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A MicroRNA Link Between Tumor Invasion and Radioresistance in Head-and-Neck Squamous Cell Carcinoma
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Volume 84 Number 3S Supplement 2012 32%, respectively. LRC was not significantly different between the IMRT and conventional RT cohorts (pZ0.64). KPS was the only factor shown to be a significant predictor of LRC on univariate analysis (pZ0.05). Thirty patients experienced acute grade3 mucositis, dysphagia (6), dermatitis (4), xerostomia (2), trismus (2), nausea (2), fatigue (1). Seven patients reported grade3 late complications, 3 patients developed osteoradionecrosis. Fifty-four percent of deaths were found to be cancer-related, 8% a result of treatment toxicity, and 38% other medical causes. Conclusions: While a number of OCSCC patients are not suitable candidates for primary surgical resection, a meaningful locoregional control can still be achieved with definitive RT. Alternative therapies such as induction chemotherapy or biologic therapy in addition to concurrent chemoradiation should be considered to maximize locoregional control. Author Disclosure: C. Chin: None. N. Riaz: None. F. Ho: None. M. Hu: None. J. Hong: None. E. Sherman: None. R. Wong: None. S. Wolden: None. S. Rao: None. N. Lee: None.
2654 A MicroRNA Link Between Tumor Invasion and Radioresistance in Head-and-Neck Squamous Cell Carcinoma P. Hofner,1 C. Simon,1,2 V. Misetic,1 B. George,1 A. Jensen,1 W. Weichert,1 S. Combs,1 J. Hess,1 J. Debus,1 and A. Abdollahi1,3; 1Max-Eder Molecular Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), University of Heidelberg Medical School & National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany, 2Otolaryngology, Head and Neck Surgery Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 3Center of Cancer Systems Biology, St. Elizabeth’s Medical Center, Department of Medicine, Tufts University, Boston, MA Purpose/Objective(s): The high invasiveness of head-and-neck squamous cell carcinoma (HNSCC) contributes to local radiation therapy failure. We sought to dissect the molecular mechanisms governing the tumor invasive and radioresistant phenotype in HNSCC. Materials/Methods: Invasive and non-invasive tumor cell populations from three different human HNSCC cell lines FaDu, Cal27 and SCC25 were separated using matrigel-covered Boyden-chambers. Both populations were irradiated with 0, 0.5, 1, 2, 5, 10 Gy and their clonogenic survival was determined. In parallel, microRNAs (miRs) were isolated from both populations and expression profiling was performed using NanoString technology and TaqMan real-time qRT-PCR. The pro-invasive function of identified miRs was confirmed using pre-miR and anti-miR constructs and transwell invasion assay. The modulatory role of miRs was further confirmed by clonogenic survival assay. A murine orthotopic floorof-mouth squamous cell carcinoma model was used to show the regulation of miRs in primary vs. recurrent tumors. Results: The Boyden chamber-separated invasive HNSCC cells were more resistant to radiation therapy as compared to their respective noninvasive population. The clonogenic survival fraction was reduced by 25.1%, 32.7% and 21.2% in non-invasive FaDu, Cal27 and SCC25 cells, while the survival of invasive cells was diminished by 21.7%, 16.7% and 4.9% after 2 Gy irradiation. MiR profiling was performed to dissect master regulators of HNSCC invasiveness and their crosstalk with observed tumor radioresistance. The regulation of 12 differentially expressed miRs was confirmed by qRT-PCR. Functional validation for involvement of 3 miRs was provided by pre-miR and anti-miR transfection and transmigration assay. Overexpression of miR-106a and -196b inhibited tumor invasion and was correlated with decreased urokinasetype plasminogen activator (uPA) expression. The regulation of miR106a and -196b was further confirmed in murine locally recurrent HNSCC as compared to their primary counterparts. Ongoing clonogenic survival experiments indicate a modulatory role for miR-106a in the development of radioresistance.
Conclusions: Evidence is provided for a direct link between HNSCC invasion and the development of radioresistance. Moreover, miR regulators governing this crosstalk are identified. Author Disclosure: P. Hofner: None. C. Simon: None. V. Misetic: None. B. George: None. A. Jensen: None. W. Weichert: None. S. Combs: None. J. Hess: None. J. Debus: None. A. Abdollahi: None.
2655 Radiological-Pathological Correlation for Cervical Lymph Nodes in Oral Cavity Cancers: Implications for Radiation Field Reduction P.A. Desai, S. Arora, A.G. Wernicke, D. Nori, K. Chao, and B. Parashar; Weill Cornell Medical Center, New York, NY Purpose/Objective(s): Target volume delineation in head and neck cancers is based on the extent of primary tumor and involved lymph nodes (GTV) as well as the risk of subclinical involvement(CTV). The CTV volume to be included in patients with oral cavity cancer is not clear since current recommendations are based on surgical data showing patterns of lymph node involvement for different T and N stages. However, with the advancement in imaging technology, the specificity and sensitivity of imaging has improved tremendously. The aim of this study was to evaluate radiological cervical lymph node findings with surgical pathology outcomes for oral cavity cancers treated at our institute in the last 7 years. Materials/Methods: The study is IRB approved. Forty patients with oral cavity cancers, stage II (3), III (7), IV (19) and recurrence/residual (11) were included in the study (2004-2011). Patients had a diagnostic preoperative CT and or PET-CTMRI as a part of the staging process. We assessed each level lymph node (Levels 1A-5) involved based on pathological findings with pre-operative radiology findings to determine sensitivity, specificity and predictive value of current imaging technology as it relates to CTV coverage in oral cavity cancers. Results: There were 21 males (52.5%) and 19 (47.5%) females. Median age was 62 years (range, 31-93 years). Median primary tumor size for the whole group was 2.85cm (range, 0.6-4.6cm). The Median sensitivity of imaging (CT/PET-CT/MRI) for all lymph node levels was 61.5% (range 0-83%). The median specificity of the imaging for all lymph node levels was 87.5% (range 82-92%). Median positive predictive value of imaging for all lymph node levels was 50% (range 0-83%) and the median negative predictive value was 87.5% (range 81-96%). We found only one patient each with level 4 and 5 pathological involvement without a corresponding radiological abnormality in that level. However, both these patient had multiple lymph nodes involved on the ipsilateral side. There were no patients with isolated level 4 or 5 involvement (based on pathology, negative on imaging) even for these advanced oral cavity cancers. Conclusions: Current imaging technology gives a high negative predictive value regarding cervical lymph nodes in oral cavity cancers. CTV volume reduction can be attempted as a part of study based on these findings. This has the potential of significantly improving outcomes by reducing short and long term toxicity. Author Disclosure: P.A. Desai: None. S. Arora: None. A.G. Wernicke: None. D. Nori: None. K. Chao: None. B. Parashar: None.
2656 IMRT Versus Conventional Radiation Therapy for Postoperative Treatment of Oral Cavity Squamous Cell Carcinoma (OCSCC) F. Ho, N. Riaz, C. Chin, M. Hu, J. Hong, E. Sherman, R. Wong, S. Wolden, S. Rao, and N. Lee; Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): IMRT is an accepted treatment standard for head and neck cancer. While there is level I evidence that IMRT does not
Volume 84 Number 3S Supplement 2012 32%, respectively. LRC was not significantly different between the IMRT and conventional RT cohorts (pZ0.64). KPS was the only factor shown to be a significant predictor of LRC on univariate analysis (pZ0.05). Thirty patients experienced acute grade3 mucositis, dysphagia (6), dermatitis (4), xerostomia (2), trismus (2), nausea (2), fatigue (1). Seven patients reported grade3 late complications, 3 patients developed osteoradionecrosis. Fifty-four percent of deaths were found to be cancer-related, 8% a result of treatment toxicity, and 38% other medical causes. Conclusions: While a number of OCSCC patients are not suitable candidates for primary surgical resection, a meaningful locoregional control can still be achieved with definitive RT. Alternative therapies such as induction chemotherapy or biologic therapy in addition to concurrent chemoradiation should be considered to maximize locoregional control. Author Disclosure: C. Chin: None. N. Riaz: None. F. Ho: None. M. Hu: None. J. Hong: None. E. Sherman: None. R. Wong: None. S. Wolden: None. S. Rao: None. N. Lee: None.
2654 A MicroRNA Link Between Tumor Invasion and Radioresistance in Head-and-Neck Squamous Cell Carcinoma P. Hofner,1 C. Simon,1,2 V. Misetic,1 B. George,1 A. Jensen,1 W. Weichert,1 S. Combs,1 J. Hess,1 J. Debus,1 and A. Abdollahi1,3; 1Max-Eder Molecular Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), University of Heidelberg Medical School & National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany, 2Otolaryngology, Head and Neck Surgery Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 3Center of Cancer Systems Biology, St. Elizabeth’s Medical Center, Department of Medicine, Tufts University, Boston, MA Purpose/Objective(s): The high invasiveness of head-and-neck squamous cell carcinoma (HNSCC) contributes to local radiation therapy failure. We sought to dissect the molecular mechanisms governing the tumor invasive and radioresistant phenotype in HNSCC. Materials/Methods: Invasive and non-invasive tumor cell populations from three different human HNSCC cell lines FaDu, Cal27 and SCC25 were separated using matrigel-covered Boyden-chambers. Both populations were irradiated with 0, 0.5, 1, 2, 5, 10 Gy and their clonogenic survival was determined. In parallel, microRNAs (miRs) were isolated from both populations and expression profiling was performed using NanoString technology and TaqMan real-time qRT-PCR. The pro-invasive function of identified miRs was confirmed using pre-miR and anti-miR constructs and transwell invasion assay. The modulatory role of miRs was further confirmed by clonogenic survival assay. A murine orthotopic floorof-mouth squamous cell carcinoma model was used to show the regulation of miRs in primary vs. recurrent tumors. Results: The Boyden chamber-separated invasive HNSCC cells were more resistant to radiation therapy as compared to their respective noninvasive population. The clonogenic survival fraction was reduced by 25.1%, 32.7% and 21.2% in non-invasive FaDu, Cal27 and SCC25 cells, while the survival of invasive cells was diminished by 21.7%, 16.7% and 4.9% after 2 Gy irradiation. MiR profiling was performed to dissect master regulators of HNSCC invasiveness and their crosstalk with observed tumor radioresistance. The regulation of 12 differentially expressed miRs was confirmed by qRT-PCR. Functional validation for involvement of 3 miRs was provided by pre-miR and anti-miR transfection and transmigration assay. Overexpression of miR-106a and -196b inhibited tumor invasion and was correlated with decreased urokinasetype plasminogen activator (uPA) expression. The regulation of miR106a and -196b was further confirmed in murine locally recurrent HNSCC as compared to their primary counterparts. Ongoing clonogenic survival experiments indicate a modulatory role for miR-106a in the development of radioresistance.
Conclusions: Evidence is provided for a direct link between HNSCC invasion and the development of radioresistance. Moreover, miR regulators governing this crosstalk are identified. Author Disclosure: P. Hofner: None. C. Simon: None. V. Misetic: None. B. George: None. A. Jensen: None. W. Weichert: None. S. Combs: None. J. Hess: None. J. Debus: None. A. Abdollahi: None.
2655 Radiological-Pathological Correlation for Cervical Lymph Nodes in Oral Cavity Cancers: Implications for Radiation Field Reduction P.A. Desai, S. Arora, A.G. Wernicke, D. Nori, K. Chao, and B. Parashar; Weill Cornell Medical Center, New York, NY Purpose/Objective(s): Target volume delineation in head and neck cancers is based on the extent of primary tumor and involved lymph nodes (GTV) as well as the risk of subclinical involvement(CTV). The CTV volume to be included in patients with oral cavity cancer is not clear since current recommendations are based on surgical data showing patterns of lymph node involvement for different T and N stages. However, with the advancement in imaging technology, the specificity and sensitivity of imaging has improved tremendously. The aim of this study was to evaluate radiological cervical lymph node findings with surgical pathology outcomes for oral cavity cancers treated at our institute in the last 7 years. Materials/Methods: The study is IRB approved. Forty patients with oral cavity cancers, stage II (3), III (7), IV (19) and recurrence/residual (11) were included in the study (2004-2011). Patients had a diagnostic preoperative CT and or PET-CTMRI as a part of the staging process. We assessed each level lymph node (Levels 1A-5) involved based on pathological findings with pre-operative radiology findings to determine sensitivity, specificity and predictive value of current imaging technology as it relates to CTV coverage in oral cavity cancers. Results: There were 21 males (52.5%) and 19 (47.5%) females. Median age was 62 years (range, 31-93 years). Median primary tumor size for the whole group was 2.85cm (range, 0.6-4.6cm). The Median sensitivity of imaging (CT/PET-CT/MRI) for all lymph node levels was 61.5% (range 0-83%). The median specificity of the imaging for all lymph node levels was 87.5% (range 82-92%). Median positive predictive value of imaging for all lymph node levels was 50% (range 0-83%) and the median negative predictive value was 87.5% (range 81-96%). We found only one patient each with level 4 and 5 pathological involvement without a corresponding radiological abnormality in that level. However, both these patient had multiple lymph nodes involved on the ipsilateral side. There were no patients with isolated level 4 or 5 involvement (based on pathology, negative on imaging) even for these advanced oral cavity cancers. Conclusions: Current imaging technology gives a high negative predictive value regarding cervical lymph nodes in oral cavity cancers. CTV volume reduction can be attempted as a part of study based on these findings. This has the potential of significantly improving outcomes by reducing short and long term toxicity. Author Disclosure: P.A. Desai: None. S. Arora: None. A.G. Wernicke: None. D. Nori: None. K. Chao: None. B. Parashar: None.
2656 IMRT Versus Conventional Radiation Therapy for Postoperative Treatment of Oral Cavity Squamous Cell Carcinoma (OCSCC) F. Ho, N. Riaz, C. Chin, M. Hu, J. Hong, E. Sherman, R. Wong, S. Wolden, S. Rao, and N. Lee; Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): IMRT is an accepted treatment standard for head and neck cancer. While there is level I evidence that IMRT does not