Genomic Adjusted Radiation Dose (GARD) Predicts Overall Survival and Outperforms AJCC 8th Edition in Prognostication of HPV-Positive Oropharyngeal Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Treatment decision-making in oropharyngeal squamous cell carcinoma (OPSCC) includes clinical stage, HPV status, and smoking history. Despite improvements in staging with separation of HPV positive and negative OPSCC in AJCC 8^th edition (AJCC8), patients are largely treated with a uniform approach, with recent efforts on de-intensification in low-risk patients. We have previously shown, in a pooled analysis, that the genomic adjusted radiation dose (GARD) is predictive of radiation treatment benefit and can be used to guide dose selection. We hypothesize that GARD can be used to predict overall survival (OS) in HPV-positive OPSCC patients treated with radiotherapy (RT). <h3>Materials/Methods</h3> Gene expression profiles were analyzed for 234 formalin-fixed paraffin-embedded samples from HPV-positive OPSCC patients within an international, multi-institutional, prospective/retrospective observational study (Big Data and Models for Personalized Head and Neck Cancer Decision Support (BD2Decide, NCT02832102). GARD, a measure of the biological effect of RT, was calculated for each patient as previously described. In total, 203 patients received definitive treatment (chemoradiation or RT alone), and 31 patients received post-operative RT. Two RT dose fractionations were utilized for definitive cases (70 Gy in 35 fractions or 69.96 Gy in 33 fractions). Median RT dose was 70 Gy (mean 50.88-74) for definitive cases and 66 Gy (range 44-70) for post-operative cases. 29 patients received surgery and adjuvant chemoradiation, 14 received surgery and adjuvant RT, and 19 received RT alone. The median follow up was 46.2 months (95% CI, 41.2 to 50). Cox proportional hazards analyses were performed with GARD as a continuous variable and ROC analyses comparing the performance of GARD with AJCC8. <h3>Results</h3> Despite uniform radiation dose utilization, GARD showed significant heterogeneity (range 30-110), reflecting the underlying genomic differences in the cohort. On multivariate analysis, each unit increase in GARD was associated with an improvement in OS (HR= 0.97, 95% CI 0.94-1.0, p=0.040) compared to AJCC8 (HR=1.96, 95% CI 0.90-4.32, p=0.0952). ROC analysis for GARD at 24 months yielded an AUC of 75.6 (95% CI 61.8-89.4) compared with an AUC of 73.9 (95% CI 56.9-90.9) for AJCC8. GARD ≥64.97 was associated with improved OS (HR=0.29, p=0.005). <h3>Conclusion</h3> In this multi-institutional cohort of patients with HPV-positive OPSCC, GARD predicts OS as a continuous variable and outperforms AJCC8 in prognostication. We propose that GARD, which provides the first opportunity for genomic guided personalization of radiation dose, should be incorporated in the diagnostic workup of HPV-positive OPSCC patients and can be used to guide treatment decision making.