Exploring molecular profiles of uterine carcinosarcoma with alterations in the chromatin remodeling pathway.

5587 Background: In a preliminary data analysis to identify prognostic molecular biomarkers in uterine carcinosarcoma (UCS), we found that alterations in KMT2C, a gene involved in the chromatin remodeling pathway, correlated with improved survival. We sought to explore relevant biomarkers of KMT2C-mutated (KMT2C-mut) tumors compared to wildtype (KMT2C-wt) tumors. Methods: Tumor samples were analyzed using next generation sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). Microsatelite instability (MSI) was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: Molecular analysis was performed on 1,144 UCS tumors. 7.7% were found to be KMT2C-mut. Patients with pathogenic alterations in KMT2C had longer median OS than patients without (OS not yet reached vs 19.0 months HR(95% CI): 0.37(0.19-0.72) p< 0.01). The most common mutations in KMT2C-mut tumors are shown in Table and resulted in more frequent dysregulation in the following pathways compared to KMT2C-wt tumors: chromatin remodeling (100% vs 28%; q<0.01), WNT (39% vs 12%; q=0.01), base/nucleotide excision repair (29% vs 5%; q<0.01), homologous recombination (26% vs 6%; q=0.02), DNA damage sensors (23% vs 4%; q=0.02) and Fanconi anemia (13% vs 1%; q=0.04). KMT2C-mut tumors were more frequently MSI-H (32% vs 6%; q<0.01) and TMB-H (42% vs 5%; q<0.01). Among MSS tumors, KMT2C-mut tumors had increased mutations in JAK1 and POLE (q<0.01) and higher frequency of TMB-H (24% vs 1%; q<0.01) than KMT2C-wt tumors. Additionally, MSS patients with KMT2C-mut had longer OS than patients with KMT2C-wt tumors (OS not yet reached vs 18.9 months; HR(95% CI): 0.33(0.15-0.75) p< 0.01). Conclusions: Mutations in KMT2C correlate with improved OS in UCS. KMT2C-mut tumors have distinct molecular profiles from wild type tumors. They exhibit greater immunogenicity, including more frequent MSI-H and TMB-H. This suggests a potential role for Immune-oncology (IO) therapy. Further study of the impact of IO therapies in the cohort is warranted as this may contribute to the improved survival of these patients.[Table: see text]