Abstract 500: A molecular comparison reveals distinct transcriptomic differences between uterine carcinosarcoma and papillary serous carcinoma distinguishable by DNA damage

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Abstract Background: Uterine papillary serous carcinoma (UPSC) and uterine carcinosarcoma (UCS) are rare subtypes of endometrial cancer (EMCA) with poor prognosis. Both are high risk histotypes, though their distinct molecular and genomic profiles are undefined. Recent clinical trials such as RUBY, Keynote 775, DUO-E and NRG-GY018 have shown survival benefit in subsets of EMCA with mismatch repair deficiency (MMRd), however, small numbers of patients with UPSC and UCS were included. The role of MMRd or DNA damage & response (DDR) mechanisms in general are under-explored in these EMCA subtypes. We therefore sought to characterize the immune, inflammatory, and DNA damage profiles of UPSCs and UCSs to better define the role of immunotherapy (IO) in these tumors. Methods: Total DNA damage was analyzed in 53 UPSC and 43 UCS FFPE samples collected at our institution using repair-assisted damage-detection (RADD). RNA was isolated from a subset of patients (n = 18/group) and expression (50 ng/per sample) was analyzed using the nCounter PanCancer IO 360 panel from Nanostring comprising 770 gene expression markers. Data was analyzed using the Rosalind Bioinformatics in conjunction with Nanostring’s IO360 analysis team. Results: We have previously shown a 3.6 fold decrease (p<0.0001) of unrepaired DNA damage between UCS samples compared to UPSC, suggesting greater DNA repair capacity in UCS than UPSC. Consistent with this data, transcriptional analysis revealed increased expression of DNA repair genes in UCS such as POLD1, MSH2, BRIP1, BIRC5, and CDK6, among others. Interestingly, decreased expression of DNA repair genes was noted in UPSC despite nearly 4 times the amount of unrepaired DNA damage. As expected, the immune system was activated in response to this increased DNA damage with higher levels of T cells, NK cells, IL-10, cytotoxic T cells, and Th1 cells. However, there was also increased expression of immune evasive genes such as PD-1, CD47, and VTCN1, among others. Additionally, expression of NK CD56dim was also upregulated, a known marker of immune exhaustion. This suggests DNA damage tolerance and immune exhaustion are hallmarks of UPSC. Conclusions: We present here a detailed, treatment-oriented molecular comparison between two histologically distinct EMCA subtypes, UPSC and UCS. Assessment of unrepaired DNA damage and, by proxy, DNA repair capacity, gives context to the immune transcriptomic landscape. Our data suggests that the immune exhausted molecular landscape of UPSC is more amenable to IO than that of UCS, while the DNA repair-robust UCS may be more vulnerable to agents targeting DNA Damage repair such as PARP inhibitors. Further, our data suggests that estimation of DNA repair capacity via RADD may be as treatment informative as molecular sequencing. Citation Format: Kevin J. Lee, Tanvi Joshi, Sagar Chokshi, Mackenzie Cummings, Jennifer Scalici, Nathaniel Jones. A molecular comparison reveals distinct transcriptomic differences between uterine carcinosarcoma and papillary serous carcinoma distinguishable by DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 500.

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