P53 non-disruptive mutation is a negative predictive factor in EGFR M+ NSCLC treated with TKI

Background

P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients. The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as disruptive and non-disruptive according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 M+ within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

Methods

409 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR M+ included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either MiSeq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 95% of the patients.

Results

409 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The overall EGFR M+ rate was 18% (73/409) in all patients, 73% (53/73) showing common mutations of exon 19 or 21. In 21/73 (29%) patients' p53 analysis was not successful. P53 disruptive mutations were demonstrated in 25% (13/52) of successfully tested patients, and p53 non-disruptive mutation occurred in 31% (16/52) whereas p53 WT configuration was found in 44% (23/52). Median OS was 28 months in p53 disruptive mutation and 42 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p 

Conclusions

Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 mutation status. P53 mutational status is only predictive when disruptive and non-disruptive p53 mutations are differentiated. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

Clinical trial identification

Legal entity responsible for the study

Prof. Dr. Frank Griesinger

Funding

Pius Hospital Oldenburg; University Oldenburg

Disclosure

All authors have declared no conflicts of interest.