Alessandro Santin, MD: Top takeaways from endometrial stromal sarcoma mutational analysis

Recent data from a landmark study in the Proceedings of the National Academy of Sciences has provided a comprehensive "genetic fingerprint" for endometrial stromal sarcoma (ESS), a rare and often aggressive uterine malignancy. Alessandro Santin, MD, Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, describes this five-year effort as a "mastodontic" project that analyzed 80 tumor samples to identify targetable vulnerabilities.

Santin goes into more detail regarding the genetic bifurcation of these tumors in a previous video published by Contemporary OB/GYN.²

Knowing the enemy: The case for sequencing

"We need to know our enemy," Santin said. "We must have a deep knowledge of the genetic characteristics that make this tumor so aggressive." By identifying specific alterations—such as the 18.8% of tumors harboring RAD54B amplifications or the 7.5% with POLE or mismatch repair (MMR) deficiencies observed in the study—clinicians can move beyond trial-and-error treatments.¹

Santin emphasized that sequencing provides the opportunity for immediate clinical action. If a tumor displays specific gene deficiencies or pathway alterations, clinicians can often utilize FDA-approved drugs that are already available. "We don't need to wait for trials," Santin noted, highlighting that oncology often relies on utilizing tools where the same molecular characteristic is present across different tumor types.

Leveraging tumor-agnostic FDA approvals

The "most significant take-home message" of the paper, according to Santin, is the ability to utilize current regulatory pathways for rare cancers. The FDA has transitioned toward tumor-agnostic approvals, which allow for the use of targeted therapies based on biomarkers rather than the tumor's site of origin.

For example, if a tumor has a tumor mutational burden (TMB) above 10, indications for immune checkpoint inhibitors like pembrolizumab are already in place. Santin explained that whether a tumor is endometrial, ovarian, or colorectal, “the FDA has approved that indication," Santin said, adding that similar logic applies to the use of antibodies or antibody-drug conjugates (ADCs) when specific biomarkers are overexpressed.
References:

1. 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
2. Fitch J. Alessandro Santin, MD, on investigating rare endometrial disease for potential new treatments. Contemporary OB/GYN. Published March 6, 2026. Accessed March 11, 2026. https://www.contemporaryobgyn.net/view/alessandro-santin-md-on-investigating-rare-endometrial-disease-for-potential-new-treatments