Seventeen patients with salivary gland histologies, consistent with SDC, were discussed in the institutional molecular tumor board between 2016 and 2022. After review of final histopathological diagnoses, 4 patients had salivary duct carcinoma with AR expression and HRAS/PIK3CA mutation and were included in the analysis. These patients (3 male, 1 female) were between 48-79 years old at the time of presentation at the MTB. Activating HRAS mutations were identified in the p.Q61 (3 patients) and p.G13 (1 patient) positions. Activating PIK3CA mutations were identified in the p.H1047 (3 patients) and p.E545 (1 patients) positions. Additional molecular findings were low to medium HER2-expression in 3 patients, PD-L1 expression in 2 patients, a tumor mutational burden (TMB) > 10 mutations/Megabase (mut/Mb) and an AR mutation in 1 patient, each. Median follow-up was 14.5 months. Clinical and molecular findings were summarized in  Table 2 .
The medline searches revealed 37 and 89 results, respectively. Of these, 4 studies with individual follow-up data for patients with AR+, PIK3CA/HRAS co-mutated SDC were included after manual review of the identified publications. The publications yielded a total of 9 cases (7 male, 2 female). Age was reported for 5 patients (range 38-65 years). Concurrent molecular alterations were HER2 amplification and overexpression in 1 and TP53 mutations in 2 patients, respectively. Clinical and molecular findings in these patients were summarized in  Table 3 . A consort diagram of patient identification is provided in  Supplementary Figure 1 .
Overall, 13 patients (10 male, 3 female; median age in 9 evaluable patients 61 years, range 38-79 years) with AR+, PIK3CA/HRAS co-mutated SDC were identified.
Combined analysis of 13 evaluable patients yielded information on various targeted systemic treatment strategies. Androgen deprivation therapy (ADT) was reported in 7 patients, HRAS-directed treatment in 6 patients, immune checkpoint inhibition in 1 patient and combinations of tipifarnib and ADT and alpelisib and ADT in 1 patient, each. Treatment data, including line of treatment, best response and progression-free survival (PFS) are provided, as available, in  Table 4  and  Figure 1 .
Seven patients were treated with androgen deprivation therapy alone (ADT). Among 6 patients with available data on the specific type of ADT, 3 received bicalutamide and a GnRH-analogue and 3 received bicalutamide alone. Best response was evaluable in 5 patients (1 PR, 1 SD, 3 PD). 6 patients had evaluable PFS (median PFS = 2 months) and 2 of them had PFS > 6 months.
The farnesyltransferase inhibitor tipifarnib as a single agent was administered in 6 patients. Among 5 patients with available data, 1 PR, 2 SD and 2 PD were achieved as best responses. PFS data were available for 6 patients and PFS was more than 6 months in 3 patients.
One patient received ADT (bicalutamid/GnRH-Analogue) in combination with tipifarnib after prior progression to tipifarnib after 3 months. This patient achieved stable disease for more than 6 months, which was ongoing at the time of data collection. Another patient achieved a partial response with the PI3K-inhibitor alpelisib in combination with ADT (bicalutamide) for more than 12 months (ongoing at time of publication).
Chemotherapy use with carboplatin/paclitaxel alone was reported in 4 patients. Among 3 patients with available data, 1 PR, 1 MR and 1 PD were reported. The use of alpelisib as monotherapy was only reported for one patient without information on treatment response. Immune checkpoint inhibition was also reported for one patient with a mixed response for 7 months. Following progression on the single-agent PD-1 inhibitor, this patient was treated with a combination of a PD-1 and a CTLA-4 inhibitor, which was followed by disease progression. One patient with concurrent HER2 amplification received trastuzumab in combination with chemotherapy and achieved a partial response.
No major (common terminology criteria of adverse events, CTCAE grade 4 or higher) or unexpected toxicities were observed in the 4 patients identified from the MTB database and no dose reductions were required. In published data, a dose reduction because of toxicity was required in six patients (46%) receiving tipifarnib (4 because of cytopenia, 2 because of reversible renal failures), hypoglycemia requiring dose reduction was reported for alpelisib. Toxicity data were not reported in the literature for patients receiving antiandrogen therapy in this cohort. Available data from combined ADT in SGC reported no CTCAE grade 4/5 events and discontinuation of part of the combined ADT due to adverse events in 2 out of 36 patients.