Abstract 594P
Background
Ovarian cancer (OC) is a heterogeneous disease with multiple subtypes. Previous studies have shown differences in metastatic lesions (OCM) vs primary lesions in ovarian malignancies (OCP). Correlations with genetic makeup and sites of metastatic disease have not been previously studied.
Methods
Relationships of OCM and alterations detected by DNA next-generation seq (NGS: NextSeq 592 gene panel; NovaSeq Whole Exome Seq) were investigated in 9,286 OC samples sequenced at Caris Life Sciences (Phx, AZ). PD-L1 expression was tested by IHC (22c3: cut-off >1%). Tumor mutational burden (TMB) was measured by summing somatic mutations per tumor (H: >10 mt/MB). Immune infiltrates estimated by deconvolution of Whole Transcriptome data (NovaSeq) using Quantiseq (Fintello). Statistical significance determined by chi-square and Mann-Whitney U and adjusted for multiple comparisons.
Results
OCM had lower mutation rates in CTNNB1 (1.1% vs 5.0%) and ARID1A (5.3% vs 10.1%), the PI3K pathway (PIK3CA, 5.8% vs 11.6%; PTEN, 2.5% vs 6.1%) but higher in TP53 (79.5% vs 73.2%) compared to OCP (q<0.05). OCM to the axilla had the highest PD-L1 positivity (88.2%) while the lowest rate was in breast. OCM to genitourinary organs (GU) had the highest prevalence of TMB-H (7.0%), and OCM to the brain had the highest median TMB (4.5) and dMMR/MSI-H (4.4%). Double dendrogram hierarchical clustering of OCM sites by alteration frequency revealed OCM to brain and liver having a unique alteration pattern compared to OCP and other OCM sites, with higher alteration frequencies of genes in the RTK RAS pathway. OCM to GU organs was the next most distinct OCM compared to OCP. Compared to OCP, OCM to GU had more M1 Macrophages (0.8% vs 2.9%) but decreased Neutrophils (0.5% vs 1.9%), as well as higher median expression of immune checkpoint genes (CD274, CD80, CD86, CTLA4, IFNG, LAG3 PDCD1, PDCD1LG2 and TIM3) (1.2-2.2 FC and increased T-cell inflamed score (q<0.05).
Conclusions
OCM to liver and brain have a unique molecular alteration pattern, while OCM to GU were more immune hot than OCP. The observed differences may be secondary to evolving genomics in metastatic sites. Better understanding of the varying genomic landscape can help guide future treatment options.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Caris Life Sciences.
Disclosure
S. Wu: Financial Interests, Institutional, Full or part-time Employment: Caris. A. Farrell: Financial Interests, Institutional, Full or part-time Employment: Caris. M. Oberley: Financial Interests, Institutional, Full or part-time Employment: Caris. All other authors have declared no conflicts of interest.