RT Journal Article
SR Electronic
T1 The Genomic Landscape of <em>SMARCA4</em> Alterations and Associations with Outcomes in Patients with Lung Cancer
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5701
OP 5708
DO 10.1158/1078-0432.CCR-20-1825
VO 26
IS 21
A1 Schoenfeld, Adam J.
A1 Bandlamudi, Chai
A1 Lavery, Jessica A.
A1 Montecalvo, Joseph
A1 Namakydoust, Azadeh
A1 Rizvi, Hira
A1 Egger, Jacklynn
A1 Concepcion, Carla P.
A1 Paul, Sonal
A1 Arcila, Maria E.
A1 Daneshbod, Yahya
A1 Chang, Jason
A1 Sauter, Jennifer L.
A1 Beras, Amanda
A1 Ladanyi, Marc
A1 Jacks, Tyler
A1 Rudin, Charles M.
A1 Taylor, Barry S.
A1 Donoghue, Mark T.A.
A1 Heller, Glenn
A1 Hellmann, Matthew D.
A1 Rekhtman, Natasha
A1 Riely, Gregory J.
YR 2020
UL http://clincancerres.aacrjournals.org/content/26/21/5701.abstract
AB Purpose: SMARCA4 mutations are among the most common recurrent alterations in non–small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established.Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering.Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P &lt; 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P &lt; 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P &lt; 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027).Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.