Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer

Abstract

Purpose Salivary duct carcinoma (SDC) is an aggressive salivary malignancy which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles. Experimental Design We performed whole-exome sequencing, RNA sequencing and immunohistochemical analyses in 16 SDC tumors, and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs. Results SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/megabase). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAP kinase (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared to full length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer. Conclusions This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC.

Somatic mutations in salivary duct carcinoma and potential therapeutic targets

“…Early testing can also identify alterations that may predict resistance to these drugs. The findings of our study and that of the others provide a strong biologic argument for exploring these treatment options with pragmatically designed clinical trials [4,37]. [2000][2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014][2015] and held in the archives of the department of Tissue Pathology and Diagnostic Oncology at Royal Prince Alfred Hospital were reviewed to identify 25 cases of SDCa.…”

First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition

“…9 Therefore, it only rarely expresses estrogen or progesterone receptors, but has been associated with expression of HER2 and AR, both of which might be markers for response to targeted therapies. 2 Retrospective studies have suggested that targeting HER2 with trastuzumab may be of benefit in HER2-expressing SDC, 10 and interim results from a prospective phase II trial of docetaxel plus trastuzumab were encouraging.…”

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…The overall expression pattern seems to be remarkably similar to that of apocrine breast carcinoma [49]. Whole exome sequencing of 16 SDC specimens revealed a low to moderate mutational burden compared to other solid tumors, with a relatively low rate of copy number alterations and unique fusion genes noted in about a third of the tumors [49].…”

“…Whole exome sequencing of 16 SDC specimens revealed a low to moderate mutational burden compared to other solid tumors, with a relatively low rate of copy number alterations and unique fusion genes noted in about a third of the tumors [49]. This sequencing study corroborated several common alterations noted in other studies, the most common of which was mutation of TP53 [49]. A targeted sequencing study of 30 SDC specimens also showed TP53 mutation to be the most common alteration [50].…”