5531 Background: Endocervical Adenocarcinoma (EA) makes up 20-25% of cases of cervical cancer, and has an 80-90% association with HPV infection.Treatment outcomes of EA have significant disparities: cases of EA arising from HPV have a much higher survival rate than survival rate for non-HPV-related EA. While survival outcomes with modern treatments such as radical hysterectomy are positive for HPV associated cases, increasing frequency of diagnosis and treatment heterogeneity, along with variability in diagnostic timing emphasize the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes EA's mutational landscape to identify genetic markers and therapeutic targets. Methods: The American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database was accessed using cBioPortal (v18.0-public) on November 29, 2025 to identify all patients with EA. The most common somatic point mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg false discovery rate correction. Results: This study included 257 samples from 245 patients. The patient cohort was 61.2% non-Hispanic and 13.9% Hispanic. The cohort was 10.2% Asian, 61.2% White, 4.1% Black, and 12.2% unknown/other patients. A majority of the samples used were obtained from primary tumors (60.3%), while 80 (31.1%) were from metastatic tumors. The most common mutations were identified in PIK3CA (n=68; 26.4%), TP53 (n=51; 19.8%), KRAS (n=41; 15.9%), SMAD4 (n=37; 14.4%), ERBB2 (n=35; 13.6%), ARID1A (n=32; 12.4%), KMT2D (n=26; 10.1%), GNAS (n = 26; 10.1%), ERBB3 (n = 23; 8.9%), KMT2C (n = 21; 8.1%), STK11 (n = 20; 7.8%), MED12 (n = 18; 7.0%), and ATM (n = 17; 6.6%). Several mutations were uniquely observed in Black patients, HFE,RAD54B, ADAMTS20, ADGRB3, and BCL3, with n = 1 for each observed mutation. Among exclusively primary tumor samples, the HSD3B2 mutation was identified (n = 1). RXRA (p 0.05) mutations with n = 3 each were exclusively observed in the metastatic samples. Frequencies of recurrent alterations in key genes such as KRAS (15.2%) and PRKDC (7.5%), showed substantial overlap and no significant differences between the groups. No significant mutual exclusivity patterns were identified among profiled genes. Conclusions: To the best of our knowledge, this is the first GENIE database analysis of EA, addressing a significant knowledge gap regarding its genomic landscape. These findings suggest PIK3CA and TP53 as targets for targeted inhibitors or immunomodulators. Further research is warranted to validate these genomic associations and translate them into precision medicine therapeutics for patients with endocervical adenocarcinoma.
Hafter et al. (Wed,) studied this question.