Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

Abstract

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

“…The BRAF p.V600E mutation was detected in two of our cases, similarly to the previously reported studies . Although the overall percentage of SDCs with mutated BRAF may be low, there is a potential for targeted therapy for these patients, as BRAF inhibitors are used successfully in melanoma and other BRAF ‐mutated tumors.…”

“…In our study, 4 of 5 SDC ex PA, 5 of 13 de novo SDC, and 2 of 10 recurrent/metastatic SDC were positive by HER2 IHC. In a large series of 151 SDCs, PIK3CA/HRAS/BRAF mutations and HER2 positivity were reported to be mutually exclusive . In contrast, in our 7 cases with PIK3CA/HRAS/BRAF mutations, 4 cases (all with PIK3CA/HRAS co‐mutations) showed HER2 expression by IHC.…”

“…Besides PIK3CA mutations, loss of PTEN activates the PI3K pathway and thus may represent another potential target. Several studies have reported frequent loss of PTEN expression, detected via IHC or FISH analysis, in up to 51% of SDC . In head and neck squamous cell carcinoma, tumor cells with PTEN loss were shown to be commonly resistant to pan‐PI3K inhibitors; however, in vitro studies have shown promising results for targeted PI3K therapy in SDC cells .…”

The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases

“…Although there was no significant association between p‐Akt and FOXA1 expression, intact PTEN, which suppressed the Akt pathway, was retained. We have reported previously a similar relationship between the AR and PI3K signalling pathway expression . These findings suggest that FOXA1, together with AR, has different cross‐talk with the PI3K signalling pathway in SDC.…”

“…Oncology/College of American Pathologists (ASCO/CAP) guidelines for evaluating breast cancer . HER2, status as well the results of immunohistochemical staining for AR, Ki‐67 and PI3K/p‐Akt/mTOR/PTEN, which were reported previously by our group, were compared to the results obtained from the present study …”