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

Cancer Treatment and Research Communications (Jan 2023)

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

Affiliations

Francis Proulx-Rocray: Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada
Bertrand Routy: 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
Rami Nassabein: Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada
Wiam Belkaid: 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
Danh Tran-Thanh: Pathology Department, Centre Hospitalier de l'Université de Montréal, 1051 Sanguinet Street, Montreal, QC, Canada
Julie Malo: 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
Marion Tonneau: 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
Omar El Ouarzadi: 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
Marie Florescu: 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
Mustapha Tehfe: 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
Normand Blais: 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; Corresponding author.

Journal volume & issue: Vol. 37
p. 100767

Abstract

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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 (KRASMut). 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. STK11Mut and KEAP1Mut 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, KRASMut trended to a better prognosis in STK11+KEAP1WT tumors (median OS 21.1 vs 15.8 for KRASWT, p = 0.15), but not for STK11+/-KEAP1Mut tumors. The NLR was strongly impacted by STK11 (6.0Mut vs 3.6WT, p = 0.014) and TP53 (3.2Mut vs 4.8WT, p = 0.048), but not by KEAP1 or KRAS mutations. Conclusion: STK11Mut and KEAP1Mut are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11Mut but not by KEAP1Mut, suggesting differences in their resistance mechanism. In STK11-KEAP1WT tumors, KRASMut 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.

Published in Cancer Treatment and Research Communications

ISSN: 2468-2942 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/cancer-treatment-and-research-communications

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