The role of mismatch repair deficiency (MMRd) or DNA damage & response (DDR) mechanisms in general are under-explored in rare endometrial cancer subtypes. We therefore sought to characterize the immune, inflammatory, and DNA damage profiles of uterine papillary serous carcinoma (UPSC) and uterine carcinosarcoma (UCS) to better define the role of immunotherapy (IO) in these tumors.

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 and expression was analyzed using the Nanostring nCounter PanCancer IO 360 panel.

A 3.6-fold increase (p < 0.0001) in DNA repair capacity was seen in UCS samples compared to UPSC. Transcriptional analysis confirmed increased expression of DNA repair genes in UCS. 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 markers of immune cells noted. However, there was also increased expression of immune evasive genes and markers of immune exhaustion. This suggests DNA damage tolerance and immune exhaustion are hallmarks of UPSC.

We present here a detailed, treatment-oriented molecular comparison between two histologically distinct endometrial cancer 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 may be 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.