Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non–Small-Cell Lung Cancer
Open accessAbstract
PURPOSE: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non–small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/ KRAS, 18 had STK11/ TP53, and seven had STK11/ KRAS/ TP53. Patients with STK11/ KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/ TP53 (4.3 months; log-rank P = .043), and STK11/ KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/ KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/ TP53 (28.3 months; log-rank P < .001), and STK11/ KRAS/ TP53 (22 months; log-rank P = .025). CONCLUSION: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.
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STK11 co-mutations are associated with worse survival in KRAS-mutant lung cancers.
“STK11 co-mutations have been associated with worse survival in KRAS-mutant lung cancers [54, 55].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [54]
KRAS/STK11 co-mutations often have a CD8+ T-lymphocyte deficient and T-regulatory cell rich microenvironment whereas tumours with KRAS/p53 co-mutations have an inflamed tumour microenvironment rich in CD8+ T-lymphocytes.
“KRAS/STK11 co-mutations often have a CD8 + T-lymphocyte deficient and T-regulatory cell rich microenvironment whereas tumours with KRAS/p53 co-mutations have an inflamed tumour microenvironment, rich in CD8 + T-lymphocytes [54, 56].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [54]
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- Authors
- Bange, E., Marmarelis, M. E., Hwang, W.-T., Yang, Y.-X., Thompson, J. C., Rosenbaum, J., Bauml, J. M., Ciunci, C., Alley, E. W., Cohen, R. B., Langer, C. J., Carpenter, E., & Aggarwal, C.
- Affiliations
- University of Pennsylvania (US)
- ORCID
- Venue
- JCO Precision Oncology
- Published
- 2019-12
- Volume
- 3
- Issue
- 3
- Pages
- 1-11
- ISSN
- 2473-4284 (ISSN-L)
- PMC
- PMC6699781
- OpenAlex
- W2944810278
- Cited by
- 74
- References
- 27
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 10 · 2021: 18 · 2020: 10 · 2019: 2
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JCO Precision Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K08CA234335, T32CA009679, P30CA016520)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- TP53 co-mutation, non-small cell lung cancer, metastatic lung cancer, first-line systemic therapy, progression-free survival, overall survival, tumor suppressor, somatic mutations, prognostic factors, liquid biopsy, circulating tumor DNA, immunotherapy
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