Alterations on chromosome 17 as predictive markers for neoadjuvant treatment of gastric cancer

Objective: Former published data of our group suggested that loss of heterocygocity (LOH) at chromosome 17pl3 could be associated with good clinical response to neoadjuvant cis-platinum based chemotherapy for locally advanced gastric cancer. Therefore we wanted to prove the hypothesis that altered p53 function might modulate sensitivity to chemotherapy. Patients and methods: Pretherapeutic biopsies of 53 patients (pts.) treated with more than 50% of the projected dose of cisplatinum based chemotherapy were studied at 11 microsatellite loci. A allele peak ratio of <0.6 representing an allelic signal reduction of 40% was considered as LOH. All biopsies were further analysed by denaturating high-performance liquid chromatography (DHPLC). A primer set spanning the whole coding region of the p53 was used. Biopsies with altered p53 in DHPLC were sequenced directely. Immunohistochemistry (ICH) for p53 was performed using an automatic staining device with the D07 mono-clonal antibody. Results: 49 (92%) of the 53 patients were resected. 21/53 (40%) patients were clinical responders, 14 of 48 (29%) évaluable patients with less than 10% vital tumor cells were classified as pathological responders. 15 of 45 (33%) tumors exhibited LOH at TP53 and 9 of them had a p53 mutation. 19 pts. had 20 p53 mutations proven by direct sequencing. There were 6 mutations in exon 5, 7 in exon 7, 6 in exon 8 and 1 in exon 9 (one pt. had mutations in exons 5 and 8). No correlation between réponse and type or localisation of mutation could be found. p53 overexpression was found in 17 (35%) of the biopsies whereas 31 (65%) were negative. LOH TP53 ICH mut p53 Clin. Resp. 10/18(56%)°6/19(32%) 9/21(43%) Clin. Non-R. 5/27(19%)°11/29(38%) 10/32(31%) Path. Resp. 7/11(64%)5/13(38%) 6/14(43%) Path. Non-R. 6/30(20%)12/31(39%) 11/34(32%) significant >=0,014p=0,020 28/53 pts. are still alive with a median follow up of 21,5 months (3,3-87 m.). The median survival for all pts was 35 months. LOH TP 53 mutation p53 any alteration ehr. 17 +:n=15 -:n=30 +:n=19 -:n=24 +:n=31 -: n=22 med. survival 59 32 67 28 55 22 p-value 0,09 0,18 0.01 (log-rank) Conclusion: 1. LOH at chromosome 17pl3 is associated with good response. 2. Mutation of p53 is not associated with response. 3. Other mechanisms on chr. 17 than p53 mutation must render cells more sensitive to chemotherapy and improve survival.