). P value reflect 2-sided log-rank test. Abbreviations: EC, endometrial cancer; LS, Lynch syndrome; MMR, mismatch repair; MMRd, mismatch repair-deficient;

Conclusion Identification of an underlying cause for unmethylated MMRd is feasible in the majority of EC cases applying matched tumor-normal tissue NGS. A significant proportion was confirmed to be LS-associated or sporadic MMRd, while only a small subset remained unresolved. Although this distinction did not carry prognostic relevance, identification of definitive sporadic causes may release patients and relatives from burdensome LS-surveillance.

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