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PR046/#280  The genomic landscape of distant metastatic endometrial cancer
  1. Bill Zammarrelli1,
  2. Subhiksha Nandakumar2,
  3. Elizabeth Kertowidjojo3,
  4. Bastien Nguygen2,
  5. Arrnaud Da Cruz Paula3,
  6. Eric Rios-Doria4,
  7. Shaleigh Smith2,
  8. Amir Momeni-Boroujeni3,
  9. Carol Aghajanian5,
  10. Jennifer Mueller1,
  11. Nadeem Abu-Rustum1,
  12. Nikolaus Schulz2,
  13. Lora Ellenson3 and
  14. Britta Weigelt3
  1. 1Memorial Sloan Kettering Cancer Center, Gynecology Service, Department of Surgery, New York, USA
  2. 2Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, USA
  3. 3Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, USA
  4. 4University of Washington Medical Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Seattle, USA
  5. 5Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, USA


Introduction While the genomic landscape of untreated primary endometrial carcinoma (EC) is well characterized, the molecular underpinnings of distant metastatic EC are poorly understood. We sought to define genomic alterations associated with distant metastatic EC.

Methods We obtained sequencing data from distant metastatic ECs from a total of 1888 ECs subjected to a clinical tumor-normal sequencing panel between 8/2013 and 6/2020; these metastatic ECs were compared against 711 primary ECs using appropriate statistical analyses.

Results One hundred thirty-seven ECs met the study inclusion criteria, with distant metastases in the lung (n=66, 48%), liver (n=21, 15%), soft tissue (n=15, 11%), distant lymph nodes (n=15, 11%), gastrointestinal tract (n=10, 7%), central nervous system (n=5, 4%), bone (n=4, 3%), and renal system (n=1, 1%). The majority of distant metastases were of copy number (CN)-high (42%) or CN-low (39%) molecular subtype; 18% were microsatellite instability (MSI)-high and 1% were of POLE molecular subtype. Distant EC metastases were significantly more chromosomally unstable compared with primary ECs (p<0.0001) and were enriched in AKT1, CTNNB1, ANKRD11, and ZFHX3 mutations. Clinically actionable alterations, particularly tumor mutational burden (TMB) ≥10 mut/Mb and MSI-high status, were significantly less common in metastatic compared with primary ECs (4% vs 29%; p=0.017). Epigenetic, PI3K, and TP53 pathways were the most commonly altered pathways among all anatomic sites.

Conclusion/Implications Compared with primary tumors, distant metastatic ECs exhibited increased chromosomal instability but decreased hypermutator phenotypes. Exploitation of genetic differences to understand the pathogenesis of metastatic EC is necessary to develop biomarkers for targeted therapy.

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