PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma.

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.

Biomarker driven treatment of head and neck squamous cell cancer.

ABSTRACT: 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.