Biomarkers of cetuximab resistance in patients with head and neck squamous cell carcinoma

Objective: In patients with head and neck squamous cell carcinoma (HNSCC), cetuximab [a monoclonal antibody targeting epidermal growth factor receptor (EGFR)] has been shown to improve overall survival when combined with radiotherapy in the locally advanced setting or with chemotherapy in first-line recurrent and/or metastatic (R/M) setting, respectively. While biomarkers of resistance to cetuximab have been identified in metastatic colorectal cancer, no biomarkers of efficacy have been identified in HNSCC. Here, we aimed to identify biomarkers of cetuximab sensitivity/resistance in HNSCC. Methods: HNSCC patients treated with cetuximab at the Curie Institute, for whom complete clinicopathological data and formalin-fixed paraffin-embedded (FFPE) tumor tissue collected before cetuximab treatment were available, were included. Immunohistochemistry analyses of PTEN and EGFR were performed to assess protein expression levels. PIK3CA and H/N/KRAS mutations were analyzed using high-resolution melting (HRM) and Sanger sequencing. We evaluated the predictive value of these alterations in terms of progression-free survival (PFS). Results: Hot spot activating PIK3CA and KRAS/HRAS mutations were associated with poor PFS among HNSCC patients treated with cetuximab in the first-line R/M setting, but not among HNSCC patients treated with cetuximab in combination with radiotherapy. Loss of PTEN protein expression had a negative predictive value among HNSCC patients treated with cetuximab and radiotherapy. High EGFR expression did not predict cetuximab sensitivity in our patient population. Conclusions: Hot spot activating PIK3CA and RAS mutations predicted cetuximab resistance among HNSCC patients in the first-line R/M setting, whereas loss of PTEN protein expression predicted resistance to cetuximab when combined to radiotherapy.