Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400)

David Kozono; Xing Hua; Michael C Wu; Khaled A Tolba; Saiama N Waqar; Konstantin H Dragnev; Haiying Cheng; Fred R Hirsch; Philip C Mack; Jhanelle E Gray; Karen Kelly; Hossein Borghaei; Roy S Herbst; David R Gandara; Mary W Redman

doi:10.1016/j.jtho.2024.07.024

Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400)

J Thorac Oncol. 2024 Aug 5:S1556-0864(24)00751-2. doi: 10.1016/j.jtho.2024.07.024. Online ahead of print.

Authors

Affiliations

¹ Department of Radiation Oncology, Dana-Farber Brigham Cancer Center, Boston, Massachusetts. Electronic address: dkozono@bwh.harvard.edu.
² SWOG Statistics and Data Management Center, Seattle, Washington; Biostatistics Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
³ Foundation Medicine, Cambridge, Massachusetts.
⁴ Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
⁵ Department of Medicine, Dartmouth Cancer Center, Lebanon, New Hampshire.
⁶ Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
⁷ Mt. Sinai Health System Center for Thoracic Oncology, Tisch Cancer Institute, New York, New York.
⁸ Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
⁹ Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.
¹⁰ Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
¹¹ Section of Medical Oncology, Yale University, New Haven, Connecticut.

PMID: 39111731
DOI: 10.1016/j.jtho.2024.07.024

Abstract

Introduction: Squamous cell cancer (SqCC) is a lung cancer subtype with few targeted therapy options. Molecular characterization, that is, by next-generation sequencing (NGS), is needed to identify potential targets. Lung Cancer Master Protocol Southwest Oncology Group S1400 enrolled patients with previously treated stage IV or recurrent SqCC to assess NGS biomarkers for therapeutic sub-studies.

Methods: Tumors underwent NGS using Foundation Medicine's FoundationOne research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Mutually exclusive gene set analysis and Selected Events Linked by Evolutionary Conditions across Human Tumors were performed to identify mutually exclusive and co-occurring gene alterations. Comparisons were performed with data on 495 lung SqCC downloaded from The Cancer Genome Atlas. Cox proportional hazards models were used to assess associations between genetic variants and survival.

Results: NGS data are reported for 1672 patients enrolled on S1400 between 2014 and 2019. Mutually exclusive gene set analysis identified two non-overlapping sets of mutually exclusive alterations with a false discovery rate of less than 15%: NFE2L2, KEAP1, and PARP4; and CDKN2A and RB1. PARP4, a relatively uncharacterized gene, showed three frequent mutations suggesting functional significance: 3116T>C (I1039T), 3176A>G (Q1059R), and 3509C>T (T1170I). When taken together, NFE2L2 and KEAP1 alterations were associated with poorer survival.

Conclusions: As the largest dataset to date of lung SqCC profiled on a clinical trial, the S1400 NGS dataset establishes a rich resource for biomarker discovery. Mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations suggests that PARP4 may have an uncharacterized role in a key pathway known to impact oxidative stress response and treatment resistance.

Keywords: Mutually exclusive gene sets (MEGS); Next generation sequencing; PARP4; Squamous cell lung cancer.