1. p53 adapted neoadjuvant therapy for esophageal cancer: Pilot study Gastrointestinal (Non colorectal) cancer Poster discussion session Sat, June 2, 2007

2. 2002 MRC Lancet 1988 INT NEJ The two largest trials produced conflicting results 34%13402SURGERY 0.00443%17400 CIS/5FU +SURGERY 37%16234SURGERY ns35%15233 CIS/5FU +SURGERY p OVS 2y median survival #Therapy vs …indicating moderate efficiency of standard neoadjuvant therapy

3. Pathologic response to neoadjuvant therapy improves overall survival significanty neoadjuvant therapy all OVS 3 yspCR OVS 3 ys Urba, JCO 2001 CIS/5FU, VBL, 45 Gy + Surg30%28%64%

4. Esophageal Cancer - Neoadjuvant Therapy: …Overall failure rate = p53 mutation rate (60%)… 60% 40%

5. PILOT STUDY: Prospective evaluation of hypothesis 38 operable esophageal cancer patients, prospectively recruited between 2004-2006 Neoadjuvant therapy: 30 patients CIS/5FU Cisplatin 80mg/m 2 d1, 5FU 1000mg/m 2 d1-5 2 cycles q21d 8 patients Docetaxel off label Docetaxel 75mg/m 2 2 cycles q21d

6. The presence of p53 mutations must not be assessed by immunohistochemistry …sequence analysis is the golden standard immunohistochemistrysequence analysis

7. Neoadjuvant treatment 1: CIS/5FU Response CR, PR Failure SD, PD p53 normal122 p53 mutant016 p=0,0001 30 patients

8. Neoadjuvant treatment 2 : Docetaxel Response CR, PR Failure SD, PD p53 normal02 p53 mutant6*0 8 patients off label *including 4 CR

9. p53 mutation by histology p53 normal p53 mutant adeno9950% squamous71365% 42%58% p53 mutation frequency

10. Correct response prediction in 36/38 patients (95%). CR, PRSD, PD CIS/5FU p53 normal122 p53 mutant016 Docetaxel p53 normal02 p53 mutant60

11. p53 adjusted versus non adjusted therapy p=0,027 p53 adjusted p53 not adjusted p=0,042 months median follow up: 15,4 months Overall survival

12. …Selection of the appropriate therapy based on the p53 genotype Failure Benefit side effects costs … could significantly improve likelihood of response

13. PANCHO: P53 Adapted Neoadjuvant Chemotherapy for Oesophageal cancer Prospective, randomized controlled, PREDICTIVE MARKER TRIAL …designed to test the p53 predictive factor question

14. Pancho : trial design randomize p53 mutant randomize stratify * p53 normal p53 gene analysis Patients with resectable esophageal cancer SURGERYSURGERY Cisplatin 80 mg/m², day 1, 3 cycles 5-FU 1000 mg/m² days 1-5; q 21,3 cycles Docetaxel 75 mg/m², day 1, q 21, 3 cycles Cisplatin 80 mg/m², day 1, 3 cycles 5-FU 1000 mg/m² days 1-5; q 21,3 cycles Docetaxel 75 mg/m², day 1, q 21, 3 cycles * Stratification for adeno- and squamous cell cancer Primary endpoint: RESPONSE to neaoadjuvant therapy

15. PANCHO Start: Mai 2007 84 patients to be randomized within 18 months Intended by www.p53.at Sponsored by the ASSO (Austrian Society for Surgical Oncology)