J H Shim1, H S Kim2, H Cha3, S Kim4, T M Kim5, V Anagnostou6, Y-L Choi7, H A Jung2, J-M Sun2, J S Ahn2, M-J Ahn2, K Park2, W-Y Park8, S-H Lee9. 1. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 2. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 3. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 4. Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea. 5. Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. 6. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA. 7. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 8. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea. Electronic address: woongyang.park@samsung.com. 9. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: shlee119@skku.edu.
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLCpatients and 110 melanomapatients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
Authors: Robert Bentham; Kevin Litchfield; Thomas B K Watkins; Emilia L Lim; Rachel Rosenthal; Carlos Martínez-Ruiz; Crispin T Hiley; Maise Al Bakir; Roberto Salgado; David A Moore; Mariam Jamal-Hanjani; Charles Swanton; Nicholas McGranahan Journal: Nature Date: 2021-09-08 Impact factor: 49.962
Authors: Yinjie Gao; Michelle M Stein; Matthew Kase; Amy L Cummings; Ramit Bharanikumar; Denise Lau; Edward B Garon; Sandip P Patel Journal: Cancer Immunol Immunother Date: 2022-07-26 Impact factor: 6.630