Evaluation of immunohistochemical expression of p53, p21, p27, cyclin D1, and Ki67 in oral and oropharyngeal squamous cell carcinoma.

BACKGROUND The purpose of this study was to evaluate whether the immunohistochemical expression of p53, p21, p27, cyclin D1, and Ki67 can predict therapy response and survival in patients with oral and oropharyngeal squamous cell carcinoma treated with preoperative chemoradiation. METHODS Biomarker expression was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded pretreatment biopsies of 111 homogenously treated patients. We assessed the association between clinicopathological variables including response to neoadjuvant chemoradiotherapy as well as the survival of the patients and the expression of the biomarkers as both dichotomized (positive vs. negative) and continuous variables. RESULTS Biomarker overexpression on the basis of pre-selected cutoff points was seen in 66 of 111 (59%) cases for p53, in 77 (69%) for p21, in 48 (43%) for p27, in 81 (73%) for cyclin D1, and in 54 (49%) cases for Ki67, respectively. None of the examined biomarkers was able to predict response to neoadjuvant chemoradiotherapy or was associated with survival outcome. Post-treatment pathologic TNM stage (P < 0.001), pathologic response (P < 0.001), and perineural invasion (P < 0.001) were the only factors having a significant effect on recurrence-free survival. Post-treatment pathologic N stage (P = 0.005), post-treatment pathologic TNM stage (P < 0.001), pathologic response (P < 0.001), and perineural invasion (P = 0.001) had a significant impact on overall survival. CONCLUSIONS Our results suggest that the biomarkers p53, p21, p27, cyclin D1, and Ki67 have no impact on treatment response and survival in patients with oral and oropharyngeal cancer treated with preoperative chemoradiation.

[1]  F. Esteban,et al.  Analysis of Ki-67 expression in oral squamous cell carcinoma: why Ki-67 is not a prognostic indicator. , 2010, Oral oncology.

[2]  J. Ferlay,et al.  Estimates of cancer incidence and mortality in Europe in 2008. , 2010, European journal of cancer.

[3]  Richard D Riley,et al.  A Systematic Review of p53 as a Prognostic Factor of Survival in Squamous Cell Carcinoma of the Four Main Anatomical Subsites of the Head and Neck , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[4]  Richard D Riley,et al.  Ten steps towards improving prognosis research , 2009, BMJ : British Medical Journal.

[5]  T. Ettl,et al.  Outcome and Histopathologic Regression in Oral Squamous Cell Carcinoma after Preoperative Radiochemotherapy , 2009, Strahlentherapie und Onkologie.

[6]  E. Speel,et al.  P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis , 2009, Modern Pathology.

[7]  J. Luo,et al.  Ki-67 expression predicts locoregional recurrence in stage I oral tongue carcinoma , 2008, British Journal of Cancer.

[8]  C. Tsien,et al.  EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  C. Marsit,et al.  A Genotype-Phenotype Examination of Cyclin D1 on Risk and Outcome of Squamous Cell Carcinoma of the Head and Neck , 2008, Clinical Cancer Research.

[10]  Ludger Hengst,et al.  The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy , 2008, Nature Reviews Cancer.

[11]  M. Bremer,et al.  Preoperative Paclitaxel/Carboplatin Radiochemotherapy for Stage III/IV Resectable Oral and Oropharyngeal Cancer: Seven-Year Follow-Up of a Phase II Trial , 2008, Oncology.

[12]  M. Voracek,et al.  Preoperative chemoradiotherapy in the management of oral cancer: a review. , 2008, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[13]  A. Cmelak,et al.  Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. , 2008, Journal of the National Cancer Institute.

[14]  J. Manola,et al.  TP53 mutations and survival in squamous-cell carcinoma of the head and neck. , 2007, The New England journal of medicine.

[15]  J. Pignon,et al.  Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  J. Mühling,et al.  Neoadjuvant concurrent radiochemotherapy followed by surgery in advanced oral squamous cell carcinoma (OSCC): a retrospective analysis of 207 patients. , 2007, Oral oncology.

[17]  Karen H. Vousden,et al.  p53 in health and disease , 2007, Nature Reviews Molecular Cell Biology.

[18]  R. Ralhan,et al.  Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: Relationship with cell cycle regulators , 2006, International journal of cancer.

[19]  W. Sauerbrei,et al.  REporting recommendations for tumor MARKer prognostic studies (REMARK) , 2005, Nature Clinical Practice Oncology.

[20]  John P A Ioannidis,et al.  Selective reporting biases in cancer prognostic factor studies. , 2005, Journal of the National Cancer Institute.

[21]  Z. Nemes,et al.  p21WAF1/CIP1 expression is a marker of poor prognosis in oral squamous cell carcinoma. , 2005, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[22]  David L Rimm,et al.  Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  I. Nishimoto,et al.  Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell carcinoma. A clinicopathological study. , 2004, Oral oncology.

[24]  F. Fang,et al.  Low expression levels of p27 correlate with loco-regional recurrence in nasopharyngeal carcinoma. , 2003, Cancer letters.

[25]  F. Valvo,et al.  Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  C. Hwang,et al.  Loss of cyclin D1 and p16 expression correlates with local recurrence in nasopharyngeal carcinoma following radiotherapy. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[27]  M. Fresno,et al.  Expression of cyclin D1 and Ki-67 in squamous cell carcinoma of the oral cavity: clinicopathological and prognostic significance. , 2002, Oral Oncology.

[28]  M. Dictor,et al.  Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma. , 2000, Cancer.

[29]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[30]  J. Myers,et al.  Squamous cell carcinoma of the tongue in young adults: Increasing incidence and factors that predict treatment outcomes , 2000, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[31]  G. Pruneri,et al.  Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  R. Weinberg,et al.  Control of the cell cycle and apoptosis. , 1999, European journal of cancer.

[33]  Å. Borg,et al.  p53 mutation, but not p53 overexpression, correlates with survival in head and neck squamous cell carcinoma. , 1998, British Journal of Cancer.

[34]  R. Chetty,et al.  Cyclin D1 and human neoplasia. , 1998, Molecular pathology : MP.

[35]  J. Riera,et al.  Detection of p53 protein in oropharyngeal carcinoma. Prognostic implications. , 1996, Archives of otolaryngology--head & neck surgery.

[36]  W. Sauerbrei,et al.  Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. , 1994, Journal of the National Cancer Institute.

[37]  R. Orecchia,et al.  Can Ki67 immunostaining predict response to radiotherapy in oral squamous cell carcinoma? , 1994, Journal of clinical pathology.

[38]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[39]  S. Bogart.  Histologic tumor regression grades in squamous cell carcinoma of the head and neck after preoperative radiochemotherapy , 1989 .

[40]  H. Eich,et al.  Neoadjuvant Radiochemotherapy and Radical Resection for Advanced Squamous Cell Carcinoma of the Oral Cavity , 2008, Strahlentherapie und Onkologie.

[41]  G. Adamopoulos,et al.  p53, p21 and p27 protein expression in head and neck cancer and their prognostic value. , 2001, Anticancer research.

[42]  J. Hornung,et al.  Squamous cell carcinoma of the oropharynx: Ki-67 and p53 can identify patients at high risk for local recurrence after surgery and postoperative radiotherapy. , 2000, International journal of radiation oncology, biology, physics.

[43]  J. Regezi,et al.  Expression of p21/waf1 in oral squamous cell carcinomas--correlation with p53 and mdm2 and cellular proliferation index. , 1999, Oral oncology.

[44]  K. Yoneda,et al.  Expression of p53 and p21 proteins in oral squamous cell carcinoma: correlation with lymph node metastasis and response to chemoradiotherapy. , 1998, Pathology, research and practice.

[45]  J. Pindborg,et al.  Histological Classification of Cancer and Precancer of the Oral Mucosa , 1997 .

[46]  S. Lippman,et al.  p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. , 1996, Journal of the National Cancer Institute.