Correlation of p53 genotype and response to induction chemotherapy in advanced non small cell lung cancer (NSCLC)

Abstract

7043 Background: In NSCLC mutations in the p53 gene occur in 40%. The effect of standard chemotherapeutic drugs as cisplatinum and ifosfamide, etoposide is based on the induction of DNA damage in rapidly growing cells. DNA damage is the most powerful trigger for p53 activation and subsequent - p53 based- apoptosis induction. Mutations in the p53 gene are supposed to be a major factor for chemotherapy resistance. Methods: 59 Patients with stage IIIA and IIIB NSCLC and cisplatinum based induction chemotherapy (combined either with ifosfamide or etoposide) were included. The p53 gene was analysed using complete direct sequencing of tumour DNA deriving from paraffin embedded tissue (diagnostic biopsies and surgical specimens). Endpoint of the study was response to induction chemotherapy which was assessed according to RECIST criteria and confirmed by pathohistology in resected patients. Secondary endpoints were resection rate and survival. Results: The p53 mutation frequency was 32% with a higher rate in stage IIIB. A normal p53 gene was significantly associated with response to cisplatinum based induction treatment (32/40). A mutant p53 genotype was significantly associated with treatment failure (18/19) (p value < .001). The sensitivity (probability that normal p53 characterizes responders) was 97,0% (84,2 - 99,9). The negative predictive value (probability that patients with p53 mutation have no remission) was 94,7% (CI 74.0–99.9). Radical resection was significantly associated with p53 status (6/19 for mutated and 33/40 for normal p53; p value <.001). Patients with a normal p53 gene showed a significant advantage in overall survival (p value: log rank .003, Breslow .002) with a median follow up of 53,2 months. Conclusions: In advanced NSCLC radical resection depends on response to induction treatment. Chemotherapy used for induction treatment therefore warrant highest efficacy. The p53 genotype should be tested in well designed prospective induction treatment protocols as a predictive marker for treatment response. NSCLC patients with mutant p53 may require alternative treatment options. No significant financial relationships to disclose.