Comprehensive molecular profiling of salivary gland cancers: A single-institution experience.

e18136 Background: Standardized therapeutic strategies are currently lacking for salivary gland cancers (SGCs). Molecular profiling may improve diagnostic and prognostic accuracy, and support personalized treatment. Methods: Between August 2022 and December 2025, 115 patients with SGCs were managed at the Veneto Institute of Oncology, Padua. Molecular profiling was only performed in recurrent/metastatic (R/M) patients with unknown actionable targets or those who had not previously responded to targeted therapy. Comprehensive genomic profiling was performed using the TruSight Oncology 500 panel. The aim was to evaluate the spectrum of genomic alterations and to identify predictive or prognostic biomarkers to guide personalized therapy. Molecular findings were reviewed by the Veneto Regional Molecular Tumor Board. A tumor mutational burden (TMB) ≥10 mutations/Mb was considered a potentially actionable biomarker. Results: A total of 28 patients with R/M SGCs were retrospectively analyzed. The most common primary site was the parotid gland (15 patients), followed by the submandibular gland (7 patients) and minor salivary glands (6 patients). Test failures occurred in 5 cases. Among the 23 profiled patients, ductal carcinoma was the most frequent histotype (10 patients), followed by adenoid cystic carcinoma (ACC; 9). Other non-ACC cases included two adenocarcinomas NOS, one mucoepidermoid carcinoma, and one epithelial-myoepithelial carcinoma. Overall, 76 pathogenetic/likely pathogenetic alterations were identified: 70 DNA mutations (92%) and 6 RNA fusions (8%). High TMB (TMB-H) was detected in 2 patients (9%). Nineteen actionable targets according to the ESCAT definition were identified in 14 patients (61.%). Five patients harbored more than one actionable alteration. Most therapeutic targets were found in non-ACC histotypes (Table1). Personalized treatment was administered to 7 patients (50 %) through compassionate-use, off-label programmes, or clinical trials, achieving an objective response rate (ORR) of 45%. Seven patients with actionable mutations did not receive targeted therapy due to drug unavailability or clinical decisions. Conclusions: SGCs remain a therapeutic challenge due to their biological heterogeneity and limited treatment options. Comprehensive molecular profiling is a valuable tool for characterizing the genomic landscape and identifying potential therapeutic targets, particularly in non-ACC histotypes. Actionable alterations n (%) Non-ACCn.14 ACCn.9 NTRK fusions 1 (7%) 0 PIK3CA mutations/amplification 3 (21%) 0 H-RAS mutation 4 (29%) 0 NOTCH1 0 1 (11%) BRAF V600E 3 (21%) 0 ALK/ROS1 fusion 1 (7%) 0 Her2 amplification/mutation 2 (14%) 0 HRD-like profile* 1 (7%) 0 TMB-H 1 (7%) 1 (11%) dMMR 1 (7%) 0 *HRD-like: presence of genomic alterations suggestive of homologous recombination deficiency.