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PO-100: E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer
5TH ICHNO
S45 Surgery, Nice, France 2 Centre Antoine Lacassagne, Oncopharmacology Unit, Nice, France 3 Centre Antoine Lacassagne, Pathology, Nice, France 4 Centre Jean Perrin, Pathology, Clermont-Ferrand, France Purpose/Objective: Clinical benefit has been demonstrated in patients with head and neck cancer receiving an antiepidermal growth factor receptor (EGFR) agent in combination with chemotherapy. Activation of the PI3K/AKT/mTOR signaling pathway is identified as an important mechanism implicated in resistance to EGFR inhibitors. Recent preclinical studies suggest beneficial effects from combining mTOR inhibitors with anti-EGFR drugs. The aim of this experimental study was to investigate the effects of combining the mTOR inhibitor Temsirolimus (Tem) with the anti-EGFR agent Cetuximab (Cet), and conventional chemotherapeutic drugs (Cisplatin (C) and Fluorouracil (F)) on an orthotopic model of head and neck cancer. Materials and Methods: We evaluated in vivo the antitumour efficacy of Tem, Cet and C-F, given alone and in combination. Investigations were performed using a VEGFsecreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, Tem (5 mg/kg, 5 days a week), Cet (2.5 mg/kg, once a week) and C-F (C: 4 mg/kg, F: 15 mg/kg, once a week)) were administered by intra-peritoneal injection alone or in combination for 12 days. Results: As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced an almost complete tumor growth arrest (p = 0.01). Tem significantly enhanced the impact of the Cet + C-F combination on tumor growth (p < 0.001). Tem and Cet were well tolerated as indicated by the stability of the mice weight during the treatment period. The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pP42/44 labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the association Tem-Cet. The addition of Tem+Cet to the C-F treatment significantly decreased tumor vessel formation as compared to C-F treatment alone (p = 0.002). Conclusions: The results of the present study testing the association of Tem with Cet and chemotherapy could serve as a strong preclinical basis for innovative treatments combining m-TOR/PI3K inhibition with EGFR targeting therapies for an optimal management of patients with head and neck cancer. PO-100 E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer A. Hong1, X. Zhang1, D. Jones1, M. Zhang1, C.S. Lee1, J.G. Lyons1, A.S. Veillard1, B. Rose1 1 The University of Sydney, Faculty of Medicine, Sydney, Australia Purpose/Objective: With the raising prevalence of human papillomavirus (HPV) positive oropharyngeal cancer (OSCC), a more refined prognostic marker for HPV positive OSCC is needed to guide treatment. The aim of this study was to identify prognostic indicators that could be used in conjunction with the existing clinicopathological approach to improve the management of HPV positive OSCC. Materials and Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data. Results: There were significantly more events and deaths among patients whose tumors had an E6*I/*II ratio ≥1 compared with an E6*I/*II ratio of <1 (38.5% vs 20.3%, p=0.015) and (30.2% vs 14.1%, p=0.023) respectively. In the
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5th ICHNO multivariable analysis, patients with E6*I/*II ratio ≥1 OSCC were twice as likely to have an event (HR 2.02, 95% CI 1.063.85, p=0.033) and to die (HR 1.95, 95% CI 0.89-4.26, p=0.094) relative to those with E6*I/*II ratio <1 OSCC. Conclusions: The detection of HPV 16 spliced transcripts may serve to identify risk factors for poorer outcomes for HPV positive OSCC. PO-101 Podoplanin expression in oropharyngeal cancer influences staging and prognosis only in p16 negative tumors M.A. Broglie Daeppen1, M. Roessle2, S.Y. Kiessling1, A. Soltermann3, S.R. Haile4, G.F. Huber5, S.J. Stoeckli6 1 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St Gallen, Switzerland 2 Cantonal Hospital Graubuenden, Institute of Pathology, Chur, Switzerland 3 University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland 4 Kantonsspital St. Gallen, Clinical Trials Unit, St. Gallen, Switzerland 5 University Hospital Zurich, Otolaryngology Head and Neck Surgery, Zurich, Switzerland 6 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St. Gallen, Switzerland Purpose/Objective: To assess the impact of podoplanin expression on staging and clinical outcome in relation to HPV status in patients with oropharyngeal cancer (OPSCC). Materials and Methods: 174 patients were consecutively included with tissue microarray (TMA) construction and immunohistochemical analysis. Estimation of survival times and importance of clinical and immunohistochemical factors for outcome by Kaplan-Meier analysis and Cox proportional hazard models. Results: For the entire cohort, the 5yr-Overall (OS), disease specific (DSS) and disease free survival (DFS) achieved 71%, 77% and 76%, respectively. Patients with p16 positive tumors had statistically significantly better 5yr-OS (p16 positive vs p16 negative patients 81% vs 60%, p=0.001), DSS (88% vs 66%, p=0.0001) and DFS (87% vs 64%, p=0.0001) than patients with p16 negative cancer. 56/174 (32%) tumor samples were expressing podoplanin. In the entire patient cohort as well as in the p16 positive subgroup no impact of podoplanin expression on nodal stage or survival could be demonstrated. In the p16 negative subgroup podoplanin expressing tumors had a more advanced N-category compared to podoplanin non-expressing tumors and had also a statistically significant worse 5yr-OS (42% vs. 70%), DSS (47% vs. 75%), and DFS (46% vs. 73%).
S45 Surgery, Nice, France 2 Centre Antoine Lacassagne, Oncopharmacology Unit, Nice, France 3 Centre Antoine Lacassagne, Pathology, Nice, France 4 Centre Jean Perrin, Pathology, Clermont-Ferrand, France Purpose/Objective: Clinical benefit has been demonstrated in patients with head and neck cancer receiving an antiepidermal growth factor receptor (EGFR) agent in combination with chemotherapy. Activation of the PI3K/AKT/mTOR signaling pathway is identified as an important mechanism implicated in resistance to EGFR inhibitors. Recent preclinical studies suggest beneficial effects from combining mTOR inhibitors with anti-EGFR drugs. The aim of this experimental study was to investigate the effects of combining the mTOR inhibitor Temsirolimus (Tem) with the anti-EGFR agent Cetuximab (Cet), and conventional chemotherapeutic drugs (Cisplatin (C) and Fluorouracil (F)) on an orthotopic model of head and neck cancer. Materials and Methods: We evaluated in vivo the antitumour efficacy of Tem, Cet and C-F, given alone and in combination. Investigations were performed using a VEGFsecreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, Tem (5 mg/kg, 5 days a week), Cet (2.5 mg/kg, once a week) and C-F (C: 4 mg/kg, F: 15 mg/kg, once a week)) were administered by intra-peritoneal injection alone or in combination for 12 days. Results: As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced an almost complete tumor growth arrest (p = 0.01). Tem significantly enhanced the impact of the Cet + C-F combination on tumor growth (p < 0.001). Tem and Cet were well tolerated as indicated by the stability of the mice weight during the treatment period. The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pP42/44 labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the association Tem-Cet. The addition of Tem+Cet to the C-F treatment significantly decreased tumor vessel formation as compared to C-F treatment alone (p = 0.002). Conclusions: The results of the present study testing the association of Tem with Cet and chemotherapy could serve as a strong preclinical basis for innovative treatments combining m-TOR/PI3K inhibition with EGFR targeting therapies for an optimal management of patients with head and neck cancer. PO-100 E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer A. Hong1, X. Zhang1, D. Jones1, M. Zhang1, C.S. Lee1, J.G. Lyons1, A.S. Veillard1, B. Rose1 1 The University of Sydney, Faculty of Medicine, Sydney, Australia Purpose/Objective: With the raising prevalence of human papillomavirus (HPV) positive oropharyngeal cancer (OSCC), a more refined prognostic marker for HPV positive OSCC is needed to guide treatment. The aim of this study was to identify prognostic indicators that could be used in conjunction with the existing clinicopathological approach to improve the management of HPV positive OSCC. Materials and Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data. Results: There were significantly more events and deaths among patients whose tumors had an E6*I/*II ratio ≥1 compared with an E6*I/*II ratio of <1 (38.5% vs 20.3%, p=0.015) and (30.2% vs 14.1%, p=0.023) respectively. In the
page 50
5th ICHNO multivariable analysis, patients with E6*I/*II ratio ≥1 OSCC were twice as likely to have an event (HR 2.02, 95% CI 1.063.85, p=0.033) and to die (HR 1.95, 95% CI 0.89-4.26, p=0.094) relative to those with E6*I/*II ratio <1 OSCC. Conclusions: The detection of HPV 16 spliced transcripts may serve to identify risk factors for poorer outcomes for HPV positive OSCC. PO-101 Podoplanin expression in oropharyngeal cancer influences staging and prognosis only in p16 negative tumors M.A. Broglie Daeppen1, M. Roessle2, S.Y. Kiessling1, A. Soltermann3, S.R. Haile4, G.F. Huber5, S.J. Stoeckli6 1 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St Gallen, Switzerland 2 Cantonal Hospital Graubuenden, Institute of Pathology, Chur, Switzerland 3 University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland 4 Kantonsspital St. Gallen, Clinical Trials Unit, St. Gallen, Switzerland 5 University Hospital Zurich, Otolaryngology Head and Neck Surgery, Zurich, Switzerland 6 Kantonsspital St. Gallen, Otolaryngology Head and Neck Surgery, St. Gallen, Switzerland Purpose/Objective: To assess the impact of podoplanin expression on staging and clinical outcome in relation to HPV status in patients with oropharyngeal cancer (OPSCC). Materials and Methods: 174 patients were consecutively included with tissue microarray (TMA) construction and immunohistochemical analysis. Estimation of survival times and importance of clinical and immunohistochemical factors for outcome by Kaplan-Meier analysis and Cox proportional hazard models. Results: For the entire cohort, the 5yr-Overall (OS), disease specific (DSS) and disease free survival (DFS) achieved 71%, 77% and 76%, respectively. Patients with p16 positive tumors had statistically significantly better 5yr-OS (p16 positive vs p16 negative patients 81% vs 60%, p=0.001), DSS (88% vs 66%, p=0.0001) and DFS (87% vs 64%, p=0.0001) than patients with p16 negative cancer. 56/174 (32%) tumor samples were expressing podoplanin. In the entire patient cohort as well as in the p16 positive subgroup no impact of podoplanin expression on nodal stage or survival could be demonstrated. In the p16 negative subgroup podoplanin expressing tumors had a more advanced N-category compared to podoplanin non-expressing tumors and had also a statistically significant worse 5yr-OS (42% vs. 70%), DSS (47% vs. 75%), and DFS (46% vs. 73%).