Mutational Landscape of Human Papillomavirus–Associated Oropharynx Squamous Cell Carcinoma in Patients Treated on a Phase 2 De-intensified Chemoradiation Trial

Abstract

Next-generation sequencing (NGS) technique was used to analyze the mutational landscape of a cohort of patients with favorable risk human papillomavirus (HPV)–associated OPSCC prospectively treated with de-intensified chemoradiation therapy. Patients with confirmed HPV- or p16-positive OPSCC, ≤10 pack-years smoking history or abstinent for the past 5 years, and ECOG performance status 0-1 were enrolled on a phase 2 de-intensification trial (NCT01530997). All patients were treated with intensity-modulated radiation therapy (RT) to a total dose of 60 Gy in 2 Gy fractions + concurrent weekly cisplatin (30 mg/m2) (patients with T0-T2 N0-N1 received RT only). A separate informed consent was obtained for the use of tumor samples from the initial biopsy specimen pretreatment to identify genetic aberrations of prognostic or therapeutic significance via a NGS assay protocol (NCT01457196). Targeted panel of >200 cancer-associated genes from tumor DNA were sequenced and filtered via an identical pipeline in reference to 20 non-malignant specimens. Forty-three patients were enrolled for NGS. Median age was 58; 81% of patients were male; and 53%, 35%, and 12% were never smoker, ≤10 pack-year smoker (PYS), and >10 PYS, respectively. Frequency of clinically relevant mutations are shown in the Table. Interestingly, mutations most commonly associated with HPV-negative tumors and tobacco use were present in a subset of tumors including FAT1 (20.9%), AJUBA (9.3%), FGFR1 (9.3%), CDKN2A (2.3%), and TP53 (2.3%). At a median follow-up of 16 months, 2 of the 43 patients had progression of disease. First patient (55 yo white male, T2N2b, ≤10 PYS, right lung recurrence) had paucity of notable mutations while the second patient (37 yo white female, T2N2b, never smoker, left neck recurrence) had multiple significant mutations including PIK3CA, CDKN2A, TP53, RB1, NOTCH3, MYCN, FBXW7, and FAT1. Our study confirms notable frequently mutated genes including PIK3A, NOTCH1, FGFR3, FBXW7, ZNF750, FAT1, KMT2C, and KMT2D in a cohort of favorable risk HPV-associated OPSCC. Better understanding of relevant genetic aberrations may aid patient selection for de-intensification and the development of predictive biomarkers in this favorable and increasing subset of OPSCC.Tabled 1Abstract 234Mechanism/pathwayGeneN (%)Cell cycleRB1 CDKN2A3 (7.0) 1 (2.3)Receptor tyrosine kinasesFGFR3 IGF1R FGFR1 FGFR28 (18.6) 4 (9.3) 4 (9.3) 1 (2.3)OncogenesMYCN KRAS3 (7.0) 2 (4.7)DifferentiationFBXW7 ZNF750 NOTCH111 (25.6) 10 (23.3) 9 (20.9)PI3K pathwayPIK3CA PIK3R113 (30.2) 1 (2.3)Immune evasionHLA-A TRAF3 B2M5 (11.6) 3 (7.0) 2 (4.7)Tumor suppressor geneKMT2D (MLL2) KMT2C (MLL3) FAT1 NF1 TP5316 (37.2) 12 (27.9) 9 (20.9) 3 (7.0) 1 (2.3) Open table in a new tab