Brief Report: Characterization of the Potentially Actionable TP53 Y220C Mutation in Non-Small Cell Lung Cancer. A Multicenter, European Thoracic Oncology Platform Study.
Abstract
INTRODUCTION The tumor suppressor TP53 is the most frequently mutated gene in human cancer, and drugs targeting specific mutant p53 proteins have been developed. Rezatapopt, which reactivates the Y220C p53 protein, was recently evaluated in the Phase I PYNNACLE trial in patients with solid tumors, with promising results. The trial did not enrol any non-small cell lung cancer (NSCLC) cases, and little is known about the clinicopathological characteristics and genetic profile of the TP53 Y220C NSCLC patients.
Methods
In this multicenter, European Thoracic Oncology Platform-sponsored study, we retrospectively collected data from NSCLC patients from several European institutions with Next Generation Sequencing data available.
Results
The study included 28,244 NSCLC patients. We found that 195 (0.7%) harbored the TP53 Y220C mutation, a prevalence higher than the average in solid tumors (0.4%). Half of these TP53 Y220C NSCLC patients did not carry any known drivers. No significant association was observed between the TP53 Y220C and gender, smoking status, histology or stage. However, the mutation was significantly more prevalent in EGFR-mutant than EGFR-wild-type tumors (1.7% vs. 0.7%; p=0.029). Finally, 17.0% of Y220C patients carried a second mutation in TP53.
Conclusions
The TP53 Y220C has a frequency similar to other low abundance, actionable alterations in NSCLC. Patients with NSCLC should be screened and included in future trials of Y220C reactivators. Co-mutations in TP53 should also be analyzed, since they might be associated with intrinsic resistance.