Survival association of PIK3CA in HPV-driven head and neck squamous cell carcinoma (HNSCC).

6056 Background: Across many solid tumor malignancies, including head and neck squamous cell carcinoma (HNSCC), clinical trial data has supported the integration of PD1 Immune Checkpoint Inhibitors (ICIs) into treatment algorithms; however, durable response to single agent therapy occurs in only a fraction of patients. Thus, there is a great need to understand the molecular underpinnings of response and resistance mechanisms. PIK3CA mutation is a common driver of HPV+ mediated malignancy. We sought to understand the prevalence and clinical impact of PIK3CA mutation in HPV+ and HPV- cancer by applying a multi-omics approach to a large, clinically appended dataset. Methods: HNSCC (N = 1901) patient who underwent DNA (592-gene or whole exome) and RNA (whole transcriptome) sequencing at Caris Life Sciences (Phoenix, AZ) was queried to identify HPV+ and HPV- HNSCC cohort. Tumor mutational burden (TMB) was measured by totaling all somatic mutations (mt) per tumor (TMB-H: > 10 mt/MB). Real-world overall survival (rwOS) was obtained from insurance claims data, calculated from either time of biopsy (OS) or start of immunotherapy ( IO OS) to last contact, or time on ICI ( IO TOT). Mann-Whitney U and X 2 /Fisher-Exact tests were applied, with p -values adjusted ( p < .05). Results: Compared to HPV- samples, PIK3CA mutation was highly associated with HPV+ primary (28.5% vs 11.4%, p <0.01) and metastatic (23.8% vs 11.2%, p<0.01) lesions. The prevalence of TMB-H was significantly higher in both HPV+ (30.7% vs 7.9%, p<0.01) and HPV- (30.7% vs 18.2%, p<0.01) with PIK3CA mutation compared to WT. HPV- disease showed significantly worse survival as expected (HR = 0.63, p<0.001), while PIK3CA mut /wt status was not associated with differences in OS among HPV+ (HR = 1.05, p = 0.78) or HPV- cohorts (HR = 1.11, p = 0.44). However, irrespective of tumor site and metastatic status, mutPIK3CA HPV+ patients’ trend towards an increased IO OS (HR = 0.64, p =0.176) and increased IO TOT compared to wtPIK3CA patients (HR = 0.72, p = 0.073). In contrast, mutPIK3CA HPV- HNSCC showed worse IO OS (HR = 1.65, p<0.001) and a trend toward decreased IO TOT (HR = 1.20, p=0.248) compared to wtPIK3C patients. Conclusions: Data from this cohort indicate potential survival association for PIK3CA mutation, with differing impact in HPV+ and HPV- HNSCC. Further research is needed to explore the mechanism underlying these findings and identify other molecular factors that might contribute to the observed outcomes.