Salivary Duct Carcinoma Research Articles

177Lu-PSMA radioligand therapy for patients with recurrent/metastatic (R/M) salivary gland cancer (SGC): A phase II pilot study.

6099 Background: New treatments are warranted due to limited systemic treatment options for SGC patients (pts). Gallium [68Ga]Ga prostate-specific membrane antigen (PSMA) PET imaging results in SGC pts have demonstrated PSMA expression of SGC and thus indicated that PSMA radionuclide therapy may be a useful option, especially in the case of adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC) subtypes. Therefore, this study (EudraCT number 2019-003857-27) evaluated the safety and efficacy of PSMA-targeted radionuclide therapy in AdCC and SDC pts. Methods: This was a single-center, single-arm, phase II pilot study. R/M AdCC (n = 10) and SDC (n = 5) pts with sufficient PSMA tracer uptake on [68Ga]Ga-PSMA PET imaging, i.e., ≥1 lesion ≥1.5cm with PSMA expression above mean liver level, were treated with 2-4 cycles of 7.4 GBq [177Lu]Lu-PSMA-I&T, with an interval of 6±1 weeks. Baseline imaging was repeated for evaluation 4 weeks after cycle 2; in case of progressive disease (PD) per RECIST 1.1 the treatment was discontinued; otherwise, pts received the full treatment (4 cycles). All pts received whole body post-therapeutic imaging after 1, 24, 48, 72 h and 7d after each cycle. The primary endpoint was safety. Secondary endpoints include the objective response rate, progression-free survival (PFS), and overall survival (OS). Results: Between 6-2020 and 2-2023, 15 AdCC pts and 10 SDC pts were screened for eligibility. Five AdCC pts and 8 SDC pts were screen failures due to insufficient PSMA expression in 11 pts (AdCC n = 4; SDC n = 7) or due to brain metastases in 2 pts (AdCC n = 1; SDC n = 1). Ten AdCC and 2 SDC pts received at least one cycle of 7.4 GBq [177Lu]Lu-PSMA-I&T. The most observed adverse events (grade 1-2) included: nausea (75%), dry mouth (75%), fatigue (67%), and anemia (58%). Two pts (17%) developed grade 3 toxicity; lymphocytopenia (n = 1) and hyponatremia (n = 1). No grade 4-5 toxicities were observed. Two pts (AdCC n = 1; SDC n = 1) received only 1 treatment cycle due to early PD. The interim-treatment evaluation resulted in the discontinuation of treatment after 2 cycles in an additional 3 AdCC and the second SDC pts due to PD. Six AdCC pts received the full treatment (4 cycles); no responses were observed; 3 pts (75%) showed stable disease of more than 3 months after treatment completion (5, 15 and 21 months); 3 pts showed PD at 3 months after treatment completion. Median PFS in 10 AdCC pts was 6.7 months (95%CI: 0.0-15.1); OS was not reached after a median follow-up of 11.9 months. Conclusions: [177Lu]Lu-PSMA-I&T treatment in SGC pts is well-tolerated. The efficacy in AdCC was limited; only stable disease was achieved in 3 out of 10 pts. In most screened SDC pts, PSMA expression was insufficient to undergo [177Lu]Lu-PSMA-I&T treatment; the 2 SDC pts included showed early PD. Dosimetry analyses will be performed to calculate the delivered radiation doses to organs at risk as well as tumor lesions. Clinical trial information: EUCTR2019-003857-27.

A phase II trial of nivolumab for patients with platinum-refractory recurrent or metastatic salivary gland cancer.

6092 Background: Salivary gland cancer is rare and has various pathological subtypes. With this rarity and heterogeneity, the therapeutic contribution of chemotherapy, including immune checkpoint inhibitors, for recurrent or metastatic salivary gland cancer (RM-SGC) has not been elucidated. The purpose of this trial was to investigate the efficacy and safety of nivolumab for patients with platinum-refractory RM-SGC. Methods: This open-label, single-arm, multicenter phase II trial was conducted at 9 centers in Japan. Eligible patients had platinum-refractory recurrent or metastatic salivary gland cancer with measurable lesions by RECIST v1.1 and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2. Nivolumab 240 mg/body was administered intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). We set the null hypothesis at 3% and the expected at 15% with a one-sided alfa of 0.1 and power of 80%. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-four patients (16 males; median age, 65.5 years [range, 34-78 years]) were enrolled between March 2018 and January 2022. Pathological types were salivary duct carcinoma (n = 10), adenoid cystic carcinoma (n = 6), adenocarcinoma not otherwise specified (n = 5), mucoepidermoid carcinoma (n = 2), and acinic cell carcinoma (n = 1). In the majority of cases the primary site was a major salivary gland (n = 21), namely the parotid gland in 16 patients and submandibular gland in 5. The primary endpoint of ORR was 8.3% (2/24, 80% CI, 2.2-20.6%), with 2 partial responses (PR) in patients with salivary duct carcinoma (2/10, ORR: 20.0%). DCR was 29.2% (7/24, 2 in PR and 5 in stable disease), and all of the other 17 patients（70.8%）showed progressive disease (PD) on first disease evaluation at 12 weeks. With a median follow up for survivors of 32.0 months, median PFS and OS were 3.0 months (95% CI, 2.8-3.2 months) and 25.0 months (95% CI, 10.9-39.1 months), respectively. There was no new safety concern with nivolumab monotherapy. Conclusions: This phase II trial of nivolumab monotherapy for patients with platinum-refractory RM-SGC did not meet its primary endpoint of ORR. Although nivolumab monotherapy may be worth further development in salivary duct carcinoma, these results may raise concerns over nivolumab monotherapy for RM-SGC. Translational research to elucidate the immune microenvironment of each pathological type is under investigation. Clinical trial information: UMIN000029636 .

Retrospective analysis of genetically matched therapies in salivary gland cancer entities using a real-world database in a tertiary salivary gland cancer expertise center.

6098 Background: Salivary gland cancer (SGC) is a rare cancer and includes twenty-two different entities. In the Radboudumc SGC expertise center, a real-word database was set up to uniformly collect data of SGC subtypes. More than 500 SGC patients have been enrolled and collection of data for 261 patients is currently completed. Here, we describe the retrospective analysis of genetic aberrations found in different SGC entities and the treatment of selected recurrent/metastatic (R/M) patients with genetically matched therapies (GMT). Methods: All SGC patients in the SGC registry of Radboudumc between 2017 and 2022 whose tumors underwent next generation sequencing (NGS) and/or gene fusion analysis within standard of care or clinical trial were included in this analysis. Both primary tumor specimen and metastatic tissue have been used for molecular analyses. GMT was given in basket trials or on basis of compassionate use for clinically relevant genetic aberrations that are considered actionable nowadays. Results: NGS and/or gene fusion analysis data was available for 162 out of 261 patients, and most frequently in salivary duct carcinoma (SDC) patients (82/162). The number of patients with genetic aberrations differed between SGC entities. In 112 patients at least one genetic aberration and/or gene fusion was detected regardless of whether the target was druggable. Ninety-three patients out of 112 patients had R/M disease. Both a gene fusion and one or more mutations were found in six patients (adenoid cystic carcinoma [AdCC], n = 3; SDC, n = 2; and secretary carcinoma [SC], n = 1;). Depending on the SGC subtype, in 14.3 – 100% of the R/M cases with genetic aberrations and/or gene fusions a GMT was started (SDC, 14/60; AdCC, 3/21; SC, 2/2; mucoepidermoid carcinoma, 2/4). The most given GMT among patients were monoclonal antibodies and tyrosine kinase inhibitors (TKI), respectively in nine and eleven patients, moreover immunotherapy was started in one patient. For example, eight SDC patients were treated with ERBB2 targeting agents (4/8 mutations; 4/8 copy number variants in ERBB2), showing a complete response in three patients. Additionally, one partial response and two stable diseases were observed, two patients were lost of follow-up. Two SC patients treated with a TKI based on the presence of the ETV6- NTRK gene fusion showed radiologically a partial response. Conclusions: In 69% of the SGC patients at least one genetic aberration and/or gene fusion was found, and in 23% of the R/M cases GMT was administered. Response differs between entities and GMT; a complete response was achieved after initiation of GMT in several patients. These data justify the use of NGS and gene fusion analysis in all salivary gland cancer entities, notably in subtypes lacking standard systemic therapies as this could offer other therapeutic options.

Darolutamide for patients with androgen receptor positive salivary gland cancers (DISCOVARY): The results of phase 2 study of darolutamide monotherapy.

6093 Background: There is no standard first-line treatment for recurrent/metastatic (R/M) or unresectable locally advanced (LA) salivary gland cancer (SGC). Androgen receptor (AR) overexpression is known to be particularly high (43-92%) in SDC, depending on histology, and has been identified as a potential molecular target for SGC treatment. However, the clinical utility of this approach has not been well investigated. Here, we evaluated the efficacy and safety of darolutamide for patients with AR-positive SGC. Methods: Eligibility included LA or R/M, SGC histologically confirmed positive for AR by the central laboratory; PS 0-1; adequate organ function; and no suitable local therapy. The study consists of two sequential components: a monotherapy part with darolutamide alone (monotherapy part) and a combination part with darolutamide and goserelin (combination part). Darolutamide was given orally at 1,200 mg daily until disease progression or unacceptable toxicity. Primary endpoint for the monotherapy part was overall response rate (ORR) as determined by the investigator. Secondary endpoints were ORR by independent central review (ICR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. (ClinicalTrials.gov NCT05694819). Results: From Mar 2020 to Jan 2021, 24 patients were enrolled in the monotherapy component. Median age was 64.6 years and 23 were male. ECOG PS was 0/1 in 18/6 cases. Pathological diagnosis was salivary duct carcinoma, adenocarcinoma NOS, and carcinoma ex pleomorphic adenoma in 16, 4 and 4 patients, respectively. ORR by investigator was 8.3% (90% CI 1.5–24.0) and ORR by ICR was 20.8% (95% CI 7.1–42.2). CBR and DCR were 41.7% (95% CI 22.1–63.4) and 58.3% (95% CI 36.6–77.9), respectably. Median PFS and OS were 5.7 months (95% CI, 1.9–15.2) and not reached (95% CI, 15.5–not estimable [NE]), respectively, with a median follow-up period of 19.1 months. Nine patients (37.5%) had grade 3 or 4 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: This is the first prospective trial of darolutamide for AR-positive SGC. The response rate by ICR and other secondary endpoints confirmed clinically meaningful activity and a well-tolerated safety profile. Patient enrollment to the combination component is now ongoing to evaluate additional benefits. Clinical trial information: NCT05694819 .

The influence of grade on mortality risk in salivary gland malignancy.

e18100 Background: Salivary malignancies are amongst one of the most difficult malignancies to classify.Currently, the impact of histologic variants has not been well described. The objective of this study was to evaluate histologic subtype and grade in salivary cancer staging. Methods: Salivary cancer histologies were collected from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable models were used to adjust for clinicopathologic covariates and assess for relationships between histologic subtype, grade, and survival. Results: Histologic variants have a wide range of mortality risk (e.g., acinic cell carcinoma has a favorable 5-year survival, in opposition to salivary duct carcinoma) on univariate analysis(p < 0.001). Using multivariable analysis, the survival differences disappeared. However, worsening grade corresponded signficantly with deteriorating survival (5-year OS of 89% [95% CI 88-90%] (low-grade), 81% [95% CI 79-82%] (intermediate-grade), 45% [95% CI 44-47%] (high-grade) (p < 0.001)), on both multivariable analysis and propensity score matching. Recursive partitioning analysis incorporating grade into current staging generated a TNM+G schema (c-index 0.75, 95% CI 0.745-0.755) superior to the existing system (c-index 0.73, 95% CI 0.723-0.736). Conclusions: Grade is a significant factor in determining mortality risk in salivary cancers. Including grade into staging will improve current staging systems.

A phase 2 multicenter study of docetaxel-PM and trastuzumab-pkrb combination therapy in recurrent or metastatic salivary gland carcinomas.

Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. The high positivity rate for human epidermal growth factor receptor 2 (HER2) led to an investigation of the efficacy of HER2-targeted agents. Docetaxel-PM (polymeric micelle) is a low-molecular-weight, nontoxic, biodegradable, and docetaxel-loaded micellar formulation. Trastuzumab-pkrb is a biosimilar to trastuzumab. This was a multicenter, single-arm, open-label phase 2 study. Patients with HER2-positive (immunohistochemistry [IHC] score of ≥2+ and/or HER2/chromosome enumeration probe 17 [CEP17] ratio of ≥2.0) advanced SDCs were enrolled. Patients received docetaxel-PM (75mg/m2 ) and trastuzumab-pkrb (8mg/kg in the first cycle and 6mg/kg in subsequent cycles) every 3weeks. Primary end point was objective response rate (ORR). A total of 43 patients were enrolled. The best objective responses were partial response in 30 (69.8%) patients and stable disease in 10 (23.3%) patients, leading to an ORR of 69.8% (95% confidence interval [CI], 53.9-82.8) and a disease control rate of 93.0% (80.9-98.5). Median progression-free survival, duration of response, and overall survival were 7.9 (6.3-9.5), 6.7 (5.1-8.4), and 23.3 (19.9-26.7) months, respectively. Patients with HER2 IHC score of 3+ or HER2/CEP17 ratio ≥2.0 demonstrated better efficacies compared to those with HER2 IHC score of 2+. Thirty-eight (88.4%) patients experienced treatment-related adverse events (TRAE). Because of TRAE, nine (20.9%), 14 (32.6%), and 19 (44.2%) patients required temporary discontinuation, permanent discontinuation, or dose reduction, respectively. The combination of docetaxel-PM and trastuzumab-pkrb demonstrated promising antitumor activity with a manageable toxicity profile in HER2-positive advanced SDC. Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. SDC shares morphological and histological similarities with invasive ductal carcinoma of breast, which led to an investigation of hormonal receptor and human epidermal growth factor receptor 2 (HER2)/neu expression status in SDC. In this study, patients with HER2-positive SDC were enrolled and treated with combination of docetaxel-polymeric micelle and trastuzumab-pkrb. Promising antitumor activities were shown with objective response rate of 69.8%, disease control rate of 93.0%, median progression-free survival of 7.9months, median duration of response of 6.7months, and median overall survival of 23.3months.

Effect of HER2-targeted therapy on PDX and PDX-derived organoids generated from HER2-positive salivary duct carcinoma.

We previously established a patient-derived xenograft (PDX) model, patient-derived organoids (PDOs), and PDX-derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2-positive SDC. The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice. The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice. For the first time, we demonstrated the efficacy of anti-HER2 therapy in HER2-positive SDC using preclinical models of SDC PDX and PDXO.

Frequent apocrine changes in pleomorphic adenoma with malignant transformation: a possible pre-malignant step in ductal carcinoma ex pleomorphic adenoma.

The most common type of carcinoma ex pleomorphic adenoma (CPA) is histologically equivalent to salivary duct carcinoma, which has an apocrine phenotype. Invasive CPA is often accompanied by non-invasive or in situ carcinoma, an observation that suggests the presence of precursor lesions. The aim of this study was to identify candidate precursor lesions of CPA within pleomorphic adenoma (PA). Eleven resected cases of CPA with residual PA and 17 cases of PA with atypical changes were subjected to immunohistochemistry (IHC) for p53, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), pleomorphic adenoma gene 1, gross cystic disease fluid protein-15 (GCDFP-15), and anti-mitochondrial antibody. Invasive or in situ carcinoma cells in all CPAs were positive for AR, GCDFP-15, and HER2. Atypical foci in PAs corresponded to either apocrine or oncocytic changes on the basis of their reactivity to AR, GCDFP-15, and anti-mitochondrial antibody. Atypical cells in PAs surrounding CPAs had an apocrine phenotype without HER2 expression. Our study identified frequent apocrine changes in residual PAs in CPA cases, suggesting a possible precursor role of apocrine changes. We recommend the use of HER2 IHC in atypical PAs, and that clinicians take HER2 positivity into serious consideration.

Lymph node ratio-based prognostic model for risk stratification and individualized adjuvant therapy for postoperative major salivary duct carcinoma.

To investigate the value of lymph node ratio (LNR) for postoperative major salivary duct carcinoma (MSDC) and to establish a model for prognosis assessment and treatment optimization. Data of MSDC were retrieved in public database, and prognostic factors were identified by univariate and multivariate analyses. A nomogram and risk stratification system were constructed. Four hundred and eleven eligible patients were included (training cohort vs. validation cohort: 287: 124). LNR ≥0.09 was associated with worse overall survival (OS). Age at diagnosis, sex, T stage, and LNR were identified as prognostic factors and integrated into nomogram. Low-risk patients were found to have better OS than high-risk patients. Furthermore, postoperative radiotherapy (PORT) significantly improved OS in the high-risk subgroup, but chemotherapy did not confer a long-term survival benefit. A nomogram model integrating LNR could better assess postoperative prognosis and risk stratification in MSDC, and identify patients who might benefit from PORT to avoid overtreatment.

Salivary Duct Carcinoma Originated from the Inferior Turbinate: A Rare Case Report.

Salivary duct carcinoma (SDC) is an uncommon but highly aggressive tumor with a poor prognosis. SDC mainly arises from the major salivary glands, typically the parotid gland. Here, we report a rare case of sinonasal SDC in a 54-year-old male patient that might have originated from the inferior turbinate. The patient presented with left nasal congestion and rhinorrhea. Following an endoscopic intervention, the histopathological examination revealed a diagnosis of SDC, characterized by the formation of solid cancer nests and central comedo-type necrosis. Given the highly aggressive nature and unfavorable prognosis of SDC, it is essential to consider it as a differential diagnosis for unilateral nasal tumors.

Systemic therapy for salivary gland carcinoma

Systemic therapy for salivary gland carcinoma (SGC) is indicated for recurrent and/or metastatic (RM) disease. The background, goals of therapy, organ function, symptomatic or a symptomatic, and histopathology should be considered in each case. Adenoid cystic carcinoma with only lung metastasis often progresses slowly and many cases are followed up without therapy, whereas salivary duct carcinoma, adenocarcinoma NOS, or adenoid cystic carcinoma with multiple metastases, including lung, liver, and bone, often require the early introduction of systemic therapy.

Immunohistochemical Expression Of Human Epidermal Growth Factor Receptor-2 (Her-2) In Common Salivary Gland Carcinomas.

Carcinomas of the salivary gland are known to be aggressive in nature, making them difficult to manage. The therapeutic options offered include excision of the gland (maxillectomy in cases of palatal tumours), with or without lymph node dissection, proceeded with radiotherapy. Chemotherapy has not produced promising outcomes and has a minimal impact as a therapeutic alternative. Targeted therapy against human epidermal growth factor receptor 2 (HER-2), which is a commonly used treatment modality for their mammary analogues, is not being offered to these patients since scant literature is available showing its usefulness and no promising evidence is present regarding their efficacy and efficiency in such cases. The study aimed to evaluate and quantify the immunohistochemical expression of HER-2 in cases of adenoid cystic carcinoma (AdCC), mucoepidermoid carcinoma (MEC) and salivary duct carcinoma (SDC), which are analogues of similar tumours arising in breast tissue. A retrospective, cross-sectional study was carried out in the department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, duration of which was six months. A total of 45 cases (15 of each tumour) were taken, and sampled using non-probability convenience technique. The immunohistochemical marker, monoclonal HER-2 antibody (Leica microsystem Germany) was applied on appropriate blocks of all included cases. The staining pattern and intensity were recorded after visualizing the slides under a light microscope. Seven cases of salivary duct carcinoma and a single case of mucoepidermoid carcinoma expressed positivity for HER-2, while no expression could be seen in the case of adenoid cystic carcinoma. A statistically significant difference was seen when HER-2 expression was compared among the aforementioned tumours. The use of targeted therapy against HER-2 is limited to patients of salivary duct carcinoma and a fraction of patients suffering from mucoepidermoid carcinoma.

Abstract CT165: Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid cystic carcinoma (ACC) of all anatomic sites of origin and other malignant salivary gland tumors

Abstract Introduction: Dual checkpoint inhibitor therapy with nivolumab and ipilimumab has been FDA-approved for a number of different cancers including melanoma, recurrent NSCLC, and hepatocellular carcinoma. However, their role in the treatment of ACC and other salivary gland carcinomas is not well established. Methods: We performed a Simon’s two-stage prospective single-institution phase II clinical trial of nivolumab (240 mg intravenously every 2 weeks for 16 weeks, then 480 mg every 4 weeks) with ipilimumab (1 mg/kg intravenously every 6 weeks), both of which were provided until intolerable toxicity or disease progression. Two cohorts were analyzed: patients with metastatic/recurrent ACC and patients with other salivary gland cancers. The primary endpoint was median progression-free survival (PFS) based on RECIST and immune-related RECIST (irRECIST) criteria; secondary endpoints were overall response rate (ORR), overall survival (OS), and toxicity. Results: Patients with ACC (n=19) and other salivary gland carcinomas (total n=5; parotid gland adenocarcinoma (n=3), salivary duct carcinoma (n=1), and myoepithelial carcinoma (n=1)) were enrolled between May 2017 and July 2019. Among the patients with ACC, the median OS was 30.0 months (95% confidence interval (CI) 15.3 months to not reached), the median PFS was 8.3 months (95% CI 5.5 - 30.0 months), and the disease control rate (DCR) was 53% (10/19). The ORR in the ACC group was 5% (CR 0%, n=0; confirmed PR 5%, n=1) using both RECIST and irRECIST criteria, with one patient having continued stable disease at the time of trial conclusion. In the salivary gland tumor cohort, the median OS was 10.4 months (95% CI 6.21 months to not reached), the median PFS time was 6.21 months (95% CI 2.83 months to not reached), and the DCR was 40% (2/5). The ORR in this cohort was 0% using both RECIST and irRECIST criteria. Across both cohorts, platelet counts above the joint cohort’s median were significantly associated with better OS (p=0.032) and PFS (p=0.046). Additionally, although not significant, there was a trend for improved OS and PFS among patients with neutrophil-to-lymphocyte ratios >5 (OS p=0.42, PFS p=0.25) and above median neutrophil counts (OS p=0.24, PFS p=0.18). Four patients with ACC underwent circulating tumor DNA sequencing, resulting in the identification of two MYB-NFIB translocations, one NOTCH1 Cys1383 frameshift mutation, one MTOR N1760K mutation, and one PDGFRA copy number gain. Common immune-related toxicities include fatigue (54%), lymphocytopenia (46%), and anemia (42%) with lymphocytopenia being the most common grade III/IV adverse event. Conclusion: In patients with recurrent or metastatic ACC and other salivary gland neoplasms, combination nivolumab with ipilimumab resulted in moderate disease control. Further studies are warranted to validate our findings. Citation Format: Young Kwang Chae, Richard Duan, Liam Il-Young Chung, Youjin Oh, Maria Matsangou, Mark Agulnik, Victoria Villaflor, Devalingam Mahalingam. Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid cystic carcinoma (ACC) of all anatomic sites of origin and other malignant salivary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT165.

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma

The advent of next-generation sequencing (NGS) has allowed for the identification of novel therapeutic targets for patients with uncommon cancers. It is well known that fusion translocations are potent driver of cancer pathogenesis and can render tumors exquisitely sensitive to matching targeted therapies. Here we describe a patient with ALK-fusion positive widely metastatic salivary ductal carcinoma, who achieved a durable complete response from alectinib, a potent and specific ALK tyrosine kinase inhibitor. This case serves as another reminder that ALK-fusions can be targeted regardless of histology and can afford patients dramatic and durable benefit. It also emphasizes the need for insurance coverage for such beneficial therapies. While ALK fusions are exceedingly rare in salivary ductal carcinoma, the presence of multiple other targetable aberrations supports the recommendation for universal NGS testing for such tumors.

Abstract 5563: Androgen receptor (AR) is frequently found in human cancers and inversely linked to patient outcome in breast and renal cell carcinomas

Abstract Background: Androgen receptor (AR) is a nuclear transcription regulator which mediates the growths stimulating effect of androgens. Inhibition of AR signaling is the most important first line therapy in prostate cancer. Clinical trials are ongoing for molecularly defined subsets of breast cancers expressing AR. In surgical pathology, AR immunohistochemistry is used as a marker for prostate cancer. Design: To comprehensively determine AR expression in normal and neoplastic tissues, a tissue microarray containing 18,234 samples from 141 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: AR positivity was found in 116 of 141 tumor categories, and 66 of these tumor categories contained at least one case with strong AR staining. AR positivity was most seen in different categories of prostate cancer (87.8-100%), various subtypes of breast cancer (34.3-94.9%) and ovarian cancers (48.7-97.1%), in endometrial cancers (53-61.1%), salivary duct carcinomas (70%), teratomas (60%), renal cell carcinomas (41.8-62.7%), urinary bladder cancers (43.2-48.7%), granular cell tumors (40.7%), leiomyosarcomas (33.3%), gastrointestinal stroma tumors (31.1%) and urothelial carcinomas of the kidney pelvis (30.4%). Seventy-seven additional tumor types showed AR expression in up to 30% of the analyzed samples, but AR expression was typically only weak in these tumors. Among 1,430 evaluable invasive breast carcinomas of no special type (NST), absent or low AR immunostaining was significantly linked to high BRE grade (p<0.0001), advanced pT stage (p<0.0001), presence of nodal and distant metastasis (p<0.0001 each), HER2 overexpression (p=0.005), reduced estrogen and progesterone receptor expression (p<0.0001 each), triple negative status (p<0.0001) and shortened patient survival (p=0.0024). Among 1,149 clear cell renal cell cancers (RCC), low AR immunostaining was linked to high ISUP, Fuhrman and Thoenes grades (p<0.0001 each), high UICC and pT stage (p<0.0001 each), presence of distant metastases (p=0.0075), and reduced time to recurrence (p=0.0007), overall survival (p=0.0097) and tumor-specific survival (p=0.0129). In 297 papillary RCC, low AR staining was associated with high ISUP grade (p=0.0179), advanced pT stage (p=0.0055) and nodal metastasis (p=0.0044). Low AR expression was linked to invasive growth (p<0.0001) and nodal metastasis in urothelial carcinoma (p=0.0052). Conclusion: The results of our study demonstrate AR expression in a wide range of cancers. AR expression occurs most frequent in cancers of the prostate, breast, and ovary, but can be found in many types of non-prostate and non-gynecological neoplasms. The poor prognosis of breast and kidney cancers with reduced AR expression argues against a tumor promoting role of AR in these tumor types. Citation Format: Florian Viehweger, David Dum, Anne Menz, Ria Uhlig, Andrea Hinsch, Doris Höflmayer, Tim Mandelkow, Christoph Fraune, Christian Bernreuther, Patrick Lebok, Sören Weidemann, Guido Sauter, Maximilian Lennartz, Frank Jacobsen, Till S. Clauditz, Till Krech, Andreas H. Marx, Ronald Simon, Stefan Steurer, Eike Burandt, Sarah Minner. Androgen receptor (AR) is frequently found in human cancers and inversely linked to patient outcome in breast and renal cell carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5563.

Primary salivary gland tumors from a pathology perspective : Morphomolecular peculiarities and diagnostic and therapeutic challenges

Similar to tumors of other organs, salivary gland neoplasms were historically viewed as asingle neoplastic entity and mostly treated as such. Accordingly, only the clinical tumor stage, and not the histological subtype, was considered to be of significant prognostic impact. However, over the years, several distinct sub-entities have been characterized based on morphological features, such as adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma, and salivary duct carcinoma. Most importantly, the nosology of salivary gland carcinomas has undergone adynamic "splitting" on the basis of morphological, immunophenotypic, and molecular characteristics, so that 21independent carcinomas are now listed in the current World Health Organization (WHO) classification. Moreover, it has become evident that splitting of these carcinoma subtypes no longer represents a"pathologist's hobby," but carries significant prognostic and therapeutic relevance for optimized cancer surgery and potentially systemic therapy. The current review summarizes the major features of salivary gland tumors, both benign and malignant, and gives an account of their classification systems and genetic profiles.

Clinicopathologic Factors and Their Association with Outcomes of Salivary Duct Carcinoma: A Multicenter Experience

This series reports long-term clinical outcomes of patients with salivary duct carcinoma (SDC), which is associated with a poor prognosis. Eighty-nine patients with SDC were treated with curative intent from February 5, 1971, through September 15, 2018. Kaplan-Meier and competing risk analyses were used to estimate locoregional control, distant metastasis-free survival (DMFS), progression-free survival, and overall survival (OS). Cox regression analyses of disease and treatment characteristics were performed to discover predictors of locoregional control, DMFS, and OS. Median follow-up was 44.1 months (range, 0.23-356.67). The median age at diagnosis was 66 years (interquartile range, 57-75). Curative surgery followed by adjuvant radiation therapy was performed in 73 patients (82%). Chemotherapy was delivered in 26 patients (29.2%). The 5-year local recurrence and distant metastasis rates were 27% and 44%, respectively, with death as a competing risk. Distant metastasis was associated with lymph node-positive disease (hazard ratio [HR], 3.16; 95% confidence interval [CI], 1.38-7.23; P=.006), stage IV disease (HR, 4.78; 95% CI, 1.14-20.11; P=.033), perineural invasion (HR, 4.56; 95% CI, 1.74-11.97; P=.002), and positive margins (HR, 9.06; 95% CI, 3.88-21.14; P < .001). Median OS was 4.84 years (95% CI, 3.54-7.02). The 5-year OS was 42%. Reduced OS was associated with lymphovascular space invasion (HR, 3.49; 95% CI, 1.2-10.1; P=.022), perineural invasion (HR, 2.05; 95% CI, 1.06-3.97; P=.033), positive margins (HR, 2.7; 95% CI, 1.3-5.6; P=.011), N2 disease (HR, 1.88; 95% CI, 1.03-3.43; P=.04), and N3 disease (HR, 11.76; 95% CI, 3.19-43.3; P < .001). In this single-institution, multicenter retrospective study, the 5-year survival was 42% in patients with SDC. Lymphovascular space invasion, lymph node involvement, and higher staging at diagnosis were associated with lower DMFS and OS.

6P RC48-ADC for metastatic salivary duct carcinoma with HER2 expression: A single-center retrospective study

6P RC48-ADC for metastatic salivary duct carcinoma with HER2 expression: A single-center retrospective study

25P RC48-ADC for metastatic salivary duct carcinoma with HER2-expression: A single-center retrospective study

25P RC48-ADC for metastatic salivary duct carcinoma with HER2-expression: A single-center retrospective study

Utility of Elective Neck Dissection in Clinically Node-Negative Parotid Malignancy.

We sought to investigate the utility of elective neck dissection (END) in clinically node-negative parotid malignancy through the evaluation of factors that are associated with receiving END and survival analysis of patients who received END. Retrospective cohort database study. The National Cancer Database (NCDB). The NCDB was used to extract patients with clinically node-negative parotid malignancy. END was defined as having 5or more lymph nodes examined pathologically, as previously defined in the literature. Univariate and multivariate analyses were used to compare predictors of receiving END, rates of occult metastasis, and survival. Of the 9405 included patients, 3396 (36.1%) underwent an END. END was most frequently performed for squamous cell carcinoma (SCC) and salivary duct histology. All other histologies were significantly less likely to undergo END compared to SCC (p < .05). Salivary ductal carcinoma and adenocarcinoma had the greatest rates of occult node disease (39.8% and 30.0%, respectively), followed by SCC (29.8%). Kaplan-Meier survival analysis showed a statistically significant increase in 5-year overall survival in patients who received END with poorly differentiated mucoepidermoid (56.2% vs 48.5%, p = .004) along with moderately and poorly differentiated SCC (43.2% vs 34.9%, p = .002; 48.9% vs 36.2%, p < .001, respectively). Histological classification is a benchmark for determining which patients should receive an END. We demonstrated an increase in overall survival in patients who undergo END with poorly differentiated tumors of mucoepidermoid and SCC histology. As such, histology should be considered along with clinical T-stage and rate of occult nodal metastasis to determine eligibility for END.