1. INT Translational research in head and neck cancer: preoperative chemotherapy in oral cavity cancer based on disease molecular profiling. Paolo Bossi MSO young investigator and Salvatore Venuta Prize Medical Oncology Head and Neck Unit Fondazione IRCCS Istituto Nazionale Tumori Milano INT

2. Head and Neck Cancer: a challenging field -Most “visible” cancers -They affect social functions -More frequent in socially-deprived people

3. INT Multidisciplinary work RADIOTHERAPY MEDICAL ONCOLOGY SURGERY RADIOLOGY NUTRITION MOLECULAR BIOLOGY MULTIDISCIPLINARY ASCO-ESMO Consensus on Quality Cancer Care

4. INT -Microarray analysis of preTx Nasopharyngeal Cancer  Radioresistance Profile? -HPV negative oropharyngeal cancer: biomolecular prognostic factors -Role of cytokine profile and growth factors in serum and drainage fluids Ongoing studies on Translational Research…

5. INT -The sixth most common cancer worldwide - Visible? Parallel with colon cancer: 36% rate of early stage detection -Overall Survival depending on stage: Oral Cavity Squamous Cell Cancer –OCSCC-

6. INT State of the art Treatment “The ultimate goal of treatment is to eradicate the cancer, preserve or restore form and function, minimize the sequelae of treatment and finally prevent any subsequent new primary cancers” STAGE III-IV: optimal surgery, followed by radio(chemo)therapy

7. INT Aim of the study: to improve survival of OCSCC through a molecular profiled selected treatment Phase II study of preoperative TPF chemotherapy in locally advanced resectable OCSCC

8. INT Journal of Clinical Oncology 2003 BACKGROUND –Induction PF study

9. INT 198 patients enrolled 2 treatment arms: 1) CT (CDDP-5FU)  surgery+/- RT 2) surgery+/- RT no different postoperative morbidity no difference in survival BACKGROUND - Induction PF study

10. INT

12. Less mandibulectomy and postoperative RT in chemotherapy treated arm BACKGROUND - Induction PF study

13. INT - Pathologic Response Rate similar to Radiological-Clinical one - Pathologic Complete Response (pCR) obtained in 27% of the patients treated with induction CT BACKGROUND - Induction PF study

14. INT Overall Survival according to response to chemotherapy p = 0.03

15. INT NEXT STEP  need for effective antiblastic treatment with a biological tumor selection  To spare toxic treatment to whom is not expected to optimally respond NEXT STEP

16. INT NEXT STEP: TPF better than PF

17. INT NEXT STEP: predictive factors p53 in Head and Neck Cancer - TP53 mutations recognized prognostic factor (disruptive mut and non functional protein in particular) - Predictive role of p53 in response to chemotherapy

18. INT

19. pCR non pCR pts p53 protein "functional" status p53 nonfunctional 2/14 (14%) 18/37 (49%) 20 p53 functional 12/14 (86%) 19/37 (51%) 31 P = 0.02 NEXT STEP: predictive factors

20. INT p53 translational research

21. INT NEXT STEP: predictive factors Beta-Tubulin in Head and Neck Cancer -

22. INT

24. Ongoing phase II study of preoperative TPF INCLUSION CRITERIA - Hystologically proved primary OCSCC - Stage T2 (> 3 cm)-T3, N1-N3 and T4a any N -WHO performance status < 1 - Availability of Formalin Fixed Paraffin Embedded biopsy of the tumour - Radiological imaging with MRI pre-therapy

25. INT Ongoing phase II study of preoperative TPF EXCLUSION CRITERIA - Prior antitumor therapy for head & neck cancer - Previous OCSCC to less than 2 cm from primary - Screening laboratory values - Weight loss > 20% in previous 3 months - Technical unresectability defined as: T4b staging or N ulcerating the skin or encasing internal carotid

26. INT Ongoing phase II study of preoperative TPF STUDY DESIGN Patient Selection and Informed Consent Diagnostic Biopsy and Molecular Analysis non functional p53 and high B-Tub Patient non eligible functional p53 or high B-Tub 3 cycles of TPF chemotherapy Surgery Postoperative (chemo)radiation

27. INT Ongoing phase II study of preoperative TPF PRIMARY ENDPOINT To increase rate of pCR to 50% of the patients treated with induction chemotherapy Sample Size: type I error of 10% for a mono-lateral test, power of 95% (beta=5%), plus 10% drop-out rate = 64 patients to be enrolled

28. INT Ongoing phase II study of preoperative TPF SECONDARY ENDPOINT - Early functional response evaluation by DWI and DCE MRI - Comparison between (DWI - DCE) MRI response and pathological response Functional Imaging as possible predictor of early response and for the measurement of drug effects on tumour (micro)vascularity and capillary permeability.

29. INT Ongoing phase II study of preoperative TPF SECONDARY ENDPOINT - Percentage of patient receiving postop radiotherapy and chemotherapy - Progression free survival and overall survival - Second primary tumour incidence

30. INT Ongoing phase II study of preoperative TPF STRENGHT - Molecular profiled driven treatment - Prospective trial in specialized Centers - Centralized pathologic, molecular and radiologic evaluation - Trial potentially opening new scenarios in personalized treatment

31. INT Ongoing phase II study of preoperative TPF WEAKNESS - Only 2 molecular alteration as predictor of response - Trial based on adding therapy, not on “removing” part of it (need for larger trial)

32. INT Ongoing phase II study of preoperative TPF CONCLUSIONS - Results foreseen within 2012 - Looking for increase in OS, through new therapeutic strategy - Towards an individualized treatment approach - The importance of multidisciplinary work and translational research