The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy

Francis Proulx-Rocray; Bertrand Routy; Rami Nassabein; Wiam Belkaid; Danh Tran-Thanh; Julie Malo; Marion Tonneau; Omar El Ouarzadi; Marie Florescu; Mustapha Tehfe; Normand Blais

doi:10.1016/j.ctarc.2023.100767

The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy

Cancer Treat Res Commun. 2023:37:100767. doi: 10.1016/j.ctarc.2023.100767. Epub 2023 Oct 10.

Authors

Affiliations

¹ Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada.
² Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada; Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, 900 Saint-Denis Street, Montreal, QC, Canada.
³ Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, 900 Saint-Denis Street, Montreal, QC, Canada.
⁴ Pathology Department, Centre Hospitalier de l'Université de Montréal, 1051 Sanguinet Street, Montreal, QC, Canada.
⁵ Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada; Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, 900 Saint-Denis Street, Montreal, QC, Canada. Electronic address: normand.blais.chum@ssss.gouv.qc.ca.

PMID: 37832364
DOI: 10.1016/j.ctarc.2023.100767

Abstract

Background: PD-L1 expression is used to predict NSCLC response to ICIs, but its performance is suboptimal. The impact of KRAS mutations in these patients is unclear. Studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs.

Patients & methods: This is a retrospective study of patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. ORR and safety were compared using Wald method.

Results: From 100 patients with known KRAS status, 50 were mutated (KRAS^Mut). Mutation in TP53, STK11 and KEAP1 were present, and their status known in, respectively, 19/40 (47.5 %), 8/39 (20.5 %) and 4/38 (10.5 %) patients. STK11^Mut and KEAP1^Mut were associated with shorter overall survival when compared with wild type tumors (respectively median OS of 3.3 vs 20.4, p = 0.0001 and 10.1 vs 17.7, p = 0.24). When KRAS status was compounded with STK11/KEAP1, KRAS^Mut trended to a better prognosis in STK11+KEAP1^WT tumors (median OS 21.1 vs 15.8 for KRAS^WT, p = 0.15), but not for STK11+/-KEAP1^Mut tumors. The NLR was strongly impacted by STK11 (6.0^Mutvs 3.6^WT, p = 0.014) and TP53 (3.2^Mutvs 4.8^WT, p = 0.048), but not by KEAP1 or KRAS mutations.

Conclusion: STK11^Mut and KEAP1^Mut are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11^Mut but not by KEAP1^Mut, suggesting differences in their resistance mechanism. In STK11-KEAP1^WT tumors, KRAS^Mut seem associated with improved survival in NSCLC patients treated with ICIs.

Microabstract: Response of NSCLC to immunotherapy is not easily predictable. We conducted a retrospective study in 100 patients with NSCLC and a known KRAS status. By accounting for different co-mutations, KRAS mutation was found to be associated with a better median overall survival in STK11 and KEAP1 wild-type tumors (21.1 vs 15.8, p = 0.15). NLR was impacted by STK11, but not KEAP1 mutation, suggesting a difference in their resistance mechanism.

Keywords: Immunotherapy; KEAP1; KRAS; NSCLC; STK11.

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Humans
Immunotherapy
Kelch-Like ECH-Associated Protein 1 / genetics
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Mutation
NF-E2-Related Factor 2 / genetics
Prognosis
Protein Serine-Threonine Kinases / genetics
Proto-Oncogene Proteins p21(ras) / genetics
Retrospective Studies
Tumor Suppressor Protein p53 / genetics

Substances

Proto-Oncogene Proteins p21(ras)
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Protein Serine-Threonine Kinases
TP53 protein, human
Tumor Suppressor Protein p53
KRAS protein, human
KEAP1 protein, human
STK11 protein, human