Only a minority of head and neck squamous cell carcinoma (HNSCC) patients (pts) respond to targeted agents acting on epidermal growth factor pathway. We investigated the changes of gene expression profiles in 2 preoperative window of opportunity trials, to allow a further investigation in mechanisms of response.
Thirty and 20 pts with similar characteristics were treated for 2 weeks before surgery with afatinib (EORTC 90111-24111 NOCI HNCG trial, Ann Oncology 2017) and cetuximab (Schmitz S, Ann Oncology 2013), respectively. The gene expression profile obtained by microarray platform was compared by a paired analysis pre and post treatment. Gene sets were defined according to GSEA and only sets with q-value FDR < 0.05 differences were considered. Clinical response was analysed according to primary endpoint of the trials (FDG-PET response).
Pre- and post-targeted treatment paired histological samples from 20 and 15 pts were evaluable for gene expression, from afatinib and cetuximab series, respectively. The following gene sets were commonly downregulated by the treatment: G2M checkpoint, MYC and E2F targets and MTORC. On the opposite, the gene sets which resulted upregulated were: angiogenesis, epithelial-mesenchymal transition, inflammatory response and NOTCH signalling. A substantial overlapping of molecular alteration between the 2 series has been observed, thus allowing a further meta-analysis combining the 2 datasets to analyse profiles associated to response. Preliminary data in afatinib series showed a strong downregulation of hypoxia gene signature only in responding pts.
In 2 independent studies with afatinib and cetuximab in window of opportunity setting, we observed similar molecular alterations induced by the drugs. Further insights in the pathways involved in response to both drugs are ongoing.
Clinical trial identification
Legal entity responsible for the study
AIRC and Italian Ministry of Health.
P. Bossi: Advisory Board: Merck Serono. J.-P. Machiels: Advisory board: Boerhingher-Ingelheim. L.F. Licitra: Advisory board and research supports: Merck Serono, Boehringer Ingelheim. All other authors have declared no conflicts of interest.