Introduction Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab. Methods Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing. Results For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008). Conclusion Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.

Treatment modalities of head and neck squamous cell cancer include surgery, radiation, chemotherapy, targeted agents and immune checkpoint inhibition. Treatment is often toxic and can affect long-term function and quality of life. In this context, identification of biomarker data that can help tailor therapy on an individualized basis and reduce treatment-related toxicity would be highly beneficial. A variety of predictive biomarkers have been discovered and are already utilized in clinical practice, while many more are being explored. We will review p16 overexpression as a surrogate biomarker in HPV-associated head and neck cancer and plasma EBV DNA as a biomarker in nasopharyngeal carcinoma, the two established biomarkers currently utilized in clinical practice. We will also examine novel predictive biomarkers that are in clinical development and may shape the future landscape of targeted head and neck cancer therapy. These emerging biomarkers include the tyrosine kinases and their signaling pathway, immune checkpoint biomarkers, tumor suppressor abnormalities, and molecular predictors of hypoxia-targeted therapy. We will also look at futuristic biomarkers including detection of circulating DNA from clinical specimens and rapid tumor profiling. We will highlight the ongoing effort that will see a shift from prognostic to predictive biomarker development in head and neck cancer with the goal of delivering individualized cancer therapy. Trial registration: N/A.

e17520 Background: No biomarker of C resistance has been identified in HNSCC. PTEN loss is present in approximately 30% of HNSCC. Biomarker analysis of the E5397 study suggested that addition of C to cisplatin in R/M HNSCC improves PFS in PTEN high/PIK3CA wild type patients but not those with PTEN loss or PIK3CA mutation. We hypothesized that PTEN testing may aid patient (pt.) selection for C therapy in HNSCC. Methods: MCC15780 was a phase II randomized trial of C plus sorafenib or C plus placebo in R/M HNSCC. 52/56 pts. in this study received C. PTEN analysis using AQUA as previously described was performed on tumor from 38 pts. Automated image capture was performed with HistoRx PM-2000 using the AQUAsition software. AQUA PTEN cut off determined as 1177 based on the first tertile.Fisher’s exact test used to compare low and high expression group. Event-time distributions estimated by Kaplan-Meier and compared using log-rank. Stratified Cox proportional hazards models used to estimate hazard ratios (HR) and test for significance for OS and PFS. All p-values are two-sided. A level of p < 0.05 is considered statistically significant. Results: 12/37 (32%) tumors were PTEN low. There was statistically significant improvement in PFS in PTEN high tumors compared to PTEN low tumors (HR (high/low) =0.33, 95% CI= (0.14, 0.75), p=0.008); and this remains significant after adjusting for age, sex, race, and ethnicity (HR (high/low) =0.27, 95% CI= (0.11, 0.67), p=0.004). Conclusions: PFS is significantly longer in PTEN high tumors compared to PTEN low tumors (HR=0.33, 95% CI= (0.14-0.75), p=0.008) in patients with R/M HNSCC treated with C. This finding remains significant after adjusting for age, sex, race, and ethnicity (HR=0.27, 95% CI= (0.11-0.67), p=0.004).This warrants PTEN analysis of specimens from larger cetuximab-based RCT. [Table: see text]