S. Alfieri, S. Rota, R. Romanò, Iolanda Capone, Adele Busico, Elena Conca, Elena Tamborini, S. Cavalieri, Silvia Buriolla, Carolina Sciortino, A.G. Leone, Imperia Nuzzolese, Arianna Ottini, Cristiana Bergamini, Pasquale Quattrone, A. Vingiani, L.D. Locati, L. Licitra, Giancarlo Pruneri, E. Colombo, Luca Agnelli, Federica Perrone
BACKGROUND: Salivary gland cancers (SGCs) are rare, heterogeneous malignancies with limited systemic therapies. This study aimed to define a histology-driven molecular profiling (MP) algorithm for SGCs to optimize testing strategies and support therapeutic decision-making. MATERIALS AND METHODS: We retrospectively analyzed all SGC patients who underwent MP (2016-2023) for gene rearrangements and pathogenic/likely pathogenic DNA variants (P-LPV). We considered adenoid cystic carcinomas (AdCCs) versus non-AdCCs, the latter as low aggression (LA) or high aggression (HA). MP included DNA/RNA next-generation sequencing (NGS). Immunohistochemistry (IHC) ± fluorescence in situ hybridization (FISH) were used for human epidermal growth factor receptor 2 (HER2) status, and IHC for androgen receptor (AR) status. FISH, NGS and/or IHC were used for neurotrophic tyrosine receptor kinase (NTRK) detection. RESULTS: Among a total of 253 SGCs, AdCCs (132/253, 52%) had MYB/MYBL1 fusions in 47% of cases, all lacking P-LPV. Among HA non-AdCCs (84/253, 33%), P-LPV were found in 55% of cases, including TP53 (34%), PIK3CA (18%), HRAS (14%) and PTEN (5%), in the absence of gene fusions. We found P-LPV in 50% of LA non-AdCCs (37/253, 15%), with ETV6-NTRK3 fusion in one secretory carcinoma. HER2 analysis identified HER2 positivity in 23% of cases (all HA non-AdCC), with 36% HER2-low and 41% HER2-negative. We found less P-LPV in HER2-positive (17.6%) versus HER2-low (67%) or HER2-negative (64%), regardless of AR status. MP-guided therapy was delivered in 4% of cases. Based on our results, we propose a stepwise, histology-driven MP algorithm for SGCs. In AdCCs, we recommend initial FISH for MYB/MYBL1 fusions: fusion-positive cases typically lack other P-LPV, sparing further MP. In fusion-negative cases, DNA NGS can be considered. In HA non-AdCCs, HER2 and AR should be tested upfront, proceeding with DNA NGS in HER2-low/negative tumors. In LA non-AdCCs, we recommend ETV6-NTRK3 FISH followed by DNA/RNA NGS in fusion-negative cases. CONCLUSIONS: Our data support the clinical implementation of a tailored, histology-driven MP algorithm, potentially optimizing the genomic testing resources in SGCs.