Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling
Open Access
- 14 October 2019
- journal article
- research article
- Published by Wiley in Cancer Medicine
- Vol. 8 (17), 7322-7329
- https://doi.org/10.1002/cam4.2602
Abstract
Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant-7 (AR-V7) in some SDC cases could result in resistance to anti-androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next-generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR-V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%-8%) programmed death ligand 1 (PD-L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre-treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti-androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD-L1, mitogen-activated protein kinase, and PIK3CA pathways.Keywords
This publication has 40 references indexed in Scilit:
- Clinicopathologic study of salivary duct carcinoma and the efficacy of androgen deprivation therapyAmerican Journal of Otolaryngology, 2014
- Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 TherapyClinical Cancer Research, 2014
- AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate CancerNew England Journal of Medicine, 2014
- The landscape of kinase fusions in cancerNature Communications, 2014
- Complete Response to Trastuzumab-Based Chemotherapy in a Patient with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Salivary Duct Carcinoma ex Pleomorphic AdenomaCase Reports in Oncology, 2013
- Trastuzumab for the Treatment of Salivary Duct CarcinomaThe Oncologist, 2013
- Detection of Novel Actionable Genetic Changes in Salivary Duct Carcinoma Helps Direct Patient TreatmentClinical Cancer Research, 2013
- Androgen Receptor–Positive Salivary Duct Carcinoma: A Disease Entity With Promising New Treatment OptionsJournal of Clinical Oncology, 2011
- Targeted therapy with trastuzumab for advanced salivary ductal carcinoma: case report and literature reviewMedical Oncology, 2011
- PIK3CA Cooperates with Other Phosphatidylinositol 3′-Kinase Pathway Mutations to Effect Oncogenic TransformationCancer Research, 2008