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<b>Introduction:</b> Although genetic mutations have been reported in salivary duct carcinoma (SDC), no scientifically validated targeted therapies are currently available. Moreover, cancer genomic profiling tests remain underutilized in clinical practice. These issues highlight the urgent need to elucidate the genomic landscape of SDC and its potential therapeutic relevance. <br><br><b>Aim:</b> This study aimed to characterize the mutational profile of recurrent and/or metastatic SDC. <br><br><b>Materials and methods:</b> Data were analyzed for 207 consecutive patients with SDC registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and October 2025. Genetic mutations were determined by next-generation sequencing. Survival of patients was determined by the log-rank test and the Cox proportional hazards model. <br><br><b>Results:</b> The top 10 mutations in SDC were <i>TP53</i> (74.4%), <i>ERBB2</i> (52.2%), <i>NF1</i> (32.4%), <i>CDK12</i> (29.0%), <i>PIK3CA</i> (28.0%), <i>NOTCH3</i> (19.8%), <i>LTK</i> (18.4%), <i>CDKN2A</i> (18.4%), <i>BRCA2</i> (16.9%), <i>SPEN</i> (16.9%), with 17.1 7.2 (mean standard error of the mean [SEM]) mutations/individual. <i>TP53</i> mutations (p = 0.005707) were associated with a significantly worse prognosis, as determined by log-rank test. The hazard ratios for cases with this mutation was 2.6390 (95% CI, 1.2180-5.720, p = 0.0139) for <i>TP53</i>. <br><br><b>Conclusions:</b> This study delineated the mutational spectrum of recurrent and/or metastatic SDC. Even in advanced disease, prognostically relevant mutations were identified, emphasizing the clinical importance of cancer genomic profiling tests.