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Biomarkers for Individualized Oral Cancer Therapy

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Personalized Oral Health Care

Abstract

This chapter focuses on personalized medicine for oral cancer, with emphasis on selection of current and future therapies. Specifically, treatment selection of radiation, chemotherapy, and surgery and customized strategies for selection of targeted therapy are discussed. Worldwide, head and neck cancer is the sixth most common cancer by incidence and the fifth most common cause of cancer-related deaths. More than 90 % of oral cancers are squamous cell carcinomas (SCCs), which are the focus of this chapter. SCC arises from the oral cavity including lip, oropharynx/tonsil, larynx, and hypopharynx. The risk factors for SCC are tobacco, alcohol, and human papillomavirus 16 (HPV16). HPV-positive SCC usually occurs in the oropharynx, and HPV-negative SCC usually occurs in the oral cavity, larynx, and hypopharynx. Personalized medicine is customization of treatment to the individual patient. The goals of personalized medicine are to improve clinical outcome, reduce side effects, and decrease expenses. Currently personalized medicine in oral cancer is based on tumor stage and location, but not tumor biology. Unfortunately, two patients with similar tumor stage may respond differently to the same therapy. Identification at the time of diagnosis of an early-stage lesion that will behave aggressively will facilitate selection of appropriate aggressive treatment at the time of initial diagnosis. However, aggressive treatment is not appropriate for all early-stage lesions due to toxicity of treatment. Although targeted treatment has been developed for SCC, it is not used in a customized approach. This chapter discusses evolving approaches to customize therapy based on the biology of the individual tumor. Furthermore, targeted therapy and potential biomarkers to match therapy to patients are also discussed.

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References

  1. President’s Council of Advisors on Science and Technology: priorities for personalized medicine. 2008. Available at: http://www.whitehouse.gov/files/documents/ostp/PCAST/pcast_report_v2.pdf. Accessed 26 Sep 2014.

  2. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2010;11(1):9–22.

    Article  PubMed  Google Scholar 

  3. Singh B. Molecular pathogenesis of head and neck cancers. J Surg Oncol. 2008;97(8):634–9.

    Article  PubMed  Google Scholar 

  4. Klein JD, Grandis JR. The molecular pathogenesis of head and neck cancer. Cancer Biol Ther. 2010;9(1):1–7.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Scanlon CS, Van Tubergen EA, Inglehart RC, D’Silva NJ. Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res. 2013;92(2):114–21.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Weiss J, Hayes DN. Classifying squamous cell carcinoma of the head and neck: prognosis, prediction and implications for therapy. Expert Rev Anticancer Ther. 2014;14(2):229–36.

    Article  PubMed  Google Scholar 

  7. Vaezi A, Feldman CH, Niedernhofer LJ. ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer. Pharmgenomics Pers Med. 2011;4:47–63.

    PubMed Central  PubMed  Google Scholar 

  8. Denaro N, Russi EG, Adamo V, Merlano M. State-of-the-art and emerging treatment options in the management of head and neck cancer: News from 2013. Oncology. 2014;86(4):212–29.

    PubMed  Google Scholar 

  9. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med. 1993;328(3):184–94.

    Article  PubMed  Google Scholar 

  10. Specht L. Oral complications in the head and neck radiation patient. Support Care Cancer. 2002;10(1):36–9.

    Article  PubMed  Google Scholar 

  11. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345(26):1890–900.

    Article  PubMed  Google Scholar 

  12. Razak AR, Siu LL, Le Tourneau C. Molecular targeted therapies in all histologies of head and neck cancers: an update. Curr Opin Oncol. 2010;22(3):212–20.

    Article  PubMed  Google Scholar 

  13. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359(11):1143–54.

    Article  PubMed  Google Scholar 

  14. Pfister DG, Ang K-K, Brizel DM, Burtness BA, Cmelak AJ, Colevas AD, et al. Head and neck cancers. J Natl Compr Canc Netw. 2011;9(6):596–650.

    PubMed  Google Scholar 

  15. Patel SG, Shah JP. TNM staging of cancers of the head and neck: striving for uniformity among diversity. CA Cancer J Clin. 2005;55(4):242–58.

    Article  PubMed  Google Scholar 

  16. Sessions DG, Spector GJ, Lenox J, Haughey B, Chao C, Marks J. Analysis of treatment results for oral tongue cancer. Laryngoscope. 2002;112(4):616–25.

    Article  PubMed  Google Scholar 

  17. Huang TY, Hsu LP, Wen YH, Huang TT, Chou YF, Lee CF, et al. Predictors of locoregional recurrence in early stage oral cavity cancer with free surgical margins. Oral Oncol. 2010;46(1):49–55.

    Article  PubMed  Google Scholar 

  18. Jerjes W, Upile T, Hamdoon Z, Mosse CA, Akram S, Hopper C. Prospective evaluation of outcome after transoral CO2 laser resection of T1/T2 oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(2):180–7.

    Article  PubMed  Google Scholar 

  19. Brandwein-Gensler M, Wei S. Envisioning the next WHO head and neck classification. Head Neck Pathol. 2014;8(1):1–15.

    Article  PubMed Central  PubMed  Google Scholar 

  20. D’Silva NJ, Ward BB. Tissue biomarkers for diagnosis & management of oral squamous cell carcinoma. Alpha Omegan. 2007;100(4):18–9.

    Google Scholar 

  21. Cognetti DM, Weber RS, Lai SY. Head and neck cancer. Cancer. 2008;113(S7):1911–32.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Mitra RS, Goto M, Lee JS, Maldonado D, Taylor JM, Pan Q, et al. Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma. Cancer Res. 2008;68(10):3959–69.

    Article  PubMed  Google Scholar 

  23. Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, et al. Distinct risk factor profiles for human papillomavirus type 16–positive and human papillomavirus type 16–negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407–20.

    Article  PubMed  Google Scholar 

  24. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet. 2008;371(9625):1695–709.

    Article  PubMed  Google Scholar 

  25. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565–74.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005;114(5):806–16.

    Article  PubMed  Google Scholar 

  27. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence. Cancer. 2007;110(7):1429–35.

    Article  PubMed  Google Scholar 

  28. Rettig E, Kiess AP, Fakhry C. The role of sexual behavior in head and neck cancer: implications for prevention and therapy. Expert Rev Anticancer Ther. 2015;15(1):35–49.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013;31(36):4550–9.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Mroz EA, Forastiere AA, Rocco JW. Implications of the oropharyngeal cancer epidemic. J Clin Oncol. 2011;29(32):4222–3.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Herrero R, Castellsagué X, Pawlita M, Lissowska J, Kee F, Balaram P, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst. 2003;95(23):1772–83.

    Article  PubMed  Google Scholar 

  32. Ribeiro KB, Levi JE, Pawlita M, Koifman S, Matos E, Eluf-Neto J, et al. Low human papillomavirus prevalence in head and neck cancer: results from two large case–control studies in high-incidence regions. Int J Epidemiol. 2011;40(2):489–502.

    Article  PubMed  Google Scholar 

  33. Marur S, Burtness B. Oropharyngeal squamous cell carcinoma treatment: current standards and future directions. Curr Opin Oncol. 2014;26(3):252–8.

    Article  PubMed  Google Scholar 

  34. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol. 2006;24(17):2606–11.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer. 2003;104(3):336–44.

    Article  PubMed  Google Scholar 

  36. Kumar B, Cordell KG, Lee JS, Prince ME, Tran HH, Wolf GT, et al. Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking. Int J Radiat Oncol Biol Phys. 2007;69(2):S109–11.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Worden FP, Kumar B, Lee JS, Wolf GT, Cordell KG, Taylor JM, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008;26(19):3138–46.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294–301.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Jemal A, Simard EP, Dorell C, Noone AM, Markowitz LE, Kohler B, et al. Annual Report to the Nation on the Status of Cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)–associated cancers and HPV Vaccination coverage levels. J Natl Cancer Inst. 2013;105(3):175–201.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Settle K, Posner MR, Schumaker LM, Tan M, Suntharalingam M, Goloubeva O, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila). 2009;2(9):776–81.

    Article  Google Scholar 

  41. Licitra L, Perrone F, Bossi B, Suardi S, Mariani L, Artusi R. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. 2006;24(36):5630–6.

    Article  PubMed  Google Scholar 

  42. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus–positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–9.

    Article  PubMed  Google Scholar 

  43. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–20.

    Article  PubMed  Google Scholar 

  45. Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck‐Wikland E. Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer. 2000;89(3):300–4.

    Article  PubMed  Google Scholar 

  46. Weinberger PM, Yu Z, Haffty B, Kowalski D, Harigopal M, Sasaki C, et al. Prognostic significance of p16 protein levels in oropharyngeal squamous cell cancer. Clin Cancer Res. 2004;10(17):5684–91.

    Article  PubMed  Google Scholar 

  47. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(12):1992–8.

    Article  PubMed  Google Scholar 

  48. Fischer C, Kampmann M, Zlobec I, Green E, Tornillo L, Lugli A, et al. p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters. Ann Oncol. 2010;21(10):1961–6.

    Article  PubMed  Google Scholar 

  49. O’rorke M, Ellison M, Murray L, Moran M, James J, Anderson L. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol. 2012;48(12):1191–201.

    Article  PubMed  Google Scholar 

  50. Vent J, Haidle B, Wedemeyer I, Huebbers C, Siefer O, Semrau R, et al. p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck. 2013;35(11):1521–6.

    Article  PubMed  Google Scholar 

  51. Hong A, Dobbins T, Lee C, Jones D, Harnett G, Armstrong B, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer. 2010;103(10):1510–7.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Attner P, Du J, Näsman A, Hammarstedt L, Ramqvist T, Lindholm J, et al. Human papillomavirus and survival in patients with base of tongue cancer. Int J Cancer. 2011;128(12):2892–7.

    Article  PubMed  Google Scholar 

  53. Fountzilas G, Kosmidis P, Avramidis V, Nikolaou A, Kalogera‐Fountzila A, Makrantonakis P, et al. Long-term survival data and prognostic factors of a complete response to chemotherapy in patients with head and neck cancer treated with platinum-based induction chemotherapy: a Hellenic Co-operative Oncology Group Study. Med Pediatr Oncol. 1997;28(6):401–10.

    Article  PubMed  Google Scholar 

  54. Browman GP, Mohide E, Willan A, Hodson I, Wong G, Grimard L, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: a follow-up study. Head Neck. 2002;24(12):1031–7.

    Article  PubMed  Google Scholar 

  55. Jordan RC, Lingen MW, Perez-Ordonez B, He X, Pickard R, Koluder M, et al. Validation of methods for oropharyngeal cancer HPV status determination in US Cooperative Group trials. Am J Surg Pathol. 2012;36(7):945–54.

    Article  PubMed  Google Scholar 

  56. Liang C, Marsit CJ, McClean MD, Nelson HH, Christensen BC, Haddad RI, et al. Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Res. 2012;72(19):5004–13.

    Article  PubMed Central  PubMed  Google Scholar 

  57. De Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13(6):607–15.

    Article  PubMed  Google Scholar 

  58. Lingen MW, Xiao W, Schmitt A, Jiang B, Pickard R, Kreinbrink P, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol. 2013;49(1):1–8.

    Article  PubMed  Google Scholar 

  59. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology™. Head and neck cancers. 2013;V.2.2013. Available at: http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf.

  60. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, Slotman BJ. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol. 2008;26(22):3770–6.

    Article  PubMed  Google Scholar 

  61. Francis DO, Weymuller Jr EA, Parvathaneni U, Merati AL, Yueh B. Dysphagia, stricture, and pneumonia in head and neck cancer patients: does treatment modality matter? Ann Otol Rhinol Laryngol. 2010;119(6):391.

    PubMed  Google Scholar 

  62. Cmelak A. Abstract #LBA6006. Presented at: ASCO annual meeting; 30 May–3 Jun 2014; Chicago.

    Google Scholar 

  63. Radiation therapy with cisplatin or cetuximab in treating patients with oropharyngeal cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT01302834.

  64. Huang SH, Perez-Ordonez B, Liu FF, Waldron J, Ringash J, Irish J, et al. Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82(1):276–83.

    Article  PubMed  Google Scholar 

  65. Vermorken JB, Stohlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14(8):697–710.

    Article  PubMed  Google Scholar 

  66. O’Brien CJ, Lauer CS, Fredricks S, Clifford AR, McNeil EB, Bagia JS, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer—but what thickness? Head Neck. 2003;25(11):937–45.

    Article  PubMed  Google Scholar 

  67. Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg. 1986;152(4):345–50.

    Article  PubMed  Google Scholar 

  68. Warburton G, Nikitakis NG, Roberson P, Marinos NJ, Wu T, Sauk Jr JJ, et al. Histopathological and lymphangiogenic parameters in relation to lymph node metastasis in early stage oral squamous cell carcinoma. J Oral Maxillofac Surg. 2007;65(3):475–84.

    Article  PubMed  Google Scholar 

  69. Cerezo L, Millan I, Torre A, Aragon G, Otero J. Prognostic factors for survival and tumor control in cervical lymph node metastases from head and neck cancer: a multivariate study of 492 cases. Cancer. 1992;69(5):1224–34.

    Article  PubMed  Google Scholar 

  70. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945–52.

    Article  PubMed  Google Scholar 

  71. Brockstein B, Haraf D, Rademaker A, Kies M, Stenson K, Rosen F, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol. 2004;15(8):1179–86.

    Article  PubMed  Google Scholar 

  72. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937–44.

    Article  PubMed  Google Scholar 

  73. Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167–78.

    Article  PubMed  Google Scholar 

  74. Brandwein-Gensler M, Smith RV, Wang B, Penner C, Theilken A, Broughel D, et al. Validation of the histologic risk model in a new cohort of patients with head and neck squamous cell carcinoma. Am J Surg Pathol. 2010;34(5):676–88.

    PubMed  Google Scholar 

  75. Li Y, Bai S, Carroll W, Dayan D, Dort JC, Heller K, et al. Validation of the risk model: high-risk classification and tumor pattern of invasion predict outcome for patients with low-stage oral cavity squamous cell carcinoma. Head Neck Pathol. 2013;7(3):211–23.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Sawair FA, Irwin CR, Gordon DJ, Leonard AG, Stephenson M, Napier SS. Invasive front grading: reliability and usefulness in the management of oral squamous cell carcinoma. J Oral Pathol Med. 2003;32(1):1–9.

    Article  PubMed  Google Scholar 

  77. O’Brien CJ, Smith JW, Soong S-J, Urist MM, Maddox WA. Neck dissection with and without radiotherapy: prognostic factors, patterns of recurrence, and survival. Am J Surg. 1986;152(4):456–63.

    Article  PubMed  Google Scholar 

  78. Tytor M, Olofsson J. Prognostic factors in oral cavity carcinomas. Acta Otolaryngol Suppl. 1992;492:75–8.

    Article  PubMed  Google Scholar 

  79. Jones A. Prognosis in mouth cancer: tumour factors. Eur J Cancer B Oral Oncol. 1994;30B(1):8–15.

    Article  PubMed  Google Scholar 

  80. Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A, Bosq J. Lymph node prognostic factors in head and neck squamous cell carcinomas. Am J Surg. 1994;168(5):494–8.

    Article  PubMed  Google Scholar 

  81. Woolgar JA, Scott J, Vaughan E, Brown J, West C, Rogers S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl. 1995;77(5):325–31.

    PubMed Central  PubMed  Google Scholar 

  82. Bryne M, Koppang HS, Lilleng R, Stene T, Bang G, Dabelsteen E. New malignancy grading is a better prognostic indicator than Broders’ grading in oral squamous cell carcinomas. J Oral Pathol Med. 1989;18(8):432–7.

    Article  PubMed  Google Scholar 

  83. Bryne M, Koppang HS, Lillen R, Kjærheim Å. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol. 1992;166(4):375–81.

    Article  PubMed  Google Scholar 

  84. El-Mofty SK. Histopathologic risk factors in oral and oropharyngeal squamous cell carcinoma variants: an update with special reference to HPV-related carcinomas. Med Oral Patol Oral Cir Bucal. 2014;19(4):e377–85.

    Article  PubMed Central  PubMed  Google Scholar 

  85. Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol. 2005;86(6):347–63.

    Article  PubMed Central  PubMed  Google Scholar 

  86. Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM. Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg. 2001;125(1):1–9.

    Article  PubMed  Google Scholar 

  87. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24(5):736–47.

    Article  PubMed  Google Scholar 

  88. Westra WH. The morphologic profile of HPV-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head Neck Pathol. 2012;6(1):48–54.

    Article  PubMed Central  Google Scholar 

  89. Sieczka E, Datta R, Singh A, Loree T, Rigual N, Orner J, et al. Cancer of the buccal mucosa: are margins and T-stage accurate predictors of local control? Am J Otolaryngol. 2001;22(6):395–9.

    Article  PubMed  Google Scholar 

  90. Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg. 1990;160(4):410–4.

    Article  PubMed  Google Scholar 

  91. Burri RJ, Lee NY. Concurrent chemotherapy and radiotherapy for head and neck cancer. Expert Rev Anticancer Ther. 2009;9(3):293–302.

    Article  PubMed  Google Scholar 

  92. Ang KK, Berkey BA, Tu X, Zhang H-Z, Katz R, Hammond EH, 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(24):7350–6.

    PubMed  Google Scholar 

  93. Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, Hunt JL, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12(17):5064–73.

    Article  PubMed  Google Scholar 

  94. Davies RL, Grosse VA, Kucherlapati R, Bothwell M. Genetic analysis of epidermal growth factor action: assignment of human epidermal growth factor receptor gene to chromosome 7. Proc Natl Acad Sci. 1980;77(7):4188–92.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666–72.

    Article  PubMed  Google Scholar 

  96. Ellerbroek SM, Halbleib JM, Benavidez M, Warmka JK, Wattenberg EV, Stack MS, et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res. 2001;61(5):1855–61.

    PubMed  Google Scholar 

  97. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.

    Article  PubMed  Google Scholar 

  98. Kruger JS, Reddy KB. Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells11NIH grant R01 CA 83964 (to KBR). Mol Cancer Res. 2003;1(11):801–9.

    PubMed  Google Scholar 

  99. Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, et al. Levels of TGF-α and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90(11):824–32.

    Article  Google Scholar 

  100. Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25(16):2164–70.

    Article  PubMed  Google Scholar 

  101. Hama T, Yuza Y, Saito Y, Jin O, Kondo S, Okabe M, et al. Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma. Oncologist. 2009;14(9):900–8.

    Article  PubMed  Google Scholar 

  102. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23(34):8646–54.

    Article  PubMed  Google Scholar 

  103. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171–7.

    Article  PubMed  Google Scholar 

  104. Brachman DG, Graves D, Vokes E, Beckett M, Haraf D, Montag A, et al. Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. Cancer Res. 1992;52(17):4832–6.

    PubMed  Google Scholar 

  105. Hoffmann TK, Sonkoly E, Hauser U, van Lierop A, Whiteside TL, Klussmann JP, et al. Alterations in the p53 pathway and their association with radio-and chemosensitivity in head and neck squamous cell carcinoma. Oral Oncol. 2008;44(12):1100–9.

    Article  PubMed  Google Scholar 

  106. Velculescu VE, El-Deiry W. Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem. 1996;42(6):858–68.

    PubMed  Google Scholar 

  107. Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P. The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002;19(6):607–14.

    Article  PubMed  Google Scholar 

  108. Gasco M, Crook T. The p53 network in head and neck cancer. Oral Oncol. 2003;39(3):222–31.

    Article  PubMed  Google Scholar 

  109. Nogueira CP, Dolan RW, Gooey J, Byahatti S, Vaughan CW, Fuleihan NS, et al. Inactivation of p53 and amplification of cyclin D1 correlate with clinical outcome in head and neck cancer. Laryngoscope. 1998;108(3):345–50.

    Article  PubMed  Google Scholar 

  110. Edström S, Cvetkovska E, Westin T, Young C. Overexpression of p53-related proteins predicts rapid growth rate of head and neck cancer. Laryngoscope. 2001;111(1):124–30.

    Article  PubMed  Google Scholar 

  111. Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res. 2009;15(22):6758–62.

    Article  PubMed  Google Scholar 

  112. Chen K, Hu Z, Wang L-E, Sturgis EM, El-Naggar AK, Zhang W, et al. Single-nucleotide polymorphisms at the TP53-binding or responsive promoter regions of BAX and BCL2 genes and risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2007;28(9):2008–12.

    Article  PubMed  Google Scholar 

  113. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357(25):2552–61.

    Article  PubMed Central  PubMed  Google Scholar 

  114. Sivars L, Näsman A, Tertipis N, Vlastos A, Ramqvist T, Dalianis T, et al. Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome. Cancer Med. 2014;3(2):376–84.

    Article  PubMed Central  PubMed  Google Scholar 

  115. Michaud WA, Nichols AC, Mroz EA, Faquin WC, Clark JR, Begum S, et al. Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res. 2009;15(5):1645–54.

    Article  PubMed Central  PubMed  Google Scholar 

  116. Nix P, Cawkwell L, Patmore H, Greenman J, Stafford N. Bcl-2 expression predicts radiotherapy failure in laryngeal cancer. Br J Cancer. 2005;92(12):2185–9.

    Article  PubMed Central  PubMed  Google Scholar 

  117. Gallo O, Boddi V, Calzolari A, Simonetti L, Trovati M, Bianchi S. Bcl-2 protein expression correlates with recurrence and survival in early stage head and neck cancer treated by radiotherapy. Clin Cancer Res. 1996;2(2):261–7.

    PubMed  Google Scholar 

  118. Nichols AC, Finkelstein DM, Faquin WC, Westra WH, Mroz EA, Kneuertz P, Begum S, et al. Bcl2 and human papilloma virus 16 as predictors of outcome following concurrent chemoradiation for advanced oropharyngeal cancer. Clin Cancer Res. 2010;16(7):2138–46.

    Article  PubMed  Google Scholar 

  119. Johnson SW, O’Dwyer PJ. Cisplatin and its analogues. In: DeVita VT, Rosenberg SA, editors. Principles and practice of oncology. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 380–2.

    Google Scholar 

  120. Handra-Luca A, Hernandez J, Mountzios G, Taranchon E, Lacau-St-Guily J, Soria J-C, et al. Excision repair cross complementation group 1 immunohistochemical expression predicts objective response and cancer-specific survival in patients treated by Cisplatin-based induction chemotherapy for locally advanced head and neck squamous cell carcinoma. Clin Cancer Res. 2007;13(13):3855–9.

    Article  PubMed  Google Scholar 

  121. Jun H, Ahn M, Kim H, Yi S, Han J, Lee S, et al. ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation. Br J Cancer. 2008;99(1):167–72.

    Article  PubMed Central  PubMed  Google Scholar 

  122. Mehra R, Zhu F, Yang D-H, Cai KQ, Weaver J, Singh MK, et al. Quantification of excision repair cross-complementing group 1 and survival in p16-negative squamous cell head and neck cancers. Clin Cancer Res. 2013;19(23):6633–43.

    Article  PubMed Central  PubMed  Google Scholar 

  123. Ang M-K, Patel MR, Yin X-Y, Sundaram S, Fritchie K, Zhao N, et al. High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2011;17(20):6542–52.

    Article  PubMed Central  PubMed  Google Scholar 

  124. Pignataro L, Pruneri G, Carboni N, Capaccio P, Cesana BM, Neri A, et al. Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma. J Clin Oncol. 1998;16(9):3069–77.

    PubMed  Google Scholar 

  125. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429–37.

    Article  PubMed Central  PubMed  Google Scholar 

  126. Zhao Z, Ge J, Sun Y, Tian L, Lu J, Liu M, et al. Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis. Oral Oncol. 2012;48(9):761–7.

    Article  PubMed  Google Scholar 

  127. Goto M, Mitra RS, Liu M, Lee J, Henson BS, Carey T, et al. Rap1 stabilizes β-catenin and enhances β-catenin–dependent transcription and invasion in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2010;16(1):65–76.

    Article  PubMed Central  PubMed  Google Scholar 

  128. Molina MA, Cheung MC, Perez EA, Byrne MM, Franceschi D, Moffat FL, et al. African American and poor patients have a dramatically worse prognosis for head and neck cancer. Cancer. 2008;113(10):2797–806.

    Article  PubMed  Google Scholar 

  129. Schrank TP, Han Y, Weiss H, Resto VA. Case-matching analysis of head and neck squamous cell carcinoma in racial and ethnic minorities in the United States—possible role for human papillomavirus in survival disparities. Head Neck. 2011;33(1):45–53.

    Article  PubMed Central  PubMed  Google Scholar 

  130. Slaughter DP, Southwick HW, Smejkal W. “Field cancerization” in oral stratified squamous epithelium. Clinical implications of multicentric origin. Cancer. 1953;6(5):963–8.

    Article  PubMed  Google Scholar 

  131. Koch WM, Boyle JO, Mao L, Hakim J, Hruban RH, Sidransky D. p53 gene mutations as markers of tumor spread in synchronous oral cancers. Arch Otolaryngol Head Neck Surg. 1994;120(9):943–7.

    Article  PubMed  Google Scholar 

  132. Cohen RB. Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)-and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat Rev. 2014;40(4):567–77.

    Article  PubMed  Google Scholar 

  133. Vermorken J, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol. 2010;21 Suppl 7:vii252–61.

    PubMed  Google Scholar 

  134. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.

    Article  PubMed  Google Scholar 

  135. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.

    Article  PubMed  Google Scholar 

  136. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–8.

    Article  PubMed  Google Scholar 

  137. Gill GN, Kawamoto T, Cochet C, Le A, Sato J, Masui H, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem. 1984;259(12):7755–60.

    PubMed  Google Scholar 

  138. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1(11):1311–8.

    PubMed  Google Scholar 

  139. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol. 2001;13(6):506–13.

    Article  PubMed  Google Scholar 

  140. Sharafinski ME, Ferris RL, Ferrone S, Grandis JR. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck. 2010;32(10):1412–21.

    Article  PubMed Central  PubMed  Google Scholar 

  141. Bleeker WK, van Bueren JJL, van Ojik HH, Gerritsen AF, Pluyter M, Houtkamp M, et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol. 2004;173(7):4699–707.

    Article  PubMed  Google Scholar 

  142. Dechant M, Weisner W, Berger S, Peipp M, Beyer T, Schneider-Merck T, et al. Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies. Cancer Res. 2008;68(13):4998–5003.

    Article  PubMed  Google Scholar 

  143. Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie H-B, Davidson HC, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen–specific t-cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72.

    Article  PubMed Central  PubMed  Google Scholar 

  144. Trivedi S, Concha-Benavente F, Srivastava RM, Jie HB, Gibson SP, Schmitt NC, et al. Immune biomarkers of anti-EGFR monoclonal antibody therapy. Ann Oncol. 2015;26(1):40–7.

    Article  PubMed Central  PubMed  Google Scholar 

  145. Mahipal A, Kothari N, Gupta S. Epidermal growth factor receptor inhibitors: coming of age. Cancer Control. 2014;21(1):74–9.

    PubMed  Google Scholar 

  146. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22(1):77–85.

    Article  PubMed  Google Scholar 

  147. Roskoski Jr R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmaco Res. 2014;79:34–74.

    Article  Google Scholar 

  148. Lothaire P, de Azambuja E, Dequanter D, Lalami Y, Sotiriou C, Andry G, et al. Molecular markers of head and neck squamous cell carcinoma: promising signs in need of prospective evaluation. Head Neck. 2006;28(3):256–69.

    Article  PubMed  Google Scholar 

  149. Le Tourneau C, Siu LL. Molecular-targeted therapies in the treatment of squamous cell carcinomas of the head and neck. Curr Opin Oncol. 2008;20(3):256–63.

    Article  PubMed  Google Scholar 

  150. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  PubMed  Google Scholar 

  151. Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med. 1995;332(11):712–7.

    Article  PubMed  Google Scholar 

  152. Yoo GH, Moon J, LeBlanc M, Lonardo F, Urba S, Kim H, et al. A phase 2 trial of surgery with perioperative INGN 201 (Ad5CMV-p53) gene therapy followed by chemoradiotherapy for advanced, resectable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx: report of the Southwest Oncology Group. Arch Otolaryngol Head Neck Surg. 2009;135(9):869–74.

    Article  PubMed Central  PubMed  Google Scholar 

  153. Selzer E, Kornek G. Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments. Expert Rev Clin Pharmacol. 2013;6(6):663–76.

    Article  PubMed  Google Scholar 

  154. Dorsey K, Agulnik M. Promising new molecular targeted therapies in head and neck cancer. Drugs. 2013;73(4):315–25.

    Article  PubMed  Google Scholar 

  155. Worsham MJ, Ali H, Dragovic J, Schweitzer VP. Molecular characterization of head and neck cancer. Mol Diagn Ther. 2012;16(4):209–22.

    Article  PubMed Central  PubMed  Google Scholar 

  156. Egloff AM, Grandis JR. Improving response rates to EGFR-targeted therapies for head and neck squamous cell carcinoma: candidate predictive biomarkers and combination treatment with src inhibitors. J Oncol. 2009;2009:896407.

    Article  PubMed Central  PubMed  Google Scholar 

  157. Argiris A, Lee SC, Feinstein T, Thomas S, Branstetter IV BF, Seethala R, et al. Serum biomarkers as potential predictors of antitumor activity of cetuximab-containing therapy for locally advanced head and neck cancer. Oral Oncol. 2011;47(10):961–6.

    Article  PubMed Central  PubMed  Google Scholar 

  158. Licitra L, Mesia R, Rivera F, Remenar E, Hitt R, Erfan J, Rottey S, Kawecki A, Zabolotnyy D, Benasso M. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011;22(5):1078–87.

    Article  PubMed Central  PubMed  Google Scholar 

  159. Reimers N, Kasper HU, Weissenborn SJ, Stützer H, Preuss SF, Hoffmann TK, Speel EJM, Dienes HP, Pfister HJ, Guntinas‐Lichius O. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer. 2007;120(8):1731–8.

    Article  PubMed  Google Scholar 

  160. Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH, Wolf GT, Urba SG, Chepeha DB, Teknos TN. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol. 2008;26(19):3128–37.

    Article  PubMed Central  PubMed  Google Scholar 

  161. Study of Panitumumab Efficacy in Patients with Recurrent and/or Metastatic Head and Neck Cancer (SPECTRUM). Available at: http://clinicaltrials.gov/show/NCT00460265.

  162. Forastiere AA, Burtness BA. Epidermal growth factor receptor inhibition in head and neck cancer—more insights, but more questions. J Clin Oncol. 2007;25(16):2152–5.

    Article  PubMed  Google Scholar 

  163. Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N, Du Y, et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS One. 2013;8(2):e56823.

    Article  PubMed Central  PubMed  Google Scholar 

  164. Martinez I, Wang J, Hobson KF, Ferris RL, Khan SA. Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas. Eur J Cancer. 2007;43(2):415–32.

    Article  PubMed Central  PubMed  Google Scholar 

  165. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803–12.

    Article  PubMed  Google Scholar 

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  1. Division of Oral Medicine, Pathology and Radiology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA

    Nisha J. D’Silva BDS, MSD, PhD

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  1. School of Dentistry, The University of Michigan, Ann Arbor, Michigan, USA

    Peter J. Polverini

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D’Silva, N.J. (2015). Biomarkers for Individualized Oral Cancer Therapy. In: Polverini, P. (eds) Personalized Oral Health Care. Springer, Cham. https://doi.org/10.1007/978-3-319-23297-3_4

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