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.PIK3 CA 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 PIK3 CA 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 PIK3 CA and RAS mutations predicted cetuximab resistance among HNSCC patients in the firstline R/M setting,whereas loss of PTEN protein expression predicted resistance to cetuximab when combined to radiotherapy.