Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours.
BACKGROUND
Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified.


METHODS
Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology.


RESULTS
Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations.


CONCLUSIONS
Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.
Department of Pathology, G. Pompidou European Hospital APHP-Université Paris Descartes, Paris.
J
J
Cros
Department of Public Health, University Paris Est Créteil-EA4393, Creteil.
E
E
Sbidian
Departments of Head and Neck Surgery.
S
S
Hans
Department of Pathology, G. Pompidou European Hospital APHP-Université Paris Descartes, Paris.
H
H
Roussel
Oncology, G. Pompidou European Hospital-Université Paris Descartes, Paris.
F
F
Scotte
INSERM U970 Paris-Centre de recherche Cardiovasculaire Team 10, Paris.
E
E
Tartour
Departments of Head and Neck Surgery.
D
D
Brasnu
Department of Biochemistry and Molecular Oncology, G. Pompidou European Hospital-Université Paris Descartes, Inserm Unité Mixte de Recherche-S775, Paris, France.
P
P
Laurent-Puig
Department of Pathology, G. Pompidou European Hospital APHP-Université Paris Descartes, Paris.
P
P
Bruneval
Department of Biochemistry and Molecular Oncology, G. Pompidou European Hospital-Université Paris Descartes, Inserm Unité Mixte de Recherche-S775, Paris, France.
H
H
Blons
Department of Pathology, G. Pompidou European Hospital APHP-Université Paris Descartes, Paris; INSERM U970 Paris-Centre de recherche Cardiovasculaire Team 10, Paris. Electronic address: cecile.badoual@egp.aphp.fr.
C
C
Badoual
D059002:Androgen Receptor Antagonists / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018277:Carcinoma, Mucoepidermoid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009208:Myoepithelioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D013534:Survival
D059002:Androgen Receptor Antagonists; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C512478:EGFR protein, human; C508053:ERBB2 protein, human
C-KIT; EGFR; HER2; malignant salivary gland tumours; targeted therapies