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Oncology Scan—Nodal Regions, Nodal Regression, and Molecular Biomarkers: New Thinking in Head and Neck Radiation Therapy
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandNodal Regions, Nodal Regression, and Molecular Biomarkers: New Thinking in Head and Neck Radiation Therapy By Juliette Thariat, MD, PhD, Associate Editor, Sue S. Yom, MD, PhD, Senior Editor, Giuseppe Sanguineti, MD, Associate Editor, June Corry, MD, Associate Editor
Gre´goire et al. Delineation of the neck node levels for head and neck tumors: A 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol 2014. (1) Summary: Bidimensional projection of nodal areas on axial computed tomography (CT) images from anatomic data obtained from peroperative or necropsy examination is not intuitive. In their landmark 2003 article, Gre´goire et al (2) provided a common definition for nodal areas of the neck and highly valuable guidelines to delineate node levels individually on axial CT slices in a practical annotated axial view that is key information for radiation oncologists. Neck nodes were annotated according to the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery and TNM atlas with respect to main neck node anatomic boundaries and normal juxtaposed structures. The current consensus Danish Head and Neck Cancer Group (DAHANCA), European Organisation for Research and Treatment of Cancer (EORTC), Hong Kong Nasopharyngeal Carcinoma Study Group (HKNPCSG), National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG), National Cancer Research Institute (NCRI), Radiation Therapy Oncology Group (RTOG), and Trans Tasman Radiation Oncology Group (TROG) paper (1) is a comprehensive update by an international panel of outstanding head and neck experts who propose axial anatomy definitions for all axial nodal areas of the head and neck region (1). Parotid (VIII), facial (IX, eg, buccal and parotid nodes), and scalp (X, eg, retroauricular and occipital nodes) have been added. Some areas have been further divided into sublevels, like the lower neck (eg, supraclavicular nodes into lateral and lateral more caudal areas). The medial retropharyngeal nodes have been omitted for Int J Radiation Oncol Biol Phys, Vol. 90, No. 3, pp. 477e479, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.05.045
consideration of lateral retropharyngeal nodes only for delineation. The current guidelines (1) provide a unique and timely way to fuel quality efforts toward delineation harmonization in the radiation oncology community. It is anticipated that the adjuncts and corrections made in the updated guidelines will favor more consistent use of recommendations for neck node delineation. This guideline corrects such previous recommendations as nodes with extracapsular spread. Based on interval publications showing metastatic spread within 8 mm in 95% of cases (3, 4), the panel no longer advocates including the whole adjacent muscle within the clinical target volume. Their assumption that extracapsular spread patterns are similar in human papillomavirus (HPV)-positive and HPV-negative cancers, however, might not be correct. Prospectively examined pathology reports are warranted before any extrapolation can be made. Preliminary data have indeed suggested that extracapsular spread in HPV-positive cancers is not associated with similarly poor outcomes, and data are yet scarce regarding extent of microscopic implants around the involved nodes in HPV-positive nodes. Comment: Practically, level-by-level delineation is time consuming. Automatic segmentation of the head and neck structures has been challenging for anatomic and technical reasons, and most atlases have not truly reached the level of entering routine practice. The introduction of more segmented areas with low contrast boundaries constitutes an additional challenge in the field of automatic segmentation. Such guidelines may thus only be applicable for routine practice in university hospitals. The 2013 delineation guideline does not intend to lay out prescription guidelines. The article does not address certain details such as when to irradiate the “new” level X, a decision that is rare in routine practice, or how to irradiate
478
Oncology Scan
retropharyngeal nodes craniocaudally in tumors in the base of the tongue. A consensus of what nodes to irradiate depending on the primary site and staging would be very timely, particularly in the era of HPV-positive disease and deintensification strategies. One of the current deintensification strategies that should be considered is reducing from bilateral to unilateral nodal irradiation in low-risk tonsilar cancer patients. Another important area of uncertainty is prophylactic coverage of the likely primary sites in HPVþ unknown primaries. Such guidelines, however, are not provided in the current article. As stated by the panel of experts, such risk-adapted neck-level irradiation recommendations should be the focus of another work.
Huang et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head and neck cancer stratified by HPV status. Int J Radiat Oncol Biol Phys 2013. (5) Summary: Neck dissection in the context of chemoradiation for regionally advanced head and neck cancer has been a highly controversial issue (6). While complete response (CR) in N1 disease is widely accepted, CR after N2 to N3 disease remains a matter of debate because of the risk of nonsalvageable nodal failure. Several authors have shown, however, that isolated nodal failure is very rare (7). Because of its poor positive predictive value, fluorodeoxyglucose-labeled positron emission tomography (FDG-PET) at 8 to 12 weeks postradiation has not yet provided a definitive answer to the question of omitting neck dissection following CR. Despite their consistently better outcomes for chemotherapy, surgery, and radiation, HPVþ cancers (compared to HPV cancers) are prone to advanced nodal stage, typically N2 to N3, and cystic presentation with delayed response. Huang et al (5) conducted a 493-patient cohort study investigating the nodal regression patterns of HPVþ versus HPV N2 to N3 nodes in patients undergoing definitive chemoradiation (3D or intensity modulated radiation therapy [IMRT]) with curative intent. A radiological CR was defined as complete resolution or regression less than 1 cm of maximal axial diameter. Patients not experiencing CR underwent neck dissection within 20 weeks. HPVþ cancer patients were younger, had less advanced T stage, and more cystic and larger nodes. CR rates were identical (roughly 50%) between HPVþ and HPV patients. Half the non-CR patients underwent neck dissection, resulting in lower positive pathology rates in HPVþ patients. More than half the patients did not receive neck dissection despite non-CR. In these patients, nodal regression continued after 12 weeks in HPVþ cancers, and the subsequent regional failure rates were very low. Comment: The differences shown between HPVþ and HPV cancers should be tempered by the inclusion in the HPV group of hypopharyngeal cases, as these might behave differently regardless of HPV status (6). This article
International Journal of Radiation Oncology Biology Physics
goes a step farther toward an evidence-based strategy to avoid neck dissection in CR patients (N2 and N3) and in N2 HPVþ patients not experiencing a CR. It highlights the different temporal regression patterns of HPVþ nodes with a possibly quicker initial CR or a prolonged involution. The positive predictive value of non-CR for regional failure in HPV patients and non-CR N3 patients, however, corroborates the need for neck dissection. The “neck dissection philosophy” is highly institution-dependent, but this work helps to address neck dissection issues in the postradiation context. Unfortunately, the current study does not address the issue of initial neck dissection, an attitude that is preemptively practiced in many institutions. The initial versus postradiation neck dissection battle is still alive despite growing evidence for omission of postradiation dissection, including in those paradoxically bulky cystic nodes of HPVþ cancers. Resolution of this debate will ultimately require a randomized trial (8).
Lui et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013. (9) Summary: Despite the discovery of epidermal growth factor receptor (EGFR) expression as a strong prognostic factor and later of the oncogenic HPV in irradiated patients (10, 11), the relative paucity of predictive biomarkers in head and neck cancers has held back further guidance of treatment based upon biomarker status. Moreover, head and neck cancers had lagged behind other cancer types like lung cancer and melanomas with regard to application of genomics. In particular, EGFR mutations have not been consistently identified as a relevant predictor of responsiveness to EGFR inhibitors. Two parallel landmark genomics (exome) studies in head and neck cancer patients paved the way in 2011 (12, 13) for other genomic studies. These works have fueled the hope that we may soon identify predictive genomic alterations that could be both “actionable” and “druggable,” yet to date, very few pathways seem mature. The recent paper by Lui et al (9) suggests that mutations in the phosphoinositide 3-kinase (PI3K) pathway, downstream of EGFR, are frequent (30.5%) in head and neck cancer patients. These alterations are readily druggable and are predictive of outcomes to PI3K inhibitors in head and neck cancer patient-derived xenograft tumors (9). Their work was based on exome-sequencing in cohorts of patients. Concurrent mutations of multiple PI3K pathway genes were mostly observed in advanced stages, suggesting involvement of the PI3K pathway in tumor progression. In contrast to most mutations, including p53 mutations identified in up to 80% of tobacco-related head and neck tumors, mutations in the PI3K pathway were also present in HPV-related tumors. Comment: These results obtained in preclinical models along with the consistent observation of PI3KCA pathway
Volume 90 Number 3 2014
mutations in patients are certainly encouraging as they suggest that these mutations may serve as predictive biomarkers for treatment selection. With the development of high throughput next generation sequencing methods, this proof of concept that theragenomics has arrived is very timely; yet, genomic profiles reveal a high level of heterogeneity among head and neck cancers. Other studies performed both in Asia and the West have shown different patterns of mutations in anatomic subsites of the oral cavity, suggesting that genomic profiles may be tissue-specific and related to exposure to different mutagens (14, 15). This observation is in line with recent work with Ras mutations, showing that Ras isoforms exhibit distinctive codon mutation signatures and that some of the observed mutational heterogeneity is due to tissue-specific exposure to different mutagens (16). Thus, enthusiasm toward genomics-driven therapeutics should probably be tempered by an understanding of and allowances made for patient heterogeneity. One additional limitation of the rapid expansion of genomics in head and neck cancers is the prevailing tumor suppressor gene mutation profile that may require complex synthetic lethality approaches.
References 1. Gre´goire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol 2014;110:172-181. 2. Gre´goire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines. Radiother Oncol 2003;69:227-236. 3. Apisarnthanarax SL, Elliott DD, El-Naggar AK, et al. Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes. Int J Radiat Oncol Biol Phys 2006;64:678-683.
Oncology Scan
479
4. Ghadjar P, Schreiber-Facklam H, Gra¨ter R, et al. Quantitative analysis of extracapsular extension of metastatic lymph nodes and its significance in radiotherapy planning in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2010;76:1127-1132. 5. Huang SH, O’Sullivan B, Xu W, et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV status. Int J Radiat Oncol Biol Phys 2013;87:1078-1085. 6. Thariat J, Ang KK, Allen PK, et al. Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2012;82:e367-e374. 7. Hamoir M, Ferlito A, Schmitz S, et al. The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. Oral Oncol 2012; 48:203-210. 8. Thariat J, Hamoir M, Garrel R, et al. Management of the neck in the setting of definitive chemoradiation: Is there a consensus? A GETTEC study. Ann Surg Oncol 2012;19:2311-2319. 9. Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013;3:761-769. 10. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62: 7350-7356. 11. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363: 24-35. 12. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333: 1157-1160. 13. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333:1154-1157. 14. India Project Team of the International Cancer Genome Consortium. Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nat Commun 2013;4:2873. 15. Pickering CR, Zhang J, Yoo SY, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013;3:770-781. 16. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res 2012;72:2457-2467.
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandNodal Regions, Nodal Regression, and Molecular Biomarkers: New Thinking in Head and Neck Radiation Therapy By Juliette Thariat, MD, PhD, Associate Editor, Sue S. Yom, MD, PhD, Senior Editor, Giuseppe Sanguineti, MD, Associate Editor, June Corry, MD, Associate Editor
Gre´goire et al. Delineation of the neck node levels for head and neck tumors: A 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol 2014. (1) Summary: Bidimensional projection of nodal areas on axial computed tomography (CT) images from anatomic data obtained from peroperative or necropsy examination is not intuitive. In their landmark 2003 article, Gre´goire et al (2) provided a common definition for nodal areas of the neck and highly valuable guidelines to delineate node levels individually on axial CT slices in a practical annotated axial view that is key information for radiation oncologists. Neck nodes were annotated according to the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery and TNM atlas with respect to main neck node anatomic boundaries and normal juxtaposed structures. The current consensus Danish Head and Neck Cancer Group (DAHANCA), European Organisation for Research and Treatment of Cancer (EORTC), Hong Kong Nasopharyngeal Carcinoma Study Group (HKNPCSG), National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG), National Cancer Research Institute (NCRI), Radiation Therapy Oncology Group (RTOG), and Trans Tasman Radiation Oncology Group (TROG) paper (1) is a comprehensive update by an international panel of outstanding head and neck experts who propose axial anatomy definitions for all axial nodal areas of the head and neck region (1). Parotid (VIII), facial (IX, eg, buccal and parotid nodes), and scalp (X, eg, retroauricular and occipital nodes) have been added. Some areas have been further divided into sublevels, like the lower neck (eg, supraclavicular nodes into lateral and lateral more caudal areas). The medial retropharyngeal nodes have been omitted for Int J Radiation Oncol Biol Phys, Vol. 90, No. 3, pp. 477e479, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.05.045
consideration of lateral retropharyngeal nodes only for delineation. The current guidelines (1) provide a unique and timely way to fuel quality efforts toward delineation harmonization in the radiation oncology community. It is anticipated that the adjuncts and corrections made in the updated guidelines will favor more consistent use of recommendations for neck node delineation. This guideline corrects such previous recommendations as nodes with extracapsular spread. Based on interval publications showing metastatic spread within 8 mm in 95% of cases (3, 4), the panel no longer advocates including the whole adjacent muscle within the clinical target volume. Their assumption that extracapsular spread patterns are similar in human papillomavirus (HPV)-positive and HPV-negative cancers, however, might not be correct. Prospectively examined pathology reports are warranted before any extrapolation can be made. Preliminary data have indeed suggested that extracapsular spread in HPV-positive cancers is not associated with similarly poor outcomes, and data are yet scarce regarding extent of microscopic implants around the involved nodes in HPV-positive nodes. Comment: Practically, level-by-level delineation is time consuming. Automatic segmentation of the head and neck structures has been challenging for anatomic and technical reasons, and most atlases have not truly reached the level of entering routine practice. The introduction of more segmented areas with low contrast boundaries constitutes an additional challenge in the field of automatic segmentation. Such guidelines may thus only be applicable for routine practice in university hospitals. The 2013 delineation guideline does not intend to lay out prescription guidelines. The article does not address certain details such as when to irradiate the “new” level X, a decision that is rare in routine practice, or how to irradiate
478
Oncology Scan
retropharyngeal nodes craniocaudally in tumors in the base of the tongue. A consensus of what nodes to irradiate depending on the primary site and staging would be very timely, particularly in the era of HPV-positive disease and deintensification strategies. One of the current deintensification strategies that should be considered is reducing from bilateral to unilateral nodal irradiation in low-risk tonsilar cancer patients. Another important area of uncertainty is prophylactic coverage of the likely primary sites in HPVþ unknown primaries. Such guidelines, however, are not provided in the current article. As stated by the panel of experts, such risk-adapted neck-level irradiation recommendations should be the focus of another work.
Huang et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head and neck cancer stratified by HPV status. Int J Radiat Oncol Biol Phys 2013. (5) Summary: Neck dissection in the context of chemoradiation for regionally advanced head and neck cancer has been a highly controversial issue (6). While complete response (CR) in N1 disease is widely accepted, CR after N2 to N3 disease remains a matter of debate because of the risk of nonsalvageable nodal failure. Several authors have shown, however, that isolated nodal failure is very rare (7). Because of its poor positive predictive value, fluorodeoxyglucose-labeled positron emission tomography (FDG-PET) at 8 to 12 weeks postradiation has not yet provided a definitive answer to the question of omitting neck dissection following CR. Despite their consistently better outcomes for chemotherapy, surgery, and radiation, HPVþ cancers (compared to HPV cancers) are prone to advanced nodal stage, typically N2 to N3, and cystic presentation with delayed response. Huang et al (5) conducted a 493-patient cohort study investigating the nodal regression patterns of HPVþ versus HPV N2 to N3 nodes in patients undergoing definitive chemoradiation (3D or intensity modulated radiation therapy [IMRT]) with curative intent. A radiological CR was defined as complete resolution or regression less than 1 cm of maximal axial diameter. Patients not experiencing CR underwent neck dissection within 20 weeks. HPVþ cancer patients were younger, had less advanced T stage, and more cystic and larger nodes. CR rates were identical (roughly 50%) between HPVþ and HPV patients. Half the non-CR patients underwent neck dissection, resulting in lower positive pathology rates in HPVþ patients. More than half the patients did not receive neck dissection despite non-CR. In these patients, nodal regression continued after 12 weeks in HPVþ cancers, and the subsequent regional failure rates were very low. Comment: The differences shown between HPVþ and HPV cancers should be tempered by the inclusion in the HPV group of hypopharyngeal cases, as these might behave differently regardless of HPV status (6). This article
International Journal of Radiation Oncology Biology Physics
goes a step farther toward an evidence-based strategy to avoid neck dissection in CR patients (N2 and N3) and in N2 HPVþ patients not experiencing a CR. It highlights the different temporal regression patterns of HPVþ nodes with a possibly quicker initial CR or a prolonged involution. The positive predictive value of non-CR for regional failure in HPV patients and non-CR N3 patients, however, corroborates the need for neck dissection. The “neck dissection philosophy” is highly institution-dependent, but this work helps to address neck dissection issues in the postradiation context. Unfortunately, the current study does not address the issue of initial neck dissection, an attitude that is preemptively practiced in many institutions. The initial versus postradiation neck dissection battle is still alive despite growing evidence for omission of postradiation dissection, including in those paradoxically bulky cystic nodes of HPVþ cancers. Resolution of this debate will ultimately require a randomized trial (8).
Lui et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013. (9) Summary: Despite the discovery of epidermal growth factor receptor (EGFR) expression as a strong prognostic factor and later of the oncogenic HPV in irradiated patients (10, 11), the relative paucity of predictive biomarkers in head and neck cancers has held back further guidance of treatment based upon biomarker status. Moreover, head and neck cancers had lagged behind other cancer types like lung cancer and melanomas with regard to application of genomics. In particular, EGFR mutations have not been consistently identified as a relevant predictor of responsiveness to EGFR inhibitors. Two parallel landmark genomics (exome) studies in head and neck cancer patients paved the way in 2011 (12, 13) for other genomic studies. These works have fueled the hope that we may soon identify predictive genomic alterations that could be both “actionable” and “druggable,” yet to date, very few pathways seem mature. The recent paper by Lui et al (9) suggests that mutations in the phosphoinositide 3-kinase (PI3K) pathway, downstream of EGFR, are frequent (30.5%) in head and neck cancer patients. These alterations are readily druggable and are predictive of outcomes to PI3K inhibitors in head and neck cancer patient-derived xenograft tumors (9). Their work was based on exome-sequencing in cohorts of patients. Concurrent mutations of multiple PI3K pathway genes were mostly observed in advanced stages, suggesting involvement of the PI3K pathway in tumor progression. In contrast to most mutations, including p53 mutations identified in up to 80% of tobacco-related head and neck tumors, mutations in the PI3K pathway were also present in HPV-related tumors. Comment: These results obtained in preclinical models along with the consistent observation of PI3KCA pathway
Volume 90 Number 3 2014
mutations in patients are certainly encouraging as they suggest that these mutations may serve as predictive biomarkers for treatment selection. With the development of high throughput next generation sequencing methods, this proof of concept that theragenomics has arrived is very timely; yet, genomic profiles reveal a high level of heterogeneity among head and neck cancers. Other studies performed both in Asia and the West have shown different patterns of mutations in anatomic subsites of the oral cavity, suggesting that genomic profiles may be tissue-specific and related to exposure to different mutagens (14, 15). This observation is in line with recent work with Ras mutations, showing that Ras isoforms exhibit distinctive codon mutation signatures and that some of the observed mutational heterogeneity is due to tissue-specific exposure to different mutagens (16). Thus, enthusiasm toward genomics-driven therapeutics should probably be tempered by an understanding of and allowances made for patient heterogeneity. One additional limitation of the rapid expansion of genomics in head and neck cancers is the prevailing tumor suppressor gene mutation profile that may require complex synthetic lethality approaches.
References 1. Gre´goire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol 2014;110:172-181. 2. Gre´goire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines. Radiother Oncol 2003;69:227-236. 3. Apisarnthanarax SL, Elliott DD, El-Naggar AK, et al. Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes. Int J Radiat Oncol Biol Phys 2006;64:678-683.
Oncology Scan
479
4. Ghadjar P, Schreiber-Facklam H, Gra¨ter R, et al. Quantitative analysis of extracapsular extension of metastatic lymph nodes and its significance in radiotherapy planning in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2010;76:1127-1132. 5. Huang SH, O’Sullivan B, Xu W, et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV status. Int J Radiat Oncol Biol Phys 2013;87:1078-1085. 6. Thariat J, Ang KK, Allen PK, et al. Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2012;82:e367-e374. 7. Hamoir M, Ferlito A, Schmitz S, et al. The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. Oral Oncol 2012; 48:203-210. 8. Thariat J, Hamoir M, Garrel R, et al. Management of the neck in the setting of definitive chemoradiation: Is there a consensus? A GETTEC study. Ann Surg Oncol 2012;19:2311-2319. 9. Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013;3:761-769. 10. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62: 7350-7356. 11. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363: 24-35. 12. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333: 1157-1160. 13. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333:1154-1157. 14. India Project Team of the International Cancer Genome Consortium. Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nat Commun 2013;4:2873. 15. Pickering CR, Zhang J, Yoo SY, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013;3:770-781. 16. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res 2012;72:2457-2467.