Abstract 73: Preclinical evaluation of chemoradiation with cetuximab HPV-positive head and neck cancer suggests significant radiosensitization.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC PURPOSE: Whether cetuximab, a monoclonal antibody to the epidermal growth factor receptor, should be combined with radiation in patients with human papillomavirus (HPV) positive locally advanced head and neck cancer (HNC) is not known. Currently available data are inadequate to address this important therapeutic question. We sought to examine the ability of cetuximab to act as a radiosensitizer and to examine the mechanism of action of this combination in a model system of HPV+ HNC. METHODS: Four cell lines (UD-SCC2, UM-SCC47, UPCI-SCC90, 93-VU-147T) validated for HPV expression were used for all assays. Subcutaneous flank xenografts were performed in Hsd:athymic Nude-Foxn1nu female mice treated with intraperitoneal cetuximab (0.2mg/mouse) or flank radiation (2 Gy/fraction) delivered twice weekly for 2 weeks. Time to tumor quadrupling from baseline was assessed by Kaplan-Meier method. Flow cytometry was used to assess apoptosis by Annexin V staining and cell cycle distribution by propidium iodide staining. RESULTS: While there was minimal in vitro radiosensitization after treatment with cetuximab (similar to that seen in HPV-negative HNC), cetuximab + radiation resulted in a significant increase in time to tumor quadrupling compared to cetuximab alone (p=0.001) or radiation alone (p<0.0001) in HPV+ HNC xenografts. Increased apoptosis was seen in cetuximab and radiation treated cells. Analysis of cell cycle distribution 24 hours after drug treatment showed that cetuximab induced a modest G1 cell cycle arrest when given prior to radiation, but that 24 hours after combined therapy, a significant G2 arrest was present. CONCLUSIONS: Using HPV+ HNC cell lines, radiation and cetuximab appear to be beneficial compared to either treatment alone. This combination, currently undergoing study in randomized clinical trial is being further evaluated in a direct from patient tumorgraft model of HPV+ HNC to further understand predictors of response. Citation Format: Molly A. Smith, Grace C. Blitzer, Alexandra D. Torres, Eric A. Armstrong, Paul F. Lambert, Paul M. Harari, Randall J. Kimple. Preclinical evaluation of chemoradiation with cetuximab HPV-positive head and neck cancer suggests significant radiosensitization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 73. doi:10.1158/1538-7445.AM2013-73