Nicole C. Schmitt

A 20-year review of 75 cases of salivary duct carcinoma

IMPORTANCE Salivary duct carcinoma is a rare, aggressive malignancy of the salivary glands. Owing to its rare nature, clinical data are limited, and only a few clinical studies comprise more than 50 patients. OBJECTIVE To review the University of Pittsburgh Medical Centers experience with salivary duct carcinoma over a 20-year period, focusing on demographics, presentation, treatment, and outcome. DESIGN, SETTING, AND PARTICIPANTS This investigation was a retrospective cohort study in a multihospital institution with tertiary referral. A pathology database was reviewed for all cases of histopathologically diagnosed salivary duct carcinoma from January 1, 1995, to October 20, 2014. Patients who were referrals for pathology review only and were never seen at the institution were excluded. In total, 75 study patients were identified. The electronic medical record was reviewed for details regarding demographics, presentation, treatment, and outcome, including overall survival (OS) and disease-free survival (DFS). This study was supplemented with a review of the institutions Head and Neck Oncology Database for further clinical details. MAIN OUTCOMES AND MEASURES Primary outcome measures consisted of OS and DFS. RESULTS The study sample comprised 75 participants with a mean age at diagnosis of 66.0 years (age range, 33-93 years), and 29% (n = 22) were female. Most primary tumors were from the parotid gland (83%), with the next most frequent site being the submandibular gland (12%). Overall, 41% of the cases were carcinoma ex pleomorphic adenoma. Rates of other histologic features included the following: perineural invasion (69%), extracapsular spread (58%), ERBB2 (formerly HER2) positivity (31%) (62% of those who were tested), and vascular invasion (61%). The median OS was 3.1 years, and the median DFS was 2.7 years. Univariate Kaplan-Meier survival analyses demonstrated that facial nerve sacrifice and extracapsular spread were associated with lower OS (2.38 vs 5.11 years and 2.29 vs 6.56 years, respectively) and DFS (2.4 vs 3.88 years and 1.44 vs 4.5 years, respectively). Although underpowered, multivariable analysis demonstrated significantly worse OS in patients with N2 and N3 disease (hazard ratio [HR] 8.42, 95% CI, 1.84-38.5) but did not show significantly worse DFS or OS for facial nerve sacrifice or extracapsular spread. There was no association between ERBB2 positivity and survival and no difference in survival between patients receiving radiation therapy vs radiation therapy plus chemotherapy. No patients had recurrence or distant metastasis after 5 disease-free years. CONCLUSIONS AND RELEVANCE Salivary duct carcinoma is an aggressive disease. A large number of cases in this review were carcinoma ex pleomorphic adenoma and had classic negative prognostic indicators, such as perineural invasion, vascular invasion, and extracapsular spread. ERBB2 positivity was not associated with any difference in survival. Facial nerve involvement appears to indicate worse prognosis, as does nodal stage higher than N1. Recurrence and metastasis after 5 years are rare.

Human papillomavirus 16 E6 antibodies are sensitive for human papillomavirus–driven oropharyngeal cancer and are associated with recurrence

Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus–driven oropharyngeal cancer (HPV‐OPC).

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

The combination of cisplatin chemotherapy with anti–PD-1/PD-L1 immunotherapy is under investigation in clinical trials. Optimal doses of cisplatin were found to enhance the antitumor immune response, which was further improved by adding anti–PD-1/PD-L1 immunotherapy. Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti–PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti–PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti–PD-L1/PD-1 therapy. Cancer Immunol Res; 5(12); 1141–51. ©2017 AACR.

Early T Stage Salivary Duct Carcinoma: Outcomes and Implications for Patient Counseling.

Salivary duct carcinoma (SDC) is a rare salivary malignancy that often presents at advanced stage. Outcomes of low T stage patients with SDC have not been previously examined in detail. We queried our institution’s cancer database and identified 28 patients with SDC in situ or T1/T2 SDC. A retrospective chart review was performed, followed by comparison of clinicopathologic features with N stage, disease-free survival, and overall survival. Patients tended to be male, in their sixties, with a high incidence of regional metastases, as in prior reports. Five-year disease-free and overall survival were 49%. Median disease-free survival was 3.24 years, and overall survival was 4.65 years. Parotid location, vascular invasion, facial nerve sacrifice, and extracapsular extension were associated with worse survival. This study provides practical information for counseling of patients who undergo surgery for a parotid mass and are found to have this aggressive malignancy.

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

Salivary duct carcinoma (SDC) is a rare, aggressive salivary malignancy that is often diagnosed at an advanced stage. Previously, little was known about outcomes of this disease due to its rarity. In the past several years, much has been learned about salivary duct carcinoma after publication of outcomes from several large single-institution series and national database searches. Recent studies of genomic alterations have helped elucidate the biology and pathogenesis of this aggressive disease. Here we review outcomes of the disease, effects of treatment, prognostic factors, and genomic alterations in SDC. Studies of targeted therapy and promising future directions are also discussed.

PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model

Immune checkpoint inhibition used in combination with standard cisplatin-based chemotherapy regimens is currently under evaluation in clinical trials for head and neck squamous cell carcinoma (HNSCC). The impact of anti–PD-1 therapy on cisplatin-induced ototoxicity and nephrotoxicity has not been established. Here we use a murine model of cisplatin-induced hearing loss to investigate the impact of anti–PD-1 immunotherapy on auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), serum creatinine, and hair cell and renal histology. We demonstrate only mild worsening of DPOAEs at 14.4 and 16 kHz as well as a mild increase in serum creatinine. Renal and hair cell histology as well as ABR measures were unchanged by PD-1 inhibition. Thus, our data suggest that the use of PD-1 inhibition in conjunction with cisplatin results in toxicities that are similar to those of cisplatin alone.

Antagonist of cIAP1/2 and XIAP enhances anti-tumor immunity when combined with radiation and PD-1 blockade in a syngeneic model of head and neck cancer

ABSTRACT Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNFα. Using syngeneic mouse models, ASTX660 showed additive anti-tumor activity with radiation therapy (XRT), cisplatin chemotherapy, and PD-1 blockade to significantly delay or eradicate MOC1 tumors. These combinations significantly increased CD8 + T cells and dendritic cells, as well as T cell activity. ASTX660 stimulated cytotoxic T lymphocyte (CTL) killing of MOC1 cells expressing ovalbumin. Early stages of CTL killing were predominantly mediated by perforin/granzyme B, whereas later stages were mediated by death ligands TNFα, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells in vivo revealed both types of immune cells to be important components of the complete anti-tumor response enhanced by ASTX660+XRT. These findings serve to inform future studies of IAP inhibitors and support the potential for future clinical trials investigating ASTX660 with XRT and immunotherapies like PD-1/PD-L1 blockade in HNSCC.

Radiation-Associated Sarcoma of the Neck: Case Series and Systematic Review

Introduction: Radiation-associated soft tissue sarcomas of the neck (RASN) constitute a rare and aggressive tumor type. Methods: A retrospective chart review at the authors’ institution revealed 3 patients with RASN. A systematic review of the literature was also conducted using MEDLINE, Ovid, the Cochrane Library, and Embase. Results: Patients within the authors’ institutional chart review presented from 6 to 26 years after neck radiation with neck masses. All patients underwent surgical resection with clear margins, and adjuvant radiation was offered when feasible. Patients had no evidence of disease at most recent follow-up. A total of 867 articles were screened for systematic review, revealing 9 articles detailing outcomes of RASN. Studies were small and heterogeneous, precluding pooled data. The importance of complete surgical extirpation was noted. Conclusions: Complete surgical resection appears to be the mainstay of therapy, but there are limited data on management and outcomes of patients with RASN.

Putting T cells to work—outsourcing neoantigen detection in head and neck cancers?

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/odi.12604 This article is protected by copyright. All rights reserved. Received Date : 21-Oct-2016 Accepted Date : 24-Oct-2016 Article type : Invited Commentary

Abstract 2637: Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma

Rationale: Cisplatin, which remains the most commonly used systemic drug for head and neck squamous cell carcinoma (HNSCC), reduces numbers of circulating immune cells. However, recent studies suggest that cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. We previously found that cisplatin increases expression of major histocompatibility (MHC) class I and programmed death ligand 1 (PD-L1) in HNSCC cell lines in vitro. Methods: In the current study, we investigated other components of the antigen processing machinery (APM) by flow cytometry following treatment with cisplatin. Using the syngeneic mouse oral cancer 1 (MOC1) model of HNSCC, we then investigated the effects of cisplatin and anti-PD-1 antibody, alone or in combination, on tumor growth and survival. Results: Using three different HNSCC cell lines, we found that levels of the APM components LMP2, ERp57 and calreticulin increased in all cell lines treated with cisplatin, whereas TAP1/2 increased dramatically only in one cisplatin-treated cell line with wildtype TP53 (UMSCC-74A). In MOC1 tumor-bearing mice, tumor growth was partially delayed by treatment with cisplatin and anti-PD-1 antibody alone and substantially delayed when these agents were given in combination, with resultant increased survival. Comparison of different treatment schedules suggested that concurrent administration is more effective than giving cisplatin one day prior to anti-PD-1 or giving anti-PD-1 one day prior to cisplatin. Conclusions: Despite upregulating PD-L1 on tumor cells and decreasing levels of circulating immune cells, cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. While no mice were cured with concurrent cisplatin and anti-PD-1 antibody, tumor growth was substantially delayed. These results suggest a rationale for combining cisplatin and anti-PD-1 monoclonal antibodies, perhaps with radiation or other therapies, in additional preclinical studies and clinical trials of HNSCC. Supported by NIDCD intramural project ZIA-DC-DC000090. Citation Format: Linda Tran, Clint T. Allen, So-Jin Park, Roy Xiao, Carter Van Waes, Nicole C. Schmitt. Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2637. doi:10.1158/1538-7445.AM2017-2637