e17636 Background: Bone metastasis from primary endometrial cancer is rare, reported in fewer than 1% of cases. Despite this, an increasing number of bone-metastatic cases has recently been observed at our institution. The molecular drivers underlying this uncommon metastatic pattern remain poorly defined. Methods: We performed whole-exome sequencing on tumor samples from 12 patients with endometrial cancer and confirmed bone metastases identified at our institution between October 2023 and August 2025. Pathogenic variants were analyzed with a focus on recurrently altered signaling and chromatin regulatory pathways. Histologic subtypes were reviewed and correlated with molecular findings. Results: Pathogenic alterations in genes involved in the PI3K–AKT–mTOR signaling pathway (PTEN, PIK3CA, PIK3R1) were identified in 8 of 12 cases (67%). Mutations in ARID1A, a core component of the SWI/SNF chromatin remodeling complex, were present in 7 of 12 cases (58%). Notably, 6 of the 8 tumors harboring PI3K pathway alterations also demonstrated concurrent ARID1A mutations, indicating a high degree of overlap between these pathways. All six tumors with combined PI3K pathway and SWI/SNF complex alterations were histologically aggressive, comprising either uterine papillary serous carcinoma or grade 3 endometrioid adenocarcinoma. Conclusions: Bone-metastatic endometrial cancers in this cohort are characterized by frequent co-alteration of PI3K–AKT–mTOR signaling components and SWI/SNF chromatin remodeling machinery. This pattern supports a synergistic biological model in which constitutive proliferative and survival signaling driven by PI3K pathway activation cooperates with epigenetic instability resulting from ARID1A loss to enable metastatic progression to bone. These findings suggest potential therapeutic vulnerabilities, including pharmacologic inhibition of the PI3K–AKT–mTOR axis using PI3K inhibitors, AKT inhibitors, or mTOR inhibitors, as well as emerging epigenetic strategies targeting ARID1A-deficient tumors, such as EZH2 inhibition and synthetic lethal approaches exploiting SWI/SNF dysfunction. Combined pathway targeting may represent a rational treatment strategy for patients with aggressive, bone-metastatic endometrial cancer and warrants further investigation.
Desai et al. (Thu,) studied this question.