Alessandro Santin, MD, on investigating rare endometrial disease for potential new treatments

Researchers of a comprehensive genomic analysis published in Proceedings of the National Academy of Sciences investigated the molecular basis of endometrial stromal sarcoma (ESS), a rare uterine malignancy characterized by significant heterogeneity. Alessandro Santin, MD, Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, described the research as a worldwide collaboration involving institutions across the United States, Italy, and South Korea to address a "dire need" for new treatment modalities.

The study utilized integrated whole-genome, whole-exome, and transcriptome sequencing on 80 ESS tumors, consisting of 32 low-grade (LG) and 48 high-grade (HG) specimens. While surgery is curative in approximately 50% of early-stage cases, Santin noted that even in stage 1, about 50% of tumors may return as recurrent disease.

"It's only when you acquire the type of deep knowledge in the molecular characteristic that you may really identify potential targets," Santin said, adding that identifying these "Achilles heel" mutations allows for the design of personalized treatments.

Genomic drivers and grade-specific features for ESS

The analysis identified focal RAD54B amplifications in 15 tumors (18.8%), which established RAD54B as an oncogenic driver associated with significantly shorter survival. The study also identified distinct mutational landscapes between grades. HG-ESS tumors frequently exhibited mutations in tumor suppressors (PTEN, TP53), chromosomal gains, and loss of cell-cycle regulators (RB1, CDKN2A). Conversely, LG-ESS was defined by canonical fusions, such as JAZF1–SUZ12, and deletions in metabolic regulators like TSC2 and STK11.

Santin emphasized the importance of recognizing the 7.5% of hypermutated cases harboring POLE or mismatch repair mutations, as these features are predictive of immunotherapy response.

Preclinical rationale for targeted therapy

The research provided a strong preclinical rationale for precision therapies. In a HG-ESS xenograft with an activating NRAS-mutant (p.Q61R), the combination of MEK and FAK inhibition suppressed tumor growth and prolonged survival. Santin explained that when driver mutations are present, the tumor becomes "addicted" to specific pathways. By using small molecule inhibitors to affect those pathways, clinicians may be able to see significant clinical responses and prolong patient life.

The study marks the first time such a large casuistic has been analyzed with this depth of sequencing, providing a genetic fingerprint to guide future clinical trials in both the primary and recurrent settings.

Reference:

Hartwich T, Choi S, Hwang A. Integrated mutational landscape analysis of endometrial stromal sarcoma, Proc. Natl. Acad. Sci. U.S.A. (2026). 123 (5) e2531105123. doi:/10.1073/pnas.2531105123