Anti-NOTCH1 therapy with OMP-52 M51 inhibits salivary adenoid cystic carcinoma by depressing epithelial-mesenchymal transition (EMT) process and inducing ferroptosis.

Salivary adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, and the mechanisms underlying its progression still remain poorly understood without efficient therapies. NOTCH1, an evolutionally conserved cell-cell signaling pathway, is involved in the progression of ACC. In our study, we attempted to explore whether NOTCH1 suppression using the monoclonal anti-NOTCH1 antibody OMP-52 M51 could be of potential for ACC treatment. Here, we identified NOTCH1 elevation in human ACC tissues compared with the matched normal samples. Patients with metastasis expressed much higher NOTCH1. We then found that OMP-52 M51 markedly reduced the expression of NOTCH1 and its intracellular active form NICD1 (NOTCH1 intracellular domain). Importantly, OMP-52 M51 markedly reduced the proliferation, migration and invasion of ACC cells. RNA-Seq and in vitro studies further showed that OMP-52 M51 significantly induced ferroptosis in ACC cells, indicated by the increased cellular malondialdehyde (MDA), iron contents and lipid ROS production, and decreased glutathione (GSH) levels. Further, remarkable glutathione peroxidase 4 (GPX4) reduction was detected in ACC cells with OMP-52 M51 treatment. However, promoting NOTCH1 expression markedly abolished the function of OMP-52 M51 to induce ferroptosis. Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC.

A phase 2 study of MK-2206 in patients with incurable adenoid cystic carcinoma (Alliance A091104).

BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB-NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK-2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772). METHODS: Patients with progressive, incurable ACC were enrolled and received MK-2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression-free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK-2206 on MYB expression was conducted in a subset of patients. RESULTS: Sixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression-free survival was 9.7 months (95% CI, 3.8-11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8-29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment-related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB-NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK-2206 in four of five patients. CONCLUSIONS: MK-2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed.

Anti-LGALS3BP antibody-drug conjugate treatment induces durable and potent antitumor response in a preclinical model of adenoid cystic carcinoma.

OBJECTIVES: Adenoid cystic carcinoma (ACC) is a rare type of cancer that typically arises from glandular tissues, most commonly in the salivary glands. Although relatively rare, it represents a serious clinical issue as the management of the disease is highly complex being the only therapeutic options represented by invasive surgery and/or radiotherapy. In the present study, we have explored the potential of galectin-3 binding protein (LGALS3BP) as a novel target for antibody-drug conjugate (ADC) therapy in ACC. MATERIALS AND METHODS: RNAseq was conducted on a panel of 10 ACC patient-derived xenografts (PDX)s tissues and 6 normal salivary glands to analyze LGALS3BP gene expression. Protein expression was assessed in ACC PDX and primary tumor tissues using immunohistochemistry. Anti-LGALS3BP ADC named 1959-sss/DM4, was tested in high LGALS3BP expressing ACC PDX model ST1502B. RESULTS: RNAseq analysis revealed that LGALS3BP expression was highly expressed in ACC PDX tissues compared to normal salivary gland tissues. As evaluated by immunohistochemical analysis, LGALS3BP protein was found to be heterogeneously expressed in 10 ACC PDX and in tumor tissues derived from a cohort of 37 ACC patients. Further, treatment with 1959-sss/DM4 ADC led to durable tumor growth inhibition (TGI) in 100% of animals without observed toxicity. CONCLUSIONS: Our study provides strong evidence that LGALS3BP is a promising therapeutic target for ACC, warranting further expedited preclinical and clinical investigation.

HER2-targeted therapies for salivary gland cancers.

Salivary gland cancers (SGCs) are a heterogeneous group of rare tumors including various histological subtypes with different molecular profiling. Human epidermal growth factor receptor 2 (HER2) is one of the most intriguing and studied molecular alterations with prognostic and predictive roles. Indeed, HER2 overexpression is commonly correlated with aggressive histological subtypes and poorer prognosis. However, HER2 may represent the target of personalized treatment. We performed a literature review of use of anti-HER2 targeted agents for treatment of recurrent or metastatic SGCs. The efficacy and safety of anti-HER2 were firstly evaluated in patients affected with other solid tumors, mostly breast and gastric cancers. For SGCs the literature is mainly comprised of case reports or case series and small clinical trials. The most common used drug is trastuzumab in combination with chemotherapy (i.e. taxanes, capecitabine, carboplatin, eribulin) or with another anti-HER2 targeted agent (i.e. pertuzumab). The use of anti-HER2 therapies induces improvement in clinical responses, which are mostly durable. Besides, new anti-HER2 drugs such as antibody-drug conjugates (ADC) (i.e. trastuzumab emtansine, trastuzumab deruxtecan) have been introduced in this setting inducing further therapeutic advances. Anti-HER2 treatment strategy is emerging as potentially effective in selected HER2 overexpressing SGCs. However, prospective and multicentric clinical trials are needed to evaluate the efficacy of these therapeutic regimens within larger cohorts and to assess the most appropriate treatment sequence strategy.

Efficacy of Cetuximab Combined with Paclitaxel in Patients with Recurrent Salivary Gland Carcinoma: A Retrospective Observational Study.

INTRODUCTION: Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy for patients with SGC. Our study described promising results of epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel in patients with SGC. METHODS: The medical records of patients with recurrent SGC treated with weekly cetuximab combined with paclitaxel (Cmab-PTX) between December 2017 and December 2022 at our institutions were retrospectively analyzed. RESULTS: Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months (range of 2-36 months). The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response and disease control rates were 71.4% and 85.7%, respectively. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. CONCLUSION: Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC. Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy in patients with SGC. Our study described promising results of cetuximab (Cmab), epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel (PTX) in patients with SGC. Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months. The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response rate was 71.4%. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. Our study revealed a preferable objective response rate of Cmab-PTX for patients with high-grade SGC. Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC.

Systemic therapies for salivary gland carcinomas: an overview of published clinical trials.

BACKGROUND: There is no consensus about effective systemic therapy for salivary gland carcinomas (sgcs). Our aim was summarized the clinical trials assessing the systemic therapies (ST) on sgcs. MATERIAL AND METHODS: Electronic searches were carried out through MEDLINE/pubmed, EMBASE, Scopus, Web of Science, and the Cochrane Library databases, and gray literature. RESULTS: Seventeen different drugs were evaluated, and the most frequent histological subtype was adenoid cystic carcinoma (n=195, 45.5%). Stable disease, observed in 11 ST, achieved the highest rate in adenoid cystic carcinoma treated with sunitinib. The highest complete (11.1%) and partial response (30.5%) rates were seen in androgen receptor-positive tumors treated with leuprorelin acetate. CONCLUSIONS: Despite all the advances in this field, there is yet no effective evidence-based regimen of ST, with all the clinical trials identified showing low rates of complete and partial responses. Further, translational studies are urgently required to characterize molecular targets and effective ST.

The neutrophil-to-lymphocyte ratio in salivary gland cancers treated with pembrolizumab.

BACKGROUND: A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response prediction. METHODS: Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6-month progression-free survival (PFS) and secondary outcome of 2-year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed. RESULTS: Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6-month PFS (HR 1.30, 95% CI 1.10-1.54, p = 0.002) and 2-year OS (HR 1.33, 95% CI 1.07-1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17-76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67-75.77, p = 0.013). CONCLUSIONS: Higher pretreatment NLR was independently associated with inferior 6-month PFS and 2-year OS in pembrolizumab-treated R/M SGC patients.

Extracting Potential New Targets for Treatment of Adenoid Cystic Carcinoma using Bioinformatic Methods.

Background: Adenoid cystic carcinoma is a slow-growing malignancy that most often occurs in the salivary glands. Currently, no FDA-approved therapeutic target or diagnostic biomarker has been identified for this cancer. The aim of this study was to find new therapeutic and diagnostic targets using bioinformatics methods. Methods: We extracted the gene expression information from two GEO datasets (including GSE59701 and GSE88804). Different expression genes between adenoid cystic carcinoma (ACC) and normal samples were extracted using R software. The biochemical pathways involved in ACC were obtained by using the Enrichr database. PPI network was drawn by STRING, and important genes were extracted by Cytoscape. Real-time PCR and immunohistochemistry were used for biomarker verification. Results: After analyzing the PPI network, 20 hub genes were introduced to have potential as diagnostic and therapeutic targets. Among these genes, PLCG1 was presented as new biomarker in ACC. Furthermore, by studying the function of the hub genes in the enriched biochemical pathways, we found that insulin-like growth factor type 1 receptor and PPARG pathways most likely play a critical role in tumorigenesis and drug resistance in ACC and have a high potential for selection as therapeutic targets in future studies. Conclusion: In this study, we achieved the recognition of the pathways involving in ACC pathogenesis and also found potential targets for treatment and diagnosis of ACC. Further experimental studies are required to confirm the results of this study.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial.

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .

Partial response to RC-48 as palliative treatment in a patient with locallocally advanced carcinoma ex pleomorphic adenoma harboring a HER2 mutation: a case report.

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.

Nectin-4 is frequently expressed in primary salivary gland cancer and corresponding lymph node metastases and represents an important treatment-related biomarker.

Many locally advanced and metastatic salivary gland carcinomas (SGC) lack therapeutic targets. Enfortumab vedotin, an antibody-drug conjugate binding to Nectin-4, recently gained FDA approval for third-line urothelial carcinoma. Therefore, the aim of this study was to assess the expression of Nectin-4 in primary SGC and corresponding lymph node metastases and to correlate it with clinicopathological data. Immunohistochemical staining for Nectin-4 was performed for patients who had undergone surgery with curative intent for primary SGC of the parotid or submandibular gland in a tertiary referral center between 1990 and 2019. One hundred twenty-two primary SGC and twenty corresponding lymph node metastases were included. Nectin-4 was expressed in 80.3% of primary SGC with a mean Histo(H-)score of 61.2 and in 90.0% of lymph node metastases with a mean H-score of 75.6. A moderate or high Nectin-4 expression was found in 25.9% of salivary duct carcinomas (SaDu) and in 30.7% of adenoid cystic carcinomas (ACC). SaDu patients with a lower T-stage (p = 0.04), no loco-regional lymph node metastases (p = 0.049), no vascular invasion (p = 0.04), and no perineural spread (p = 0.03) showed a significantly higher mean Nectin-4 H-score. There was a statistical tendency towards a more favorable disease-free survival among SaDu patients with a higher Nectin-4 expression (p = 0.09). Nectin-4 is expressed in SGC and therefore represents a potential therapeutic target, especially in entities with a high rate of local recurrence and metastatic spread such as SaDu and ACC.

Role of Histone Deacetylases in the Pathogenesis of Salivary Gland Tumors and Therapeutic Targeting Options.

Salivary gland tumors (SGTs) comprise a rare and heterogenous category of benign/malignant neoplasms with progressively increasing knowledge of the molecular mechanisms underpinning their pathogenesis, poor prognosis, and therapeutic treatment efficacy. Emerging data are pointing toward an interplay of genetic and epigenetic factors contributing to their heterogeneity and diverse clinical phenotypes. Post-translational histone modifications such as histone acetylation/deacetylation have been shown to actively participate in the pathobiology of SGTs, further suggesting that histone deacetylating factors (HDACs), selective or pan-HDAC inhibitors (HDACis), might present effective treatment options for these neoplasms. Herein, we describe the molecular and epigenetic mechanisms underlying the pathology of the different types of SGTs, focusing on histone acetylation/deacetylation effects on gene expression as well as the progress of HDACis in SGT therapy and the current status of relevant clinical trials.

A comparison of two chemotherapy regimens in advanced, recurrent, or metastatic salivary gland carcinoma.

Background: The efficacy of chemotherapy in locally advanced, recurrent, and metastatic salivary gland carcinomas (LA-R/M SGCs) is still undefined. We aimed to compare the efficacy of two chemotherapy regimens in LA-R/M SGC. Materials and Methods: This prospective study compared paclitaxel (Taxol) plus carboplatin (TC) versus cyclophosphamide, doxorubicin, plus cisplatin (CAP) regimen in terms of overall response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Results: Between October 2011 and April 2019, 48 patients with LA-R/M SGCs were recruited. The ORRs of first-line TC and CAP regimens were 54.2% and 36.3%, respectively (P = 0.57). The ORRs in recurrent and de novo metastatic patients were 50.0% and 37.5% for TC and CAP, respectively (P = 0.26). The median PFS of TC and CAP arms were 10.2 and 11.9 months, respectively (P = 0.91). In the subanalysis, patients with adenoid cystic carcinoma (ACC) had longer PFS in the TC arm (14.5 vs. 8.2 months, P = 0.03), irrespective of the tumor grade (low grade: 16.3 vs. 8.9 months, high grade: 11.7 vs. 4.5 months; P = 0.03). The median OS rates were 45.5 and 19.5 months for TC and CAP groups, respectively (P = 0.71). Conclusion: For patients with LA-R/M SGC, there was no significant difference between first-line TC and CAP in terms of ORR, PFS, and OS.

Precision oncology using organoids of a secretory carcinoma of the salivary gland treated with TRK-inhibitors.

The use of anticancer drugs targeting specific molecular tumor characteristics is rapidly increasing in clinical practice, but selecting patients to benefit from these remains a challenge. It has been suggested that organoid cultures would be ideally suited to test drug responses in vitro. Here we describe and characterize in depth a case of ETV6-NTRK3 gene fusion-positive secretory carcinoma of the salivary glands and corresponding organoid cultures that responded and subsequently acquired resistance to TRK targeting therapy with larotrectinib. This case-culture-characterization illustrates the advances made in precision oncology, but also exposes important caveats in using organoids to predict treatment response.

Systemic and Targeted Therapies in Adenoid Cystic Carcinoma.

OPINION STATEMENT: Adenoid cystic carcinoma (ACC) is an often-indolent type of salivary gland cancer (SGC). A subset of patients develops progression or aggressive disease warranting systemic therapy in the recurrent/metastatic (R/M) setting. We recommend genomic testing for all patients with R/M disease to aid with prognostication and eligibility for potential experimental therapies. Here, we review the currently available treatment options (cytotoxic chemotherapies and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs)). Based on limited data, we nominate regimens which may have more favorable efficacy profiles. Among the cytotoxic chemotherapies, several regimens are acceptable when incorporating a platinum agent. Among the VEGFR-targeting TKIs, lenvatinib and axitinib are the preferred options. Larger, randomized studies prioritizing combinations with mechanistic synergism are needed. Predictive biomarkers are critical, as there is currently little evidence to guide sequencing of available options for individual patients. Immunotherapy is an available option, but has been associated with only modest benefit in ACC. We go on to review other therapies that have been studied and nominate those with promise based on early clinical data.

A Case of Metastatic Submandibular Salivary Duct Carcinoma that Completely Responded to Pembrolizumab Monotherapy.

Salivary gland carcinoma is a rare cancer and has more than 20 histopathological types. Although chemotherapy has been the mainstay of treatment for unresectable carcinomas such as multiple recurrence and distant metastasis, no standard regimen is available. In this article, we report a case of poorly differentiated salivary duct carcinoma of the submandibular gland with distant metastases that was successfully treated with pembrolizumab monotherapy. A 66-year-old man became aware of a left submandibular mass 2 months before his first visit to our department. A needle biopsy at a previous hospital revealed carcinoma, not otherwise specified. The combined positive score on a programmed death ligand-1 immunohistochemistry test was 1-10%. The patient was referred to our department for further treatment. Computed tomography revealed left level II and IV neck lymphadenopathy, bilateral lung shadowing, and osteolytic changes in the 12th thoracic vertebra. Needle biopsy showed poorly differentiated carcinoma, positive human epidermal growth factor receptor 2, and positive androgen receptor, which suggested salivary duct carcinoma. These findings indicated a diagnosis of submandibular carcinoma T4aN2bM1 stage IVC. Pembrolizumab monotherapy was started, and tumor shrinkage was observed after three courses of treatment. At 1 year, complete response was achieved without adverse events, and treatment is ongoing. Despite a lack of evidence for the efficacy of immune checkpoint inhibitors in salivary gland carcinoma, the present case suggests that some patients might respond to this treatment. Hence, clinical trials are warranted.

Capecitabine is effective as palliative chemotherapy in a patient with androgen receptor and HER2 positive metastatic salivary duct carcinoma. A case report.

ABSTRACT: Metastatic salivary duct carcinomas (SDC) are rare tumors and evidence-based guidelines for their treatment have not yet been established. Reports of such cases like ours could be beneficial in the decision-making in the similar clinical circumstances. Here we present the 64-year-old Caucasian man with bone pain and pancytopenia two years after local treatment of SDC, in whom a bone marrow biopsy revealed poorly differentiated carcinoma of salivary origin with nuclear androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2/neu) positivity. Clinical response was achieved with cis-platin based cytotoxic therapy and maintenance hormonal treatment. At progression after 12 months, he was treated with anti-HER2 therapy combined with taxanes. The response lasted for 14 months. Then palliative therapy with capecitabine was introduced. With a relatively sustained quality of life, the response lasted for 15 months.

No survival benefit from adding chemotherapy to adjuvant radiation in advanced major salivary gland cancer.

This study aimed to compare survival of patients with advanced major salivary gland cancers treated with adjuvant chemoradiation therapy (CRT) versus radiotherapy (RT) alone, after surgical resection. The Taiwan Cancer Registry database was used to identify patients (2009-2017) with advanced (T3-4 or nodal positivity) major salivary gland cancers, treated post-surgically with adjuvant CRT or RT alone. Overall survival (OS) and disease-specific survival (DSS) evaluated using Kaplan-Meier. Stratified analyses conducted on clinicopathological features. A total of 395 patients were analyzed: 178 (45.1%) received adjuvant CRT; 217 (54.9%) received adjuvant RT alone. Median radiation dose was 66 Gy in 33 fractions. Cisplatin was most common chemotherapy regimen. After a median follow-up of 3.37 years, there was no significant difference in OS or DSS (p = 0.1354 and 0.3361, respectively) between groups. Adding chemotherapy to adjuvant RT was not significantly associated with improved OS (adjusted hazard ratio [aHR] 0.94; 95% CI 0.72-1.23) and DSS (aHR 0.96; 95% CI 0.72-1.28). Stratified analysis of clinicopathological features found no significant advantages for improved OS or DSS from adding chemotherapy to adjuvant RT. Thus, in this population database, the use of chemotherapy provided limited survival benefits in advanced major salivary gland cancers after surgical resection.