Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

Abstract

Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

“…Approximately 15–20% of advanced gastric and gastroesophageal junction cancers, have overexpression or amplification of HER2 [ 2 ]. Mutations and amplification of ERBB2 have also been reported in ~4% of NSCLC, 2–5% of colorectal cancers, 5–20% of biliary tract tumors, and in up to 60% of salivary duct carcinomas [ 6 , 7 , 8 , 15 ].…”

Anti-Tumoral Effects of a (1H-Pyrrol-1-yl)Methyl-1H-Benzoimidazole Carbamate Ester Derivative on Head and Neck Squamous Carcinoma Cell Lines

“…HNSCC are collocated at the sixth position among more diffuse malignant tumors in the world [17], being characterized by a poor prognosis, mainly due to metastases, the development of multiple primary tumors, and local and regional, often inoperable, relapses [18,19]. The presence of distant metastases at the moment of diagnosis is associated with a high mortality rate for HNSCC [20], since the chemotherapy used for metastatic disease gives often low responses [21,22].…”

Anticancer Effects of Sublingual Type I IFN in Combination with Chemotherapy in Implantable and Spontaneous Tumor Models

“…Overexpression and/or amplification of proto-oncogene Her-2/neu has been reported in up to 90% of cases, although there is considerable variation between different antibody clones and scoring systems [ 4 , 5 , 6 , 7 ]. The role of Her-2/neu overexpression in prognosis and treatment decisions is still controversial [ 8 , 9 , 10 ]. Regardless of its histological subtype, gold standard treatment of early stage salivary gland tumors consists of surgical resection with or without adjuvant radiation therapy depending on resection margins and nodal involvement [ 11 , 12 ].…”

“…Cytotoxic chemotherapy, including combinations of cisplatin (CDDP), doxorubicin (DOXO), and cyclophosphamide (CTX), has been poorly effective so far [ 10 , 13 , 14 , 15 ]. Instead, targeted treatments are gaining interest based on molecular characterization and subtypes classification (e.g., Her-2+, androgen receptor+) [ 10 , 16 ]. Expression of the programmed death ligand-1 (PDL-1) has been also reported in 30–60% of SDC [ 17 ].…”