Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.

Abstract

5590 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing 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%). 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. Real-world 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 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p < 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.