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, >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: >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<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<0.05). TMB-H was highest in ECM to GI (34.2%) compared to Uterine (22.4%) (q<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<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<0.05). IFN score was 1.21-fold higher in ECM to Bone compared to ECP of Uterus (q<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=<0.01). ECM to Liver (PD-1/PD-L1i: n=27, HR: 2.4, 165 days, p=<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.
5580 Background: Emerging data suggests that key differences exist between BRCA1 and BRCA2 associated OC, including response to therapy and survival. The purpose of this study was to identify the gene expression profiles, interacting pathways and immune microenvironment of BRCA1 mutant (BRCA1mut), BRCA2 mutant (BRCA2mut) and homologous recombination wild-type (HRwt) associated high grade serous OC (HGSOC). Methods: Next-generation sequencing (592, NextSeq; WES, NovaSeq) and Whole Transcriptome Sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ) were performed in 8196 OC tumors classified into 3 groups: BRCA1mt; BRCA2mt; and HRwt. BRCA mutations were defined as variants that result in loss-of-function of the BRCA protein and HRwt was defined as samples negative for aberrations in both BRCA1 and BRCA2, as well as for 28 other homologous recombination genes Microsatellite instability (MSI) was tested by fragment analysis, IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations (TMB-H: >10 mutations/MB). LOH cut-off >16%. Immune cell infiltrates were calculated by XCell. Differential gene expression was calculated using Limma. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value < 0.05). Results: We identified 677 BRCA1mt, 439 BRCA2mt, and 7080 HRwt OC tumors. HGSOC made up the largest portion of BRCA1mt (523; 77%), BRCA2mt (306; 70%), and HRwt (4281; 60%) tumors. TP53 was most commonly mutated gene in all three groups. LOH (>16%) was highest in BRCA1mt (86.8%) compared to BRCA2mt (74.8%) and HRwt (38.4%). TMB-H was highest in BRCA2mt (6.29%) than in BRCA1mt (1.35%) and HRwt (0.91%) HGSOC (all q < 0.05). Expression of immune checkpoint genes CD80, CD86, CD274, CTLA4, HAVCR2/TIM3, IFNG, IDO1, LAG3, PDCD1 and PDCD1LG2 were significantly higher in BRCA1 and BRCA2 mt compared to HRwt HGSOC (FC: 1.12-1.59, q < 0.05). HRwt tumors had decreased infiltration of Activated Dendritic cells compared to BRCA1mt, and lower Macrophage M1 compared to both BRCA1mt and BRCA2mt (all q < 0.05). Additionally, T-inflamed score was higher in BRCA1mt compared to HRwt, while IFN score was higher in BRCA1mt compared to both BRCA2mt and HRwt (all q < 0.05). From 17,408 genes with measured expression. 522 (3.0%) differentially expressed genes (DEG) were found between BRCA2mt vs BRCA1mt; 1487 (8.54%) between BRCA2mt vs HRwt; and 9297 (53.4%) between BRCA1mt and HRwt HGSOC. Pathway analysis identified Fatty Acid Metabolism, Myc targets, ROS pathway, Oxidative Phosphorylation, and Wnt B-catenin signaling pathways as differentially regulated between the 3 groups. Conclusions: We describe the genomic, pathway and immunologic analyses in the largest cohort of BRCA1 and 2 mutated HGSOC to date. Both metabolic and immune response pathways are differentially regulated between the groups. Results can potentially inform targeted therapeutic studies based on unique BRCA genotype.
For women with uterine cancer with metastases isolated to the adnexa (stage IIIA) optimal adjuvant therapy is unknown. We performed a population-based analysis to examine the use of chemotherapy, vaginal brachytherapy, and external beam therapy (in women with stage IIIA uterine cancer.The National Cancer Database was used to identify women with stage IIIA uterine cancer with ovarian metastasis from 2004 to 2012. We explored the use of chemotherapy, vaginal brachytherapy, and external beam therapy over time. Multivariable models were developed to examine factors associated with survival.We identified 4088 women with uterine cancer and ovarian metastases. Overall, 56.2% of women received chemotherapy. Vaginal brachytherapy was used in 11.1%, while 36.6% received external beam therapy. Five-year survival was 64.7 % (95% CI, 62.9% to 66.5%). In a multivariable model, chemotherapy was associated with a 38% decrease in mortality (HR = 0.62; 95% CI, 0.54 to 0.71). Similarly, both external beam therapy (HR = 0.74; 95% CI, 0.65 to 0.85) and vaginal brachytherapy (HR = 0.67; 95% CI, 0.53 to 0.85) were associated with improved survival. When the cohort was limited to women who received chemotherapy, radiation was associated with improved overall survival (HR 0.74, 95% CI 0.61 to 0.90). There was no difference in survival between the use of external beam therapy and vaginal brachytherapy.Chemotherapy was associated with a decrease in mortality in women with endometrial cancer and ovarian metastases. The addition of radiation therapy was associated with improved overall survival, although there was no difference between external beam therapy and vaginal brachytherapy.
