Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma

Theresa Guo; Fernando Zamuner; Stephanie Ting; Liam Chen; Lisa Rooper; Pablo Tamayo; Carole Fakhry; Daria Gaykalova; Ranee Mehra

doi:10.3389/fonc.2024.1336577

Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma

Front Oncol. 2024 Mar 5:14:1336577. doi: 10.3389/fonc.2024.1336577. eCollection 2024.

Authors

Theresa Guo¹, Fernando Zamuner², Stephanie Ting³, Liam Chen⁴, Lisa Rooper⁵, Pablo Tamayo³, Carole Fakhry², Daria Gaykalova^{6

7

8

9}, Ranee Mehra⁷

Affiliations

¹ Department of Otolaryngology, Moores Cancer Center, University of California, San Diego, San Diego, CA, United States.
² Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States.
³ Department of Medicine, Division of Hematology-Oncology, University of California, San Diego, San Diego, CA, United States.
⁴ Division of Neuropathology, Department of Pathology, University of Minnesota Medical School, Minneapolis, MN, United States.
⁵ Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, United States.
⁶ Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, United States.
⁷ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States.
⁸ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States.
⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.

Abstract

Introduction: Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy.

Methods: Patients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors.

Results: Ten patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples.

Conclusion: Chemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

Keywords: HPV; genomics; oropharyngeal squamous cell carcinoma; persistent disease; platinum resistance; treatment resistance.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Gleiberman Head & Neck Cancer Early Career Fellowship (TG), 1KL2TR001444 KL2 Training Grant (TG), RSG-21-020-01-MPC from the American Cancer Society (DG), and R01DE027809 from the National Institute of Health (DG).