Genetic alterations and targeted therapies in salivary gland neoplasms

Abstract

Salivary gland neoplasms (SGNs) represent a diverse group of benign and malignant tumors characterized by distinct genetic abnormalities that contribute to their pathogenesis and variable clinical behavior. This review synthesizes current evidence on the molecular alterations underlying SGNs and highlights emerging therapeutic targets with translational potential. A comprehensive literature search was conducted across PubMed, Google Scholar, Cochrane, and SCOPUS for studies published between 1990 and 2025, focusing on genetic aberrations, oncogenic fusions, and targeted treatment strategies. Data reveal that small molecule inhibitors and other targeted agents may offer promising alternatives to conventional chemotherapy. For instance, pleomorphic adenomas often have PLAG1 overexpression and FGFR1 fusions, activating the IGF and WNT signaling pathways; linsitinib, a dual IGF1R and tyrosine kinase inhibitor, has demonstrated antitumor activity in other malignancies and may hold potential in this context. Similarly, alterations in EGFR, HER2, and PI3K pathways across multiple salivary tumor subtypes highlight opportunities for small molecular inhibitor therapy. However, current data remain limited, and therapeutic applications are largely extrapolated from other cancers. Further research is needed to validate these findings in clinical trials. Overall, integrating molecular diagnostics with pathway-specific targeted therapies may enhance outcomes and expand treatment options for patients with SGNs.

Introduction

Salivary gland neoplasms (SGNs) are rare tumors with more than 30 histologically and genetically distinct subtypes.^1–3 Approximately 5 per 100,000 individuals are diagnosed with SGNs annually, the majority of which are benign and arise from either major or minor salivary glands, each with differing malignant potential.^4–6 Major histologic subtypes of benign salivary gland tumors include pleomorphic adenoma (60–70%), papillary cystadenoma, myoepithelioma, and Warthin's tumor. ³ Major types of malignant salivary gland neoplasms include mucoepidermoid carcinoma (MEC; 30–35%), adenoid cystic carcinoma (ACC), acinic cell carcinoma (ACiCC), and salivary duct carcinoma (SDC). ² Collectively, these tumors exhibit marked heterogeneity in clinical behavior, prognosis, and therapeutic responsiveness.

Although surgery with or without adjuvant radiotherapy remains the primary treatment modality for most SGNs, management of recurrent, unresectable, or metastatic disease remains challenging. Systemic treatment options are limited, and traditional cytotoxic chemotherapy has demonstrated only modest and transient benefit. The rarity of SGNs, combined with their biological diversity, has hindered the development of large, histology-specific, biomarker-driven clinical trials, resulting in a lack of a standardized systemic treatment algorithm.

Recent advances in molecular and genetic profiling have identified recurrent chromosomal rearrangements, gene fusions, and dysregulated signaling pathways across both benign and malignant SGNs. These alterations may serve as diagnostic adjuncts, prognostic markers, and potential therapeutic targets. For example, MEC frequently harbors the CRTC1–MAML2 fusion, which promotes oncogenesis through activation of cAMP/CREB-dependent transcriptional programs. ⁵ Some studies have shown small molecular inhibitors of these target genes to inhibit the proliferation of MEC tumors. ⁵ However, clinical translation of such molecular discoveries remains limited.

This review highlights tumor-specific molecular alterations in SGNs and evaluates their current or potential roles in diagnosis, prognosis, and targeted therapy. By synthesizing existing genomic data and emerging therapeutic strategies, this work aims to underscore the unmet need for biomarker-guided treatment approaches and to identify opportunities for future translational and clinical investigation. ⁶

Methods

Our aim was to perform a qualitative, narrative review and assess the current genetic abnormalities that underlie SGNs. Given the broad and evolving nature of this topic, a qualitative narrative topic review approach was chosen to synthesize key findings across a wide range of studies.

Search strategy

The two reviewers, S.K. and R.V.S, developed a search strategy that entailed querying PubMed, Google Scholar, Cochrane, and SCOPUS—comprehensive journals for the topic. The search encompassed articles published between 1 January 1990 and 31 May 2025. The database search was completed in May to July 2025. The following combination of terms and keywords were used:

(“salivary gland neoplasms” OR “salivary gland tumors”) AND

(“genetic abnormalities” OR “gene fusions” OR “molecular alterations” OR “chromosomal rearrangements”) AND

(“therapeutic targets” OR “targeted therapy” OR “small molecule inhibitors”)

Reference lists of selected articles and relevant review papers were also manually screened to identify additional studies.

Inclusion and exclusion criteria

All articles that were relevant to SGN genetic abnormalities were included in the study. A comprehensive review was completed to include articles that addressed the genetic abnormalities underlying both benign and malignant SGNs as well as therapeutic implications and potential targeted agents. All study design types were included. Articles were limited to English and those that did not address gene aberrations were excluded. Relevancy of these articles were determined by the authors. Articles were removed if found to not meet the inclusion criteria.

Study selection

A total of 41 articles were initially identified. After screening for relevance and application of inclusion/exclusion criteria, 33 articles were included in the final review.

Discussion/observations

Assessment and diagnosis

Benign salivary gland tumors pathogenesis and treatment

Pleomorphic adenoma

Pleomorphic adenoma, with components of epithelial and mesenchymal cells, accounts for 60–70% of the SGNs.^3,7–9 The primary gene abnormalities described in pleomorphic adenomas are overexpression of PLAG1 (>50%) and HMGA2 (10–20%).^7,10 The PLAG1 gene, found on chromosome 8q12, encodes the transcription factor for DNA-binding zinc finger domains. The HMGA2 gene, found on chromosome 12q14, encodes a nonhistone component of chromatin used to regulate transcription. Varying translocations lead to PLAG1 fusions with multiple genes including FGFR1, CTNNB1 (β-catenin), TCEA1, and CHCHD7 as well as HMGA2 fusions with NFIB, WIF1, and FHIT.^11,12 These fusions affect regulation of the cell cycle, growth factors, and induce instability of the genome (Table 1). ¹³

Table 1.

Genetic targets of benign salivary gland neoplasms.

Benign tumors	PLAG 1	HMGA2	Deletions of 22, 17p, and 12q	CTNNB1	Gain of 6q, 13q, 4q
Pleomorphic adenoma	✓	✓		✓
Myoepithelioma	✓			✓
Warthin's tumor			✓		✓

From a diagnostic standpoint, PLAG1 and HMGA2 rearrangements are well-established molecular markers that aid in confirming the diagnosis of pleomorphic adenoma. Detection of these alterations using FISH or immunohistochemistry has become an important adjunct to histopathologic evaluation. ³

PLAG1 translocations have been shown to upregulate IGF2 expression and activate the WNT signaling pathway, making these pathways potential therapeutic targets. ¹⁴ The therapeutic relevance of HMGA2 is even less well defined, although its fusion partners suggest potential modulation of downstream WNT and PI3K–AKT signaling pathways. While these molecular insights raise interest in therapeutic targeting, their role in treatment remains theoretical. ³ Linsitinib, a dual inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor tyrosine kinases, has demonstrated antitumor activity in other malignancies, including melanoma and adrenocortical carcinoma.^14–16 However, no clinical trials have evaluated linsitinib or other targeted agents in pleomorphic adenoma or SGNs, and extrapolation from other tumor types remains speculative at this time. More importantly, the standard of care for pleomorphic adenoma remains surgical excision, which is associated with excellent outcomes and cure rates approaching 95%, with radiation used in an adjuvant setting for recurrent lesions and/or positive margins. Therefore, systemic targeted therapy would not be indicated for routine management and would only be relevant in rare cases of unresectable disease, multiply recurrent tumors, or patients who are poor surgical candidates. Further functional studies are required to clarify whether these molecular alterations represent actionable therapeutic targets or remain primarily of diagnostic significance.^1,3

Warthin's tumor

Warthin's tumor, also known as papillary cystadenoma lymphomatosum, is the second most common salivary tumor of benign origin with 95% of cases occurring in the parotid gland. The majority of Warthin's tumors have a normal karyotype, with approximately 10% containing genetic aberrations. ¹⁷ Although the etiology and causative genetic abnormality of Warthin's tumor has not been elucidated, the most common alteration was loss of chromosome 22, 17p, and 12q and gain of chromosome 6q, 13q, and 4q. ¹⁷ Recently, genomic alterations to 9p and 8p were also noted. The affected genes are involved in cell cycle control, such as CDKN2A, CDKN2B, and FYN. Gains on 6q were found to affect the FYN oncogene, a mediator of the PI3K and MAPK pathways. These are known to be involved in cell cycle regulation and cell migration (Table 1). ¹⁷

Among these, gains involving chromosome 6q have been associated with increased activity of FYN, a member of the Src family kinases that participates in downstream PI3K and MAPK signaling, pathways known to regulate cell proliferation and migration. ¹⁸ While these findings suggest a potential role for FYN signaling in tumor biology, the functional significance of these alterations in Warthin's tumor remains incompletely understood.

Given the benign nature and indolent clinical course of Warthin's tumor, surgical excision remains the definitive and curative treatment, and molecular targeted therapies are not currently clinically indicated. Although Fyn kinase inhibitors such as saracatinib have demonstrated biologic activity in other disease contexts, including liver fibrosis, their relevance to Warthin's tumor remains purely theoretical. ¹⁹ At present, discussion of FYN inhibition is mainly hypothesis-generating, rather than a near-term therapeutic strategy.

Nonetheless, Warthin's tumor represents a useful model for studying early or low-grade genomic alterations in salivary gland tumors. Further functional studies may help clarify whether aberrations involving FYN or related pathways contribute meaningfully to tumor initiation and growth, and whether these pathways have value as biologic markers rather than therapeutic targets. To date, however, no targeted therapies have entered clinical trials for Warthin's tumor, underscoring the limited translational relevance of these findings in routine clinical practice.

Myoepithelioma and basal cell adenoma

Myoepithelioma and basal cell adenoma (BCA) are uncommon benign SGNs that share overlapping morphologic features but represent distinct pathologies. Myoepithelioma is composed predominantly of myoepithelial cells and accounts for approximately 1–3% of SGNs, most frequently arising in the parotid gland. In contrast, BCA is characterized by basaloid epithelial cells arranged in trabecular, tubular, or membranous growth patterns and represents a separate diagnostic category. ²⁰

Molecular alterations involving CTNNB1 are most strongly associated with BCA, rather than myoepithelioma. CTNNB1 mutations, located on chromosome 3p21, have been reported in approximately 33–50% of BCAs and result in stabilization and nuclear accumulation of β-catenin.^20,21 These mutations most commonly affect exon 3, leading to impaired β-catenin degradation and constitutive activation of downstream WNT signaling, which regulates cellular proliferation and differentiation (Table 1).^3,22 Additional alterations reported less frequently in BCAs include mutations in APC, AXIN1, and CYLD, all of which are also components of the WNT/β-catenin pathway. ¹²

From a diagnostic perspective, nuclear β-catenin expression is a useful marker in identifying CTNNB1-mutated BCAs and distinguishing them from other basaloid salivary gland tumors. However, their therapeutic relevance remains uncertain. Recent preclinical studies in non-salivary malignancies have suggested that TTK inhibitors, which target a spindle assembly checkpoint kinase involved in mitotic regulation, may demonstrate selective activity in CTNNB1-mutant tumors. ²³ The proposed mechanism involves shortened mitotic duration, limiting the ability of β-catenin-mutated cells to suppress WNT signaling during cell division. However, no preclinical or clinical studies have evaluated TTK inhibitors in SGNs, including BCAs or myoepitheliomas. Any discussion of TTK inhibition, therefore, constitutes preclinical extrapolation.

Given the indolent behavior and excellent outcomes with surgical excision, molecularly targeted therapies are not currently indicated for either myoepithelioma or BCA. Future studies may help clarify whether CTNNB1-associated signaling alterations have value as biologic markers or impact therapeutic strategies in rare cases of unresectable or recurrent disease, but at present their relevance remains primarily diagnostic.

Malignant salivary gland tumors pathogenesis and treatment

Mucoepidermoid carcinoma

MECs, the most prevalent malignant SGN, arise from salivary duct epithelium. While most MECs are low-grade with favorable outcomes, a subset can exhibit aggressive behavior. The primary gene abnormality for MECs involves a chromosomal translocation t(11;19)(q21;p13), causing fusion of the CRTC1 and MAML2 genes. This gene mutation is present in 55–88% of patients diagnosed with MECs. The CRTC1 and MAML2 genes are involved in the Notch signaling pathway, responsible for cell proliferation and differentiation. This fusion protein activates transcription of cAMP/CREB-dependent genes (e.g. AREG, PEPCK1, IL6, and MMP10) and enhances oncogenic signaling through interaction with MYC and AP-1. These downstream alterations promote cell proliferation, survival, and invasion, contributing to MEC pathogenesis (Table 2). ¹²

Table 2.

Genetic targets of malignant salivary gland neoplasms.

Malignant tumors	CRTC1	MAML2	MYB	NFIB	Wnt	MTOR	SCPP	PLAG1	ETV6	NTRK3	IGF1R	AR	HER2	EGFR
Mucoepidermoid carcinoma	✓	✓											✓	✓
Adenoid cystic carcinoma			✓	✓									✓	✓
Acinic cell carcinoma					✓	✓	✓						✓	✓
Carcinoma ex-pleomorphic adenoma								✓			✓		✓	✓
Secretory carcinoma									✓	✓			✓	✓
Salivary duct carcinoma												✓	✓	✓

Among these targets, AREG (amphiregulin), a ligand of EGFR, has been associated with poor prognosis and therapeutic resistance. Targeting EGFR signaling has thus emerged as a rational therapeutic strategy. A study by Sama et al. evaluated the efficacy of targeted molecular inhibitors such as lapatinib, which inhibits both EGFR and receptor tyrosine protein kinase HER2. Although no objective responses were observed, a phase II study by Agulnik et al. investigating lapatinib in patients with recurrent or metastatic salivary gland tumors demonstrated disease stabilization, lasting over six months in 36% of patients. Given its cytostatic properties, lapatinib warrants further investigation for its potential antitumor effects in this population. ²⁴ Recent preclinical evidence has demonstrated that CREB inhibition, using the small molecule 666.15, significantly reduces MEC cell survival and tumor spheroid formation, particularly in CRTC1-MAML2 fusion-positive cells. The compound upregulates E-cadherin and impairs cell migration and invasion by downregulating MMP-2 and MMP-9 (matrix metalloproteinases), implicating CREB as a regulator of the metastatic phenotype.^25,26

Moreover, MEC is enriched with cancer stem cells (CSCs), a subpopulation known for resistance to chemotherapy and radiation. Studies by Guimaraes et al. showed that cisplatin alone had limited efficacy in depleting CSCs from MEC cell lines. ²⁷ However, histone deacetylase inhibitors (HDACi) like Vorinostat, when administered prior to cisplatin, effectively depleted CSCs, enhanced chemosensitivity, and lowered the cisplatin IC50. This thereby reduced the cytotoxic dose required. ²⁸ These strategies not only target bulk tumor cells but also impair CSC-driven tumor maintenance and metastasis, which are critical to achieving stable responses.

Collectively, these data highlight several molecule-based therapeutic strategies for MEC, though their levels of supporting evidence vary substantially. Targeting EGFR/HER2 signaling (e.g. lapatinib) has been evaluated in early-phase clinical trials, demonstrating disease stabilization but limited objective responses. In contrast, CREB inhibition using small-molecule agents such as 666.15 remains supported by preclinical in vitro and spheroid model data only, with no human studies to date. Similarly, strategies aimed at disrupting CSC populations, including HDACi in combination with cisplatin, are based on preclinical CSC-directed studies and have not yet been translated into clinical trials. These distinctions underscore both the promise and current limitations of biomarker-driven therapeutic approaches in MEC.

While surgery remains the mainstay of treatment, the molecular insights outlined above have the potential to guide personalized therapy for MEC patients, particularly those with unresectable, recurrent, or high-grade disease. Future research should prioritize biomarker-driven trials, validation of CREB inhibitors in human studies, and further investigation into the therapeutic modulation of CSCs.

Adenoid cystic carcinoma

ACC is a rare but aggressive salivary malignancy, characterized by perineural invasion, late distant metastases, and long-term disease-specific mortality. A defining molecular feature among these tumors is a t(6;9)(q22–23;p23–24) translocation, causing the fusion protein MYB-NFIB, seen in approximately 80% of the cases.^12,29 This gene mutation leads to alteration of downstream targets involved in cell-cycle control, cell growth, and apoptosis. ³⁰ The MYB gene found on chromosome 6q specifically regulates growth and differentiation of hematopoietic and neural stem cells. When fused with NFIB (chromosome 9p), the resulting chimeric protein enhances MYB expression and activity, leading to upregulation of target genes such as CCNA1, BCL-2, c-KIT, and COX-2, which contribute to oncogenesis via promotion of cell survival and inflammation (Table 2).

Despite MYB–NFIB being a central oncogenic driver in ACC, no clinically available therapies directly target MYB signaling. A study by Yusenko et al. has identified monensin as a potent inhibitor of the MYB gene in both acute myeloid leukemia and ACCs. Monensin downregulated MYB expression and its downstream effectors (CXCR4, VEGF, FABP5, SFN) in a dose-dependent manner, impairing tumor cell viability. However, these findings remain limited to cell-line studies, and no MYB-targeted therapy has reached clinical trials, representing a major gap in translational progress. ³¹ Other studies, such as that by Sahara et al., indicate c-KIT and EGFR to have high levels of expression in ACC cells. ³² However, c-Kit inhibitor imatinib and EGFR inhibitors cetuximab, gefitinib, and lapatinib did not provide any objective response.

In contrast, VEGFR-targeted multikinase inhibitors have demonstrated modest clinical activity and currently represent the most commonly utilized systemic therapies for progressive or metastatic ACC. Small molecular inhibitors such as lenvatinib, sorafenib, and axitinib have demonstrated objective response rates of 9–16%, with Lenvatinib currently demonstrating the longest median survival time of 17.5 months. ³² In a phase II trial conducted at Memorial Sloan Kettering Cancer Center, 32 patients had received at least one dose of Lenvatinib. About 75% of the patients had stable disease, with 15.6% of the patients achieving a partial response to the drug. ³³ Currently, no drug has been fully approved by the FDA for treatment of ACC. There have been 33 clinical trials to date investigating systemic therapy for ACC, with Apatinib, Dovitinib, Lenvatinib, and Axitinib being studied in more than one. However, their role at this time is palliative rather than curative. Several VEGFR inhibitors including dovitinib, para-toluenesulfonamide, AL101, and Apatinib have received orphan drug designation for ACC, with Apatinib being the most promising drug with the longest median survival time of 19.7 months.^34–36 In current clinical practice, these agents are generally reserved for patients with radiographically progressive disease who are not candidates for surgery or radiation, often after multidisciplinary discussion. Similarly, NOTCH pathway inhibition has shown early signals of activity in a small subset of ACC patients harboring NOTCH1 mutations, but remains investigational and confined to clinical trials. ³⁷

Despite these advances, no FDA-approved targeted therapy currently exists for ACC. The contrast between the central role of MYB–NFIB in ACC biology and the absence of effective MYB-targeted therapies highlights a critical translational gap. Continued development of biomarker-driven trials will be essential to bring effective targeted therapies to this challenging malignancy.

Acinic cell carcinoma

ACiCC, primarily a low-grade tumor, comprises approximately 10% of all salivary gland cancers. ³⁵ A defining molecular feature of ACiCC is the recurrent SCPP–NR4A3 fusion, resulting from a t(4;9)(q13;q31) translocation. NR4A3 encodes a nuclear receptor transcription factor that functions as a lineage-specific oncogene, and its overexpression drives transcriptional programs involved in cellular proliferation and survival. This fusion is considered both highly sensitive and specific for ACiCC and serves as an important diagnostic adjunct, particularly in histologically ambiguous cases. ³⁵

Beyond its diagnostic utility, NR4A3 has not yet been successfully targeted therapeutically. Preclinical models of ACiCC have demonstrated activation of the WNT and mTOR signaling pathways, particularly in the context of conditional inactivation of tumor suppressor genes such as APC and PTEN (Table 2). ² In these models, mTOR inhibition with agents such as rapamycin has resulted in tumor growth suppression, supporting the biologic relevance of this pathway. However, evidence supporting mTOR inhibition in ACiCC remains limited to preclinical studies and isolated anecdotal observations, and no prospective clinical trials evaluating mTOR inhibitors in ACiCC have been completed to date. As such, mTOR-directed therapy should be regarded as investigational, with no established role in current clinical practice.

Additional molecular markers have been described in ACiCC that may aid in diagnosis rather than therapy. A recent study by Sheng et al. has shown that all classic ACiCCs have strong cytoplasmic expression of LMO2, a key marker for identifying germinal center differentiation, specifically in B-cell lymphomas. LMO2, as such, has been found to differentiate between ACiCCs and other SGNs, due to its high expression in both high-grade and zymogen-poor cases. Due to its frequent use and easy availability, LMO2 appears to be more advantageous as a gene marker than NR4A3. ³⁷ It does not currently represent a therapeutic target, and its role in tumorigenesis remains unclear. Less common fusions, such as HTN–MSANTD3, have also been reported in a minority of cases (4–16%), though their biologic and therapeutic significance has yet to be defined. ³⁵

Overall, ACiCC remains a tumor in which molecular abnormalities have a primary role in diagnostic accuracy rather than systemic therapy. Translation of these pathway-level insights, including mTOR and WNT signaling alterations, into clinically effective targeted treatments will require prospective, tumor-specific trials, which are currently lacking.

Carcinoma ex-pleomorphic adenoma

Carcinoma ex-pleomorphic adenoma is seen in 8–12% of all SGNs. Carcinoma ex-pleomorphic adenoma is not seen as a single diagnosis and contains components of ACC, MEC, and salivary ductal carcinoma. Similar to benign pleomorphic adenoma, gene fusions involving PLAG1 have been observed in 86% of the cases, with HMGA2 gene abnormalities seen less commonly (Table 2). These fusion events often lead to upregulation of downstream oncogenic pathways including IGF2, FGFR2, EGFR, and WNT/β-catenin, many of which are shared with their benign counterparts. However, transformation into carcinoma introduces additional complexity, marked by overexpression or activation of growth factor receptors such as TGFβ-1, TGFα, HER2, EGFR, and IGF-1R which collectively promote proliferation, angiogenesis, and invasion.

As such, targeted therapy can be developed based on the gene-positive subtypes. Among these, HER2 amplification, particularly in Ca ex-PA with SDC differentiation, has emerged as the most clinically actionable alteration. Evidence supporting HER2-directed therapy in Ca ex-PA, however, remains limited to individual case reports and very small case series. In one reported instance, a 58-year-old man with metastatic Ca ex-PA achieved symptomatic relief and partial metabolic response on PET imaging following treatment with trastuzumab, capecitabine, and zoledronic acid, showing the potential of precision-based combination regimens. ³⁵ While informative, such reports do not establish efficacy and should be interpreted cautiously.

Importantly, patients with Ca ex-PA are occasionally included within broader clinical trials of HER2-positive SDC, particularly when the malignant component demonstrates SDC-like histology. However, these patients are rarely analyzed as a distinct subgroup, and no prospective trials have specifically evaluated HER2-targeted therapy in Ca ex-PA. As a result, treatment decisions are often extrapolated from SDC data and guided by molecular profiling rather than tumor origin.

Overall, while HER2 represents a promising therapeutic target in select Ca ex-PA cases, current evidence remains sparse. Clinical trials evaluating agents such as EGFR inhibitors (e.g. cetuximab) and IGF1R inhibitors (e.g. linsitinib) in broader salivary gland malignancies have yet to demonstrate consistent benefit in this subset. Prospective studies and systematic reporting of molecularly characterized cases will be essential to determine whether HER2-directed therapies can be reliably integrated into management algorithms for this heterogeneous and aggressive entity.

Secretory Carcinoma

Secretory carcinoma, previously known as mammary analogue secretory carcinoma (MASC), is rare, with a favorable prognosis. A defining molecular feature is the ETV6-NTRK3 fusion, resulting from the t(12;15)(p13;q25) translocation, seen in 95–98% of cases. This chimeric protein leads to activation of the PI3K-AKT and RAS-MAPK signaling pathways, driving tumorigenesis through cellular proliferation and survival (Table 2). ¹²

Targeting NTRK fusions has emerged as one of the most successful examples of precision oncology in salivary gland tumors. TRK inhibitors, such as larotrectinib and entrectinib, have demonstrated efficacy in early-phase trials across multiple solid tumors with NTRK fusions, including secretory carcinoma. In a phase II trial, larotrectinib achieved a 75% objective response rate in patients with MASC, while entrectinib, across pooled early-phase trials, demonstrated an 83% response rate in NTRK fusion-positive tumors, including 20 out of 24 patients with measurable responses. These outcomes have led to FDA approval of both agents, making TRK inhibition a frontline option in both localized and metastatic settings, especially where surgery may compromise function or cosmesis. ³⁵

However, the majority of efficacy data supporting TRK inhibitors derive from basket trials enrolling patients with diverse tumor histologies. Within these studies, the number of salivary gland tumors, including secretory carcinoma, remains relatively small, and tumor-specific outcomes are not reported as standalone cohorts. Despite this limitation, responses observed in secretory carcinoma have been rapid, durable, and clinically meaningful, supporting TRK inhibition as a frontline systemic therapy in patients with locally advanced or metastatic disease, when surgical resection would result in unacceptable morbidity.

However, several challenges remain, including the emergence of acquired resistance to first-generation TRK inhibitors through secondary kinase domain mutations. The efficacy of next-generation TRK inhibitors, such as selitrectinib and repotrectinib, in secretory carcinoma specifically remains under investigation, and long-term outcome data are limited. Continued prospective data collection and tumor-specific reporting will be essential to refine treatment sequencing and resistance management in this rare but highly targetable malignancy.

Salivary Duct Carcinoma

SDC is an aggressive cancer comprising 4–10% of SGCs. It is notable for its poor prognosis, early locoregional recurrence, and high metastatic potential. Due to the advanced stage at which many patients present, systemic therapy plays a central role in management alongside surgery and radiation.

The most clinically relevant molecular features of SDC include overexpression of the androgen receptor (AR) and HER2, both of which have emerged as actionable therapeutic targets (Table 2). A phase II prospective trial evaluated the impact of combined androgen blockade using leuprorelin acetate and bicalutamide in 36 patients with SGNs of whom 34 had SDC. About 41.7% of patients achieved a partial or complete response, and 44.4% achieved stable disease. Androgen deprivation therapy (ADT) has been found to be beneficial in adjuvant modality settings as well, showing a 20.5% improvement in 3-year disease free survival period compared to no ADT given to the control group. ³⁵

In addition, SDC shares a strong resemblance to high-grade ductal carcinoma of the breast, making HER2 a strong target. ³⁶ Prior studies have shown the combination of trastuzumab, a HER2 targeted inhibitor, and taxane chemotherapy to have a response rate of 70.2% in 57 SDC patients. Studies on HER2 +  breast cancer have shown positive results when patients are given triple therapy with pertuzumab, docetaxel, and trastuzumab.^35,36 In a retrospective case series by Uijen et al., 13 patients with SDC underwent the triple therapy, of which 6 had a partial response and 1 had a complete response. The median progression-free survival was 6.9 months. ³⁸ Further studies are necessary to evaluate the impact of this triple therapy, as well as ADT, in disease management. Beyond AR and HER2, recurrent alterations involving TP53 and the PI3K–AKT–mTOR pathway have been described in SDC and may contribute to treatment resistance and disease progression, highlighting potential avenues for future therapeutic strategies. ³⁸

In routine clinical practice, immunohistochemical testing for AR and HER2 and next-generation sequencing (NGS)-based molecular profiling should be standard to identify patients most likely to benefit from androgen blockade and HER2-targeted regimens. Such biomarker-driven approaches are essential for optimizing outcomes in this aggressive and molecularly distinct salivary gland malignancy.

Implications for practice

Targeting molecular and genetic alterations has revolutionized therapeutic approaches in numerous solid tumors, most notably seen in breast, lung, and prostate cancers. Similar paradigms are increasingly being explored in SGNs. Although SGNs are biologically heterogeneous, recent advances in molecular profiling have unveiled a growing number of genetic alterations, oncogenic fusions, and pathway dysregulations that may serve as viable diagnostic, prognostic, and therapeutic targets.

Understanding the specific gene mutation or fusion driving tumorigenesis is a critical first step. However, translating this knowledge into actionable therapies requires delineating the functional role of the mutated gene within the networks/pathways and assessing its downstream effects on tumor growth, invasion, recurrence, and metastasis. Although each SGN subtype exhibits distinct translocation profiles, some common therapeutic vulnerabilities are emerging. Notably, EGFR and HER2 signaling pathways have been found to be significantly overexpressed across multiple malignant SGNs, including MEC, SDC, and carcinoma ex-pleomorphic adenoma. As highlighted in Figure 1, these pathways are implicated in advanced disease stages and correlate with tumor grade, nodal involvement, and distant metastasis. Their recurrent activation across subtypes suggests that EGFR/HER2-directed therapies (e.g. trastuzumab, lapatinib, pertuzumab) may offer broader clinical utility beyond any one histologic diagnosis. ²

Figure 1.

Biochemical gene pathway and associated targets. The underlying gene abnormalities within the benign and malignant salivary gland tumors are identified with their associated targeted therapy. (Figure was made by the authors of the manuscript, no AI usage.).

In addition, emerging pan-cancer pathways such as TP53 mutations, PI3K/Akt/mTOR signaling, and dysregulation of the cyclin–CDK axis have also been reported across both benign and malignant salivary gland tumors. ³⁹ These alterations suggest that SGNs, despite their relative rarity, may benefit from molecular tumor board-based treatment planning, with targeted therapies developed for more common malignancies.

Nonetheless, several challenges exist in integrating molecularly guided therapies into routine practice. One major barrier is limited clinical trial enrollment, given the rarity of SGNs, which hampers large-scale validation of promising targeted therapies. Another is the emergence of tumor heterogeneity and resistance mechanisms, such as secondary mutations in NTRK3, HER2, or EGFR. This may limit the long-term efficacy of treatment. Furthermore, the lack of universal infrastructure for molecular profiling, such as routine NGS, impedes the timely identification of actionable alterations during clinical decision-making.

To overcome these challenges, standardized molecular testing panels and the integration of oncology platforms into head and neck cancer workflows are essential. Additionally, collaborative efforts across institutions will be critical to obtain sufficient data to inform drug development, validate biomarkers, and stratify patients for personalized interventions. Ultimately, the future of salivary gland cancer care lies in a multidisciplinary, biomarker-driven approach, where histopathologic diagnosis is complemented by molecular analysis, and where targeted therapies can be matched to each tumor's unique genomic blueprint.

Abbreviations

Term

Definition

PLAG 1

Pleomorphic adenoma Gene 1

HMGA2

High mobility group A2

CTNNB1

Catenin Beta1

CRTC1

CREB-regulated transcription coactivator-1

MAML2

Mastermind-like transcriptional coactivator-2

MYB

Myeloblastosis

NFIB

Nuclear factor 1B

Wnt

Wingless-related integration site

mTOR

Mammalian target of rapamycin

SCPP

Secretory calcium-binding phosphoprotein

ETV6

ETS variant transcription factor 6

NTRK3

Neurotrophic receptor tyrosine kinase 3

IGF1R

Insulin like growth factor 1 receptor

AR

Androgen receptor

HER2

Human epidermal growth factor receptor 2

EGFR

Epidermal growth factor receptor

MEC

Mucoepidermoid Carcinoma

ACC

Adenoid Cystic Carcinoma

ACiCC

Acinic Cell Carcinoma

SDC

Salivary Duct Carcinoma