The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer Journal Article

Authors: Schoenfeld, A.; Bandlamudi, C.; Lavery, J. A.; Montecalvo, J.; Namakydoust, A.; Rizvi, H.; Egger, J.; Concepcion, C. P.; Paul, S.; Arcila, M. E.; Daneshbod, Y.; Chang, J.; Sauter, J. L.; Beras, A.; Ladanyi, M.; Jacks, T.; Rudin, C. M.; Taylor, B. S.; Donoghue, M. T. A.; Heller, G.; Hellmann, M. D.; Rekhtman, N.; Riely, G. J.
Article Title: The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer
Abstract: 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 1⁄4 407) 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 < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 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 < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P 1⁄4 0.01), with class 1 mutations having the best response to ICIs (P 1⁄4 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. © 2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 26
Issue: 21
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2020-11-01
Start Page: 5701
End Page: 5708
Language: English
DOI: 10.1158/1078-0432.Ccr-20-1825
PUBMED: 32709715
PROVIDER: scopus
PMCID: PMC7641983
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Natasha Rekhtman
    360 Rekhtman
  2. Glenn Heller
    375 Heller
  3. Marc Ladanyi
    1191 Ladanyi
  4. Gregory J Riely
    505 Riely
  5. Maria Eugenia Arcila
    555 Arcila
  6. Matthew David Hellmann
    375 Hellmann
  7. Barry Stephen Taylor
    236 Taylor
  8. Charles Rudin
    346 Rudin
  9. Jason Chih-Peng Chang
    84 Chang
  10. Hira Abbas Rizvi
    103 Rizvi
  11. Jennifer Lynn Sauter
    86 Sauter
  12. Amanda Marie Beras
    12 Beras
  13. Jessica Ann Lavery
    49 Lavery
  14. Jacklynn V Egger
    41 Egger