Oncogene Driver Status Modulates TP53 Prognostic Impact in Advanced NSCLC
- 1Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
Abstract
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 Permanent 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.
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BibTeX
@misc{pan2026oncogene,
title = {{Oncogene Driver Status Modulates TP53 Prognostic Impact in Advanced NSCLC}},
author = {M. Pan and C. Jiang and J. Song and S. Kudrimoti and J. V. Aredo and H. A. Wakelee and J. W. Neal and J. Zhao and Y. Kamgarhaghighi and N. S. Achacoso and A. V. Solorzano and P. Tse and E. Chung and L. Sakoda and M. J. Suga and S. Thomas and L. Habel},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.26362258},
url = {https://www.medrxiv.org/content/10.64898/2026.09.04.26362258v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - Oncogene Driver Status Modulates TP53 Prognostic Impact in Advanced NSCLC
AU - M. Pan
AU - C. Jiang
AU - J. Song
AU - S. Kudrimoti
AU - J. V. Aredo
AU - H. A. Wakelee
AU - J. W. Neal
AU - J. Zhao
AU - Y. Kamgarhaghighi
AU - N. S. Achacoso
AU - A. V. Solorzano
AU - P. Tse
AU - E. Chung
AU - L. Sakoda
AU - M. J. Suga
AU - S. Thomas
AU - L. Habel
PY - 2026
DA - 2026/09/04
PB - medRxiv
DO - 10.64898/2026.09.04.26362258
UR - https://www.medrxiv.org/content/10.64898/2026.09.04.26362258v1
AB - 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 Permanent 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.
ER -