PMID- 32320754
OWN - NLM
STAT- MEDLINE
DCOM- 20210106
LR  - 20210106
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Linking)
VI  - 31
IP  - 7
DP  - 2020 Jul
TI  - HLA-corrected tumor mutation burden and homologous recombination deficiency for 
      the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung 
      cancer patients.
PG  - 902-911
LID - S0923-7534(20)39295-4 [pii]
LID - 10.1016/j.annonc.2020.04.004 [doi]
AB  - 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.
CI  - Copyright (c) 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
FAU - Shim, J H
AU  - Shim JH
AD  - 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.
FAU - Kim, H S
AU  - Kim HS
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Cha, H
AU  - Cha H
AD  - 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.
FAU - Kim, S
AU  - Kim S
AD  - Seoul National University Cancer Research Institute, Seoul, Republic of Korea; 
      Biomedical Research Institute, Seoul National University Hospital, Seoul, 
      Republic of Korea.
FAU - Kim, T M
AU  - Kim TM
AD  - 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.
FAU - Anagnostou, V
AU  - Anagnostou V
AD  - 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.
FAU - Choi, Y-L
AU  - Choi YL
AD  - 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.
FAU - Jung, H A
AU  - Jung HA
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Sun, J-M
AU  - Sun JM
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Ahn, J S
AU  - Ahn JS
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Ahn, M-J
AU  - Ahn MJ
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Park, K
AU  - Park K
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Park, W-Y
AU  - Park WY
AD  - 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.
FAU - Lee, S-H
AU  - Lee SH
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200419
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (B7-H1 Antigen)
RN  - 0 (HLA Antigens)
RN  - 0 (Programmed Cell Death 1 Receptor)
SB  - IM
MH  - B7-H1 Antigen/genetics
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
MH  - HLA Antigens
MH  - Homologous Recombination
MH  - Humans
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Mutation
MH  - Programmed Cell Death 1 Receptor/genetics
OTO - NOTNLM
OT  - PD-L1
OT  - homology-dependent recombination deficiency
OT  - human leukocyte antigen
OT  - immunotherapy
OT  - non-small-cell lung cancer
OT  - tumor mutation burden
COIS- Disclosure JSA reports personal fees from Amgen, personal fees from Pfizer, 
      personal fees from AstraZeneca, personal fees from Menarini, personal fees from 
      Roche, personal fees from Eisai, personal fees from Boehringer Ingelheim, 
      personal fees from Bristol-Myers Squibb-Ono, personal fees from Merck Sharp & 
      Dohme (MSD), personal fees from Janssen, personal fees from Samsung Bioepis, 
      outside the submitted work. S-HL reports grants and personal fees from MSD, 
      personal fees from Novartis, personal fees from AstraZeneca, personal fees from 
      Bristol-Myers Squibb, personal fees from Roche, outside the submitted work. KP 
      reports personal fees from Astellas, Astra Zeneca, AMGEN, Boehringer Ingelheim, 
      Clovis, Eli Lilly, Hanmi, KHK, Merck, MSD, Novartis, ONO, Roche, BluePrint, 
      outside the submitted work. VA receives research funding from Bristol-Myers 
      Squibb. All remaining authors have declared no conflicts of interest.
EDAT- 2020/04/23 06:00
MHDA- 2021/01/07 06:00
CRDT- 2020/04/23 06:00
PHST- 2019/06/20 00:00 [received]
PHST- 2020/04/07 00:00 [revised]
PHST- 2020/04/07 00:00 [accepted]
PHST- 2020/04/23 06:00 [pubmed]
PHST- 2021/01/07 06:00 [medline]
PHST- 2020/04/23 06:00 [entrez]
AID - S0923-7534(20)39295-4 [pii]
AID - 10.1016/j.annonc.2020.04.004 [doi]
PST - ppublish
SO  - Ann Oncol. 2020 Jul;31(7):902-911. doi: 10.1016/j.annonc.2020.04.004. Epub 2020 
      Apr 19.