Oncogene Driver Status Modulates TP53 Prognostic Impact in Advanced NSCLC

Purpose: We compared the association of concurrent TP53 pathogenic variants (PV) with overall survival (OS) by driver status in non-small cell lung cancer (NSCLC). Patients and Methods: The discovery cohort included 3,295 patients with stage IV NSCLC treated at Kaiser Permanente Northern California. The validation cohort included 12,982 NSCLC from 37 public cBioPortal studies. Driver-positive disease was defined as presence of EGFR, ALK, or ROS1 alteration. We used Cox regression modeling to estimate hazard ratios (HRs) for mortality, adjusting for demographics and other factors. Results: Among the discovery cohort, TP53 PV was associated with worse OS among patients with an EGFR, ALK, or ROS1 alteration (HR = 1.80, [95% confidence interval (CI), 1.50-2.15]) but not among those without a driver mutation (HR = 1.08, [95% CI, 0.97-1.21]). Among the validation cohort, TP53 PV was associated with worse OS with HR of 2.27 [1.92-2.69], 2.42 [1.42-4.10], 1.30 [1.20-1.42], and 3.09 [95% CI, 1.47-6.47], for EGFR-activating, ALK-fusion, EGFR/ALK wild-type disease and RET-fusion respectively. The differential association was largest in EGFR exon 20 insertion tumors, in which TP53 PV carried HR = 4.68 [95% CI, 2.34-9.37], 3.9-fold that in driver-negative disease; the corresponding ratio for ERBB2 exon 20 insertions were 1.23 [95% CI, 0.75-2.02]. TP53 PV was not associated with OS in squamous carcinoma. Conclusions: Association of TP53 PV with OS in advanced NSCLC appears to depend on co-occurrence of other driver mutations. This driver-dependent effect modification informs interpretation of TP53 status and may be useful for risk stratification in clinical practice.