Modulation of the peritumoral microenvironment by cetuximab:a window pre-operative study in patients with squamous cell carcinoma of the head and neck (SCCHN)

Background : Only a subset of SCCHN pts benefits from anti-EGFR mAbs. Trials with pre- and post-therapy tumor biopsies (windows studies) in treatment-naïve patients are crucial to better characterize the molecular pathways involved in treatment response or resistance. Methods : Cetuximab (C) (400mg/m2 first wk followed by 250mg/m2/wk) was given pre-operatively during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0) to 20 treatment-naïve SCCHN pts selected for primary curative surgery. As controls, 5 additional pts were included without C treatment but with the same requirements regarding biopsies and imaging. Tumour biopsies, FDG/PET, and CT were performed at diagnosis and surgery. The aims of the study were (i) safety, (ii) C activity by FDG-PET (Po = 0.10, P1 = 0.35, a = 0.05 and b= 0.10) and (iii) translational research. We compared pathologic changes in surgical specimens of the C group with control specimens and correlated these results with microarray analysis performed on paired biopsies in the C group. Results : C infusion given 24 hrs before surgery was safe. 90 % had a FDG-PET partial response (PR) (EORTC guideline) in the C group vs 0% in the controls. 52% had a ΔSUVmax decrease of >50%. In surgical specimens we detected modifications of the peritumoral environment. By immunochemistry, we found more fibrosis arranged in a compact manner in the C group than in the non-treated samples (histological score) (p = 0.04). Genome-wide expression analysis (Affymetrix HG U133 Plus 2.0) of the paired biopsies taken in the tumor center before and after C supports this histological observation. Results show a significant increase in expression (Student's T test p = 0.02; n = 20) of a previously published stroma signature (Finak et al., Breast Cancer Res 2006) after C. A trend was also observed between this stroma signature score and the fibrosis histological score. Conclusions : Pre-operative study with C is safe. Our findings suggest that C induces quantitative modifications in the microenvironment of the tumor. We are currently investigating other components of the peri-tumoral environment (inflammation and vascularization).

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Schmitz, S., Hamoir, M., Reychler, H., Magremanne, M., Weynand, B., Lhommel, R., Hanin, F.-X., Rommel, D., Michoux, N., & Machiels, J.-P. (2012). Modulation of the peritumoral microenvironment by cetuximab:a window pre-operative study in patients with squamous cell carcinoma of the head and neck (SCCHN). Annals of Oncology, 23(9), ix336. https://doi.org/10.1093/annonc/mds402 (Original work published 2012)