Abstract 3362: Describing the molecular landscape of cervical cancer metastases: Implications for future therapeutic targets
Authors: Hadfield Matthew J. , Wu Sharon , Farrell Alex , Oberly Matthew , Sun Grace , Thaker Premal , Wellcome Jody , Anderson Matthew , Dizon Don 
Published: March 2024

Introduction: Cervical Cancer (CC) is a heterogenous disease with multiple histological sub-types. Early screening has led to a reduction in disease related mortality, but a significant number of patients present with or progress to advanced disease. Studies between the molecular and immune alterations in CC primaries (CCP) and CC metastases (CCM) are needed to explore potential therapeutic strategies.

Methods: Relationships of CCM and alterations detected by NGS (592, NextSeq; WES, NovaSeq) were investigated in 2,668 (1,393 primary Cervix samples, 383 local metastatic GYN samples, and 892 distant metastatic samples) CC samples (Caris Life Sciences, Phx, AZ). PD-L1+ was tested by IHC (22c3, &gt;1%). 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 Quantiseq. Statistical significance determined by chi-square and Mann-Whitney U and adjusted for multiple comparisons (q&lt;0.05).

Results: Hierarchical clustering of CCM sites by alterations (mutations, amplifications and fusions) frequency revealed CCM to Liver (n=77) and Lymph Nodes (n=265) as the most distinct from CCP while Vagina/Vulva (V/V) (n=196) and Lung (n=115) CCM were most similar. Lymph Nodes had decreased TP53-mt (6.6% vs 14.7%) and ARID1A-mt (4.53% vs 8.27%) but higher BRCA1-mt (3.03% vs 0.87%) compared to CCP (p&lt;0.05). Liver had higher BRCA1-mt (6.67% vs 0.87%), ASXL1-mt (8.47% vs 2.96%) and APC-mt (4% vs 0.65%) compared to CCP (p&lt;0.05). CCM to Lymph Nodes had higher median TMB (median [range]: 6 [0-101] vs 5 [0-460], q&lt;0.05) and HPV16/18+ rate compared to CCP (81.2% vs 66.8%, p&lt;0.05). CCM to Liver had lower expression of CTLA4 compared to CCP (1.67-fold decrease), similarly, Ovary/FT had significantly lower expression of immune checkpoint (IC) gene expression (CD80, CD86, CD274, PDCD1, PDCD1LG2, CTLA4, HAVCR2, IDO1, LAG3, IFNG: 2.23-4.66-fold decrease) (q&lt;0.05). While Lymph Nodes had higher expression of the IC genes compared to CCP (1.30-1.49-fold, q&lt;0.05). CCM to Liver and Ovary/FT had lower median infiltration of immune cells while Lymph Nodes had higher compared to CCP of Macrophage M1 (2.7% vs 1.03% vs 3.35% vs 3.1%), B cells (3.7% vs 3.5% vs 5.6% vs 4.3%), CD8 T cells (0% vs 0% vs 1.01% vs 0.75%), and Tregs (1.6% vs 0.74% vs 2.86% vs 2.5%) (q&lt;0.05). CCM to Liver and Ovary/FT had lower median IFN score while Lymph Nodes had higher median IFN score (q&lt;0.05) compared to CCP, similarly, Ovary/FT had a lower % of T-cell inflamed tumors with Lymph Nodes having higher T-cell inflamed tumors compared to CCP (7.89% vs 47.4% vs 29.3%, q&lt;0.05).

Discussion: CCM to Lymph Nodes and Liver had the most distinct molecular and immune landscape compared to CCP while Ovary/FT had a similar molecular profile but a distinctively cold immune profile compared to CCP. Additional studies to evaluate the potential therapeutic targets are warranted.

Citation Format: Matthew J. Hadfield, Sharon Wu, Alex Farrell, Matthew Oberly, Grace Sun, Premal Thaker, Jody Wellcome, Matthew Anderson, Don Dizon. Describing the molecular landscape of cervical cancer metastases: Implications for future therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3362.