Basal subtype is predictive for response to cetuximab treatment in patient-derived xenografts of squamous cell head and neck cancer

Abstract

Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient-derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t-test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient-derived xenografts.

The Essential Factors of Establishing Patient-derived Tumor Model

“…PDX engrafted was 21.1 months in comparison to no engraftment with 28.4 months, suggesting a relatively short survival if the tumor grew on mice [21]. Later tumor stage indicates a poor prognosis for overall survival (OS) and disease-free survival (DFS), that is to say, tumor cells are more aggressive and metastatic, which contribute to engraft successfully.…”

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“…We established a panel of HPV-positive (n = 10) and HPV-negative (n = 57) PDX models of HNSCC as described previously [17,18]. In the present study, a total of thirty-three PDX models of HNSCC were used for evaluation of the in vivo efficacy of copanlisib as monotherapy and in combination with cetuximab.…”

“…Tumor RNA derived from a PDX in the control group was extracted and analyzed on gene expression array as described previously [17]. In brief, RNA from the vehicle-treated control tumors was extracted using Qiagen RNeasy Kit according to the manufacturer's protocol.…”

Therapeutic Implications of the Genetic Landscape of Head and Neck Cancer

“…The six subtypes exhibit predicted differences in sensitivities to drugs in clinical use or under preclinical investigation for HNSCC, including paclitaxel, rapamycin, afatinib/pan-EGFR inhibitor, Nutlin3a, and Z-LLNle-CHO 49 . A recent study of twenty-eight HNSCC patient-derived xenografts (PDXs) distributed over three gene expression subtypes - mesenchymal/inflamed, basal, and classical - were subjected to treatment with various chemotherapy agents, including cetuximab 50 . The basal subtype strongly correlated with response to cetuximab whereas the mesenchymal subtype was cetuximab resistant 50 .…”