STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort
Top Cited Papers
Open Access
- 1 January 2020
- journal article
- research article
- Published by Elsevier BV in ESMO Open
- Vol. 5 (2), e000706
- https://doi.org/10.1136/esmoopen-2020-000706
Abstract
Introduction Somatic mutations in STK11 and KEAP1, frequently comutated in non-squamous non-small cell lung cancer (NSQ NSCLC), have been associated with poor response to immune checkpoint blockade (ICB). However, previous reports lack non-ICB controls needed to properly ascertain the predictive nature of those biomarkers. The objective of this study was to evaluate the predictive versus prognostic effect of STK11 or KEAP1 mutations in NSQ NSCLC. Methods Patients diagnosed with stage IIIB, IIIC, IVA or IVB NSQ NSCLC from a real-world data cohort from the Flatiron Health Network linked with genetic testing from Foundation Medicine were retrospectively assessed. Real-world, progression-free survival (rwPFS) and overall survival (OS) were calculated from time of initiation of first-line treatment. Results We analysed clinical and mutational data for 2276 patients including patients treated with anti-programmed death-1 (PD-1)/anti-programmed death ligand 1 (PD-L1) inhibitors at first line (n=574). Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in ICB cohorts. There was no observable interaction between STK11 mutations and anti-PD-1/anti-PD-L1 treatment on rwPFS (HR, 1.05; 95% CI 0.76 to 1.44; p=0.785) or OS (HR, 1.13; 95% CI 0.76 to 1.67; p=0.540). Similarly, there was no observable interaction between KEAP1 mutations and treatment on rwPFS (HR, 0.93; 95% CI 0.67 to 1.28; p=0.653) or OS (HR, 0.98; 95% CI 0.66 to 1.45; p=0.913). Conclusion Our results show that STK11-KEAP1 mutations are prognostic, not predictive, biomarkers for anti-PD-1/anti-PD-L1 therapy.Keywords
Funding Information
- Bristol-Myers Squibb
This publication has 21 references indexed in Scilit:
- Effects of Co-occurring Genomic Alterations on Outcomes in Patients withKRAS-Mutant Non–Small Cell Lung CancerClinical Cancer Research, 2018
- Correction: KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancereLife, 2017
- LKB1/STK11 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic valueLung Cancer, 2017
- KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancereLife, 2017
- Predictive biomarkers for checkpoint inhibitor-based immunotherapyThe Lancet Oncology, 2016
- Complex heatmaps reveal patterns and correlations in multidimensional genomic dataBioinformatics, 2016
- STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor MicroenvironmentCancer Research, 2016
- Different prognostic impact ofSTK11mutations in non-squamous non-small-cell lung cancerOncotarget, 2015
- The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancerRedox Biology, 2013
- The LKB1–AMPK pathway: metabolism and growth control in tumour suppressionNature Reviews Cancer, 2009