Abstract 4538: The heterogeneous immune and molecular landscape of endometrial cancer metastases
Authors: Hadfield Matthew J. , Wu Sharon , Farrell Alex , Oberley Matthew , Jones Nathaniel , Herzog Thomas , Thaker Premal , Dizon Don 
Published: April 2023

Abstract
Introduction: Endometrial Cancer (EC) is a diverse malignancy with multiple histological subtypes. There is a paucity of data exploring the genomic landscape of endometrial cancer primary lesions (ECP) and endometrial metastatic lesions (ECM.) Correlations with genetic makeup and sites of metastatic disease have not been previously studied.
Methods: Relationships of ECM and alterations detected by NGS (592, NextSeq; WES, NovaSeq) were investigated in 15,489 EC samples (Caris Life Sciences, Phx, AZ). PD-L1 expression was tested by IHC (SP142, &gt;2|5%). Microsatellite instability (MSI) was tested by FA, IHC and NGS. Tumor mutational burden (TMB) was measured by summing somatic mutations per tumor (H: &gt;10 mt/MB). Immune infiltrates estimated by deconvolution of WTS data (NovaSeq) using MCP Counter. Real world overall survival (rwOS) was extracted from insurance claims and calculated using Kaplan-Meier estimates for cohorts defined by biopsy site, using start of treatment to last contact. Statistical significance determined by chi-square and Mann-Whitney U and adjusted for multiple comparisons (q&lt;0.05).
Results: ECM had higher HER2 amplification (by CISH) compared to ECP (20.4% vs. 16.9%) but lower PR positivity (45.2% vs. 50.2%) (q&lt;0.05). TMB-H was highest in ECM to GI (34.2%) compared to Uterine (22.4%) (q&lt;0.05). d-MMR/MSI-H prevalence was highest in ECM to GI (30.3%) and lowest in ECM to lung (11.5%) and liver (10.9%) compared to Uterine (19.5%) (q&lt;0.05). Hierarchical clustering of ECM sites by alteration (mutations, amplifications and fusions) frequency revealed ECM to Bone and GU having a distinct pattern compared to Uterine with increased alterations in RTK RAS (Bone vs Uterine: FGF3-amp, 3.45% vs 0.39%, FGF19-amp, 3.36% vs 0.39%), Cell Cycle (Bone vs GU vs Uterine: TP53-mt, 37.6% vs 42.3% vs 53.7%), WNT (GU vs Uterus: RNF43-mt, 15.4% vs 7.06%; CTNNB1-mt, 22.3% vs 12.9%) and Chromatin Remodeling (GU vs Uterine: ASXL1-mt, 23.1% vs 7.64%; KMT2D-mt, 18.9% vs 11.1%, ARID1A, 43.8% vs 33.8%) pathway genes.ECM to Bone had the lowest infiltration of B cells and T cells (q&lt;0.05). IFN score was 1.21-fold higher in ECM to Bone compared to ECP of Uterus (q&lt;0.05). ECM to GU (n=29, HR: 1.59, 570 days, p=0.04) had worse post-Carboplatin survival than ECP (n=3023, 1096 days) while ECM to Lung had better (n=279, HR: 0.73, 1602 days, p=&lt;0.01). ECM to Liver (PD-1/PD-L1i: n=27, HR: 2.4, 165 days, p=&lt;0.01; Bevacizumab: n=44, HR: 1.5, 286 days, p=0.03) had worse post-tx survival compared to ECP (PD-1/PD-L1i: n=607, 760 days; Bevacizumab: n=693, 463 days). ECM to GI (n=44, HR: 0.56, 1080 days, p=0.003) and Lung (n=86, HR: 0.70, 768 days, p=0.01) had improved post-Gemcitabine treatment compared to ECP (n=533, 452 days).
Conclusions: ECM to Bone and GU organs have unique molecular alterations when compared to ECP of the uterus and have lower infiltration of immune cells. We also highlight differences in OS when comparing different ECM.
Citation Format: Matthew J. Hadfield, Sharon Wu, Alex Farrell, Matthew Oberley, Nathaniel Jones, Thomas Herzog, Premal Thaker, Don Dizon. The heterogeneous immune and molecular landscape of endometrial cancer metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4538.