Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

Overview

Journal J Thorac Oncol

Publisher Elsevier

Specialties Oncology
Pulmonary Medicine

Date 2021 Nov 6

PMID 34740862

Citations 133

Authors

Biagio Ricciuti

Kathryn C Arbour

Jessica J Lin

Amir Vajdi

Natalie Vokes

Lingzhi Hong

Jianjun Zhang

Michael Y Tolstorukov

Yvonne Y Li

Liam F Spurr

Andrew D Cherniack

Gonzalo Recondo

Giuseppe Lamberti

Xinan Wang

Deepti Venkatraman

Joao V Alessi

Victor R Vaz

Hira Rizvi

Jacklynn Egger

Andrew J Plodkowski

Sara Khosrowjerdi

Subba Digumarthy

Hyesun Park

Nuno Vaz

Mizuki Nishino

Lynette M Sholl

David Barbie

Mehmet Altan

John V Heymach

Ferdinandos Skoulidis

Justin F Gainor

Matthew D Hellmann

Mark M Awad

Affiliations

Soon will be listed here.

Abstract

Introduction: STK11 and KEAP1 mutations (STK11 mutant [STK11] and KEAP1) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11 has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRAS LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRAS) LUAD is currently unknown. Whether KEAP1 differentially affects outcomes to PD-(L)1 inhibition in KRAS and KRAS LUAD is also unknown.

Methods: Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status.

Results: In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS but not KRAS LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRAS, but not in KRAS, lung cancers.

Conclusions: STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS but not among KRAS LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.

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