Abstract 4407: Clinicopathologic characteristics and mutational analysis of MYC amplified head and neck squamous cell carcinoma (HNSCC)
Authors: Cyberski Thomas , Singh Alka , Lingen Mark , Pearson Alexander , Agrawal Nishant , Izumchenko Evgeny , Rosenberg Ari 
Published: April 2023

Abstract
Amplification of MYC proto-oncogene is commonly found in many types of cancer, and frequently associated with poor clinical outcomes. Analysis of the TCGA-HNSCC dataset indicates that MYC amplification is estimated to be present in ~12% of HNSCC cases, and has a significant impact on patients’ median survival (32.2 vs 56.9 months for patients with wild-type MYC). While the association between MYC amplification and HNSCC progression was previously reported, its role in regulating mechanisms of acquired resistance to therapy remain under investigated. In this study, we seek to further characterize the clinicopathological features associated with MYC amplified HNSCC, and highlight the molecular changes that may contribute to acquired resistance to treatment.
Seven HNSCC patients with MYC amplification were identified by searching the Oncoplus database at the University of Chicago. A retrospective chart review was conducted to collect demographic and clinical data for each patient, and mutational landscape was characterized. In a single patient, MYC amplification was acquired following treatment with chemoimmunotherapy (nivolumab, carboplatin, paclitaxel), chemoradiation, and maintenance nivolumab resulting in rapidly progressive disease despite an initial response to therapy. RNA sequencing and immunohistochemical staining was performed to compare specimens collected before and after progression.
Seven patients were diagnosed with HNSCC and were found to have MYC amplification on molecular testing of their cancer between 2018 and 2021. Four were male, median age 61 (range 46-71), stage T2-4 (n=6), N2-3 (n=6), p16+ (n=2). All patients (n=7) developed recurrent and/or metastatic disease following primary therapy with locoregional recurrence (n=3), metastatic recurrence (n=2), or both (n=2). Median survival for the cohort was 3.1 years. Previous therapy included surgery (n=4), radiotherapy (n=7), chemotherapy (n=7), targeted therapy (n=4), and immunotherapy (n=4). The most common mutations co-occurring with MYC amplification were CDKN2A loss (n=5), TP53 loss (n=5), CCND1 amplification (n=2) and KDM6A loss (n=2). Acquisition of MYC amplification and acquired resistance to chemoimmunotherapy was associated with upregulation of glycolysis pathway, WNT/beta-catenin signaling, and significant changes to tumor microenvironment (TME) such as tumor infiltrating lymphocytes repertoire and PD1/PD-L1 expression levels.
Alongside the data from TCGA, the cases described in this study highlight the poor prognosis associated with MYC amplified HNSCC. While loss of function mutations in CDKN2A and TP53, upregulation of glycolysis pathway, and TME reprogramming may contribute to treatment resistance and secondary immune evasion, further studies in larger cohorts are warranted to develop therapies that target MYC mediated mechanisms of resistance in HNSCC.
Citation Format: Thomas Cyberski, Alka Singh, Mark Lingen, Alexander Pearson, Nishant Agrawal, Evgeny Izumchenko, Ari Rosenberg. Clinicopathologic characteristics and mutational analysis of MYC amplified head and neck squamous cell carcinoma (HNSCC). [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 4407.