Project 2: Optimizing patient selection and deintensified therapy for human papillomavirus positive (HPV+) oropharyngeal cancer (OPC)

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PROJECT SUMMARY – PROJECT 2 Human papillomavirus positive (HPV+) oropharynx cancer (OPC) is a national and global health issue. Because HPV+ OPC has very good survival outcomes, the long-term toxicity of current treatment, typically combined chemotherapy and radiation (CRT) is devastating. Trans-oral robotic surgery (TORS), a surgical technique pioneered by Dr. Ferris and others, has been studied to reduce toxicity of HPV+ OPC treatment, culminating in ECOG 3311, a prospective trial of TORS followed by risk-adapted adjuvant therapy depending on tumor and nodal pathology. Despite excellent survival in this trial (ASCO 2020, Abstract #6500), slightly over 30% of patients were found to have high risk neck disease (HRND), characterized by gross extranodal extension (ENE, >1mm) or ≥5 positive lymph nodes, which mandated the use of adjuvant, high dose CRT, an intensification of treatment where de-intensification is the goal. However, as ~70% of patients were candidates for de-intensification, interest remains high in TORS as a strategy, particularly if patients with HRND can be identified prior to surgery. To this end, and with the assistance of Core A and Core B we have identified 40 patients from ECOG 3311 enrolled from HCC (as the highest accruing site) and comprehensively genomically, transcriptomically and radiomically profiled their tumors. This preliminary data allowed us to generate a four- gene mutational signature present in ~80% of patients with HRND, with similar findings in the Head and Neck cohort from the Cancer Genome Atlas. Additionally, we observed a profound immune repression in tumors from patients with HRND. In this Project we expand our analysis to an additional 200 HPV+ OPC patients we have identified in the organ specific database (OSD in Core A) for which tissue is already available (Core B) and then validate our signature in over 200 additional tumors from ECOG 3311. Additionally, we plan to recapitulate the mutations from our signature, as well as others identified by our co-I Dr. Burtness, which appear to be associated with immune infiltrate in HPV+ OPC, in pre-clinical models to identify potential drivers of immune infiltrate. Finally, to address the management of HRND, we will conduct a clinical trial HCC 18-034 (PI: Ferris) designed for this SPORE project examining the combination of TORS, lower dose RT and anti-PD- 1 therapy in patients with HRND to improve toxicity and quality of life compared to chemoradiation in both a newly added control arm based on reviewer feedback as well as ECOG 3311. The effect of tumor mutation, immune infiltrate, and peripheral blood IFN signature on outcome in this trial will also be examined. Success of this project will produce: 1) a validated and immediately applicable predictive signature for HRND; 2) an explanation for the repressed immune infiltrate seen with HRND; 3) quality of life/toxicity comparisons and biologic correlatives from a novel deintensification trial in HRND.