Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer

Abstract

Background: Osimertinib was approved as a standard therapy for EGFR-mutant lung cancer with brain metastasis. It has been demonstrated that TP53 mutations was responsible for Gefitinib resistance in a preclinical study. This study was to analyze the impact of TP53 mutations on response to first-line Osimertinib in EGFR-mutant patients with brain metastasis from non-small cell lung cancer (NSCLC). Method(s): 100 EGFR-mutated NSCLC patients with brain metastasis receiving first-line Osimertinib were analyzed. TP53 mutations were evaluated in all patients in relation to disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Result(s): TP53 mutations were observed in 48 (48%), 11 (22.92%), 7 (14.58%), 12 (25%) and 18 (37.5%) patients in exon 5, 6, 7, and 8, respectively. TP53 mutations were significantly associated with increasing brain-metastatic sites (P<0.05). DCR was 29.17% in TP53-mutated patients compared to 94.23% in patients with TP53-wild type (P<0.05). All patients with TP53 exon 8 mutations had primary resistance to Osimertinib. Compared with others, significantly shorter median PFS and OS were observed both in total TP53-mutated patients (mPFS 4.8 vs 10 months, P<0.001; mOS 10.98 vs 25.45 months, P<0.001) and patients with TP53 exon 8 mutations ((mPFS 4 vs 9 months, P<0.001; mOS 8.25 vs 19.98 months, P<0.001)), compared with others. TP53 exon 8 mutation was an independent prognostic factor adjusting for other subtypes of TP53 mutation (P<0.001). Conclusion(s): TP53 mutations, especially exon 8 mutations, reduced the efficacy of Osimertinib and worsen prognosis in EGFR-mutated NSCLC patients with brain metastasis. TP53 mutation might be used as a predictor for Osimertinib therapy and a prognostic factor for EGFR-mutated NSCLC patients with brain metastasis.