G Lamberti1, L F Spurr2, Y Li2, B Ricciuti1, G Recondo1, R Umeton3, M Nishino4, L M Sholl5, M L Meyerson2, A D Cherniack2, M M Awad6. 1. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, USA. 3. Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, USA; Massachusetts Institute of Technology, Cambridge, USA. 4. Department of Imaging, Dana-Farber Cancer Institute and Department of Radiology, Brigham and Women's Hospital, Boston, USA. 5. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA. 6. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. Electronic address: mark_awad@dfci.harvard.edu.
Abstract
BACKGROUND: Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. MATERIALS AND METHODS: Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%-49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction. RESULTS: A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. CONCLUSIONS: PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.
BACKGROUND: Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. MATERIALS AND METHODS: Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%-49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction. RESULTS: A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. CONCLUSIONS: PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.
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