Steven Doerstling1, David Winski2, Evangelia Katsoulakis3, Pankaj Agarwal4, Pradeep J Poonnen4,5,6, Jane L Snowdon7, Gretchen P Jackson8,9, Dilhan Weeraratne7, Michael J Kelley4,5,6, Vishal Vashistha10,11. 1. Duke University School of Medicine, Durham, NC, USA. 2. Veterans Affairs Boston Healthcare System, Jamaica Plan Campus, Boston, MA, USA. 3. Department of Radiation Oncology, James A. Haley Veterans Affairs Healthcare System, Tampa, FL, USA. 4. Department of Veterans Affairs, National Oncology Program, Durham, NC, USA. 5. Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA. 6. Division of Hematology and Oncology, Durham Veterans Affairs Medical Center, Durham, NC, USA. 7. IBM Watson Health, Cambridge, MA, USA. 8. Intuitive Surgical, Sunnyvale, CA, USA. 9. Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. 10. Section of Hematology and Oncology, Raymond G. Murphy New Mexico Veterans Affairs Medical Center, Albuquerque, NM, 87108, USA. vishal.vashistha@va.gov. 11. University of New Mexico Cancer, Albuquerque, New Mexico, USA. vishal.vashistha@va.gov.
Abstract
BACKGROUND: Patients with advanced head and neck squamous cell carcinoma (HNSCC) associated with human papillomavirus (HPV) demonstrate favorable clinical outcomes compared to patients bearing HPV-negative HNSCC. We sought to characterize the association between HPV status and mutational profiles among patients served by the Veterans Health Administration (VHA). METHODS: We performed a retrospective analysis of all Veterans with primary HNSCC tumors who underwent next-generation sequencing (NGS) through the VHA's National Precision Oncology Program between July 2016 and February 2019. HPV status was determined by clinical pathology reports of p16 immunohistochemical staining; gene variant pathogenicity was classified using OncoKB, an online precision oncology knowledge database, and mutation frequencies were compared using Fisher's exact test. RESULTS: A total of 79 patients met inclusion criteria, of which 48 (60.8%) had p16-positive tumors. Patients with p16-negative HNSCC were more likely to have mutations in TP53 (p < 0.0001), and a trend towards increased mutation frequency was observed within NOTCH1 (p = 0.032) and within the composite CDK/Rb pathway (p = 0.065). Mutations in KRAS, NRAS, HRAS, and FBXW7 were exclusively identified within p16-positive tumors, and a trend towards increased frequency was observed within the PI3K pathway (p = 0.051). No difference in overall mutational burden was observed between the two groups. CONCLUSIONS: In accordance with the previous studies, no clear molecular basis for improved prognosis among patients harboring HPV-positive disease has been elucidated. Though no targeted therapies are approved based upon HPV-status, current efforts to trial PI3K inhibitors and mTOR inhibitors across patients with HPV-positive disease bear genomic rationale based upon the current findings.
BACKGROUND: Patients with advanced head and neck squamous cell carcinoma (HNSCC) associated with human papillomavirus (HPV) demonstrate favorable clinical outcomes compared to patients bearing HPV-negative HNSCC. We sought to characterize the association between HPV status and mutational profiles among patients served by the Veterans Health Administration (VHA). METHODS: We performed a retrospective analysis of all Veterans with primary HNSCC tumors who underwent next-generation sequencing (NGS) through the VHA's National Precision Oncology Program between July 2016 and February 2019. HPV status was determined by clinical pathology reports of p16 immunohistochemical staining; gene variant pathogenicity was classified using OncoKB, an online precision oncology knowledge database, and mutation frequencies were compared using Fisher's exact test. RESULTS: A total of 79 patients met inclusion criteria, of which 48 (60.8%) had p16-positive tumors. Patients with p16-negative HNSCC were more likely to have mutations in TP53 (p < 0.0001), and a trend towards increased mutation frequency was observed within NOTCH1 (p = 0.032) and within the composite CDK/Rb pathway (p = 0.065). Mutations in KRAS, NRAS, HRAS, and FBXW7 were exclusively identified within p16-positive tumors, and a trend towards increased frequency was observed within the PI3K pathway (p = 0.051). No difference in overall mutational burden was observed between the two groups. CONCLUSIONS: In accordance with the previous studies, no clear molecular basis for improved prognosis among patients harboring HPV-positive disease has been elucidated. Though no targeted therapies are approved based upon HPV-status, current efforts to trial PI3K inhibitors and mTOR inhibitors across patients with HPV-positive disease bear genomic rationale based upon the current findings.
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