3434 - Genomic Analysis of Clinical Outcomes in p16-Postive Oropharyngeal Cancer and Identification of Low Frequency High-Risk Mutations
Presenter(s)
M. H. Brown1, A. D. Thompson2, Y. Song3, S. S. Valluri4, D. Rajabi Abhari3, A. Shetty5, W. Mendes6, R. Mehra7, K. Hatten8, R. Taylor8, K. Moyer8, J. S. Wolf8, T. N. Tyer2, K. Steacy2, C. Eggleston1, C. Datnow-Martinez1, D. Gaykalova9, P. T. Tran10, M. J. Ferris1, and J. K. Molitoris1; 1Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 2Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, 3University of Maryland School of Medicine, Baltimore, MD, 4Univ of Maryland School of Medicine, Radiation Oncology, Baltimore, MD, 5Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine,, Baltimore, MD, 6University of Maryland School of Medicine, Baltimore, MD, USA, Baltimore, MD, 7University of Maryland Cancer Center, Baltimore, MD, 8Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, 9University of Maryland School of Medicine, BALTIMORE, MD, 10Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s):
Despite excellent overall response rates of p16+ oropharyngeal cancer (OPX) to radiation, there is a small cohort of tumors that fail. Identifying these cases would provide an opportunity to treat these patients differently. We sought to use genomic analysis of a cohort of patients with p16+ OPX to determine mutations suggestive of a high risk of early failure. This analysis was limited to early-stage disease to minimize confounding variables.Materials/Methods:
Next-generation sequencing (NGS) DNA profiling (648-gene panel) was performed on 54 tumor samples from patients with early-stage p16+ OPX, including 36 stage I and 18 stage II cases. Somatic pathogenic non-synonymous variants were identified using the ClinVar database. Genes with mutations in fewer than 3 patients were excluded from association testing to reduce instability from sparse events. Survival distributions for overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) were estimated using the Kaplan–Meier method and compared using the log-rank test.Results:
The median age at diagnosis was 63 years (41-75). The majority of patients were white (n=46) and male (n=48). 12 patients received upfront resection with adjuvant radiation and 42 received definitive chemoradiation. The ten most frequently mutated somatic genes were not significantly associated with overall survival (OS), progression-free survival (PFS), or recurrence-free survival (RFS). In contrast, somatic mutations in tumor suppressor genes, including TET2, SETD2, and CYLD, were associated with OS (p < 0.05), and SETD2 mutations were additionally associated with PFS (p=0.002). Several germline-mutated genes, including CREBBP, ERCC2, BUB1B, and KEL, were associated with PFS (p < 0.05). Furthermore, multiple DNA damage response (DDR)–related germline mutations, including ERCC2, BRCA2, ATM, FANCA, RAD51, RECQL4, CDH1, TMEM127, and XPC, were associated with RFS (p<0.05). There was no significant difference in outcomes among patients with smoking history (n=30) versus non-smokers (n=24).Conclusion:
To our knowledge, this is one of the largest outcomes based genomic analysis of de novo nonmetastatic p16+ OPX to date. Multiple high-risk mutations were identified but were not among the most common pathogenic mutations. Since this sample size is limited, these findings should be interpreted as exploratory and require validation in larger, independent cohorts. Nevertheless, the presence of low-frequency mutations associated with a high risk of post-radiation failure supports the paradigm that a small, molecularly definable subset of patients responds poorly to radiation therapy.