Predictive and Prognostic Potential of TP53 in Patients With Advanced Non-Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901).
Mutations in TP53 are commonly found in patients with epidermal growth factor receptor (EGFR) mutant advanced non-small-cell lung cancer (NSCLC). In this study, we determined the predictive and prognostic potential of different subtypes of TP53 using data from a phase III randomized trial (CTONG 0901).
The trial enrolled 195 patients who had undergone next-generation sequencing of 168 genes before treatment with EGFR tyrosine kinase inhibitors. Mutations in TP53 (exon 4 or 7, other mutations, and wild-type) were analyzed based on the therapeutic response and survival. A Cox proportional hazards model was used to determine the potential of the predictive and prognostic factors.
All 195 patients harbored activating EGFR mutations: the most common concomitant mutations were TP53 (134/195, 68.7%), CTNNB1 (20/195, 10.3%), and RB1 (16/195, 8.2%). The genetic profiles between patient subgroups administered first-line (132, 67.7%) or later-line (63, 32.3%) treatments did not significantly differ. The median progression-free survival in patients with mutations in exon 4 or 7 of TP53, other TP53 mutations, and wild-type TP53 were 9.4, 11.0, and 14.5 months (P = .009), respectively. Overall survival times were 15.8, 20.0, and 26.1 months (P = .004), respectively. Mutations in exon 4 or 7 of TP53 served as independent prognostic factors for progression-free (P = .001) and overall survival (P = .004) in patients.
Mutations in exon 4 and/or 7 in TP53 are promising predictive and prognostic indicators in EGFR-mutated NSCLC.
Publication Date: 2020-12-16
Journal: Clinical lung cancer
EGFR-mutant lung adenocarcinoma harboring co-mutational tumor suppressor genes predicts poor prognosis.
EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes.
From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed.
The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018).
Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.
Publication Date: 2020-05-04
Journal: Journal of cancer research and clinical oncology