Association of p53 mutations with progression-free survival (PFS) and overall survival (OS) in EGFR-mutated non-small cell lung cancer (NSCLC) patients (p) treated with erlotinib.

Abstract

e18143 Background: Advanced NSCLC p with EGFR mutations have a median PFS of 14 months (m) and OS of 27 m when treated with erlotinib. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent upregulation of Fas and caspase activation leading to apoptosis, but this mechanism was defective in p53-null cells. We tested whether TP53 mutations influence outcome to erlotinib in EGFR-mutated p. Expression levels of the p53 repressor MDM2 were also examined. Methods: We assessed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR-mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis followed by sequencing of the amplified products with non-wild-type (wt) melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of TP53 were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations were less frequent in p with ECOG PS >2 and more frequent in p with the T790M mutation. OS was 15 m in the 16 p with missense mutations 31 m in p with wt p53 and not reached in p with non-missense mutations (P=0.04). PFS was 9 m for 14 p with mutations in one of the p53 DNA binding motifs (DBMs), compared to 19 m for wt p and 27 m for p with non-DBM mutations. MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially in DBM mutations. In the case of wt p, high MDM2 expression correlated with longer PFS and OS in p with wt p53. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; missense mutations correlate with shorter OS and mutations in DBMs correlate with shorter PFS. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring certain types of mutations in the TP53 gene.