PMID- 35848083
OWN - NLM
STAT- MEDLINE
DCOM- 20221216
LR  - 20221221
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 113
IP  - 12
DP  - 2022 Dec
TI  - Impact of germline HLA genotypes on clinical outcomes in patients with urothelial 
      cancer treated with pembrolizumab.
PG  - 4059-4069
LID - 10.1111/cas.15488 [doi]
AB  - Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the 
      cancer response to checkpoint blockade immunotherapy. This study assessed the 
      impact of germline HLA genotypes on clinical outcomes in patients with 
      chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. 
      Zygosity, supertypes, evolutionary divergency, and specific alleles of germline 
      HLA-I and -II were evaluated using the Luminex technique in 108 patients with 
      chemoresistant metastatic or locally advanced UC treated with pembrolizumab. 
      Among the 108 patients, 69 died and 83 showed radiographic progression during 
      follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 
      supertype, and high HLA-I evolutionary divergence were associated with a 
      radiographic response, but were not associated with survival outcomes. Patients 
      with the HLA-DQB1*03:01 allele had significantly lower disease control rates than 
      patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also 
      an independent risk factor for progressive disease (hazard ratio 4.35, 95% 
      confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 
      allele had significantly worse progression-free survival than patients without 
      the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). 
      There was no significant relationship between any HLA status and the incidence of 
      severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, 
      may be associated with radiographic progression. However, their impact on 
      treatment response is limited, and germline HLA genotypes was not independently 
      associated with survival outcomes. Further prospective studies are needed to 
      confirm the relationship between germline HLA genotypes and clinical outcomes in 
      patients with chemoresistant advanced UC treated with pembrolizumab.
CI  - (c) 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Takahashi, Shuhei
AU  - Takahashi S
AUID- ORCID: 0000-0001-7423-4561
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Narita, Shintaro
AU  - Narita S
AUID- ORCID: 0000-0003-2988-1860
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Fujiyama, Nobuhiro
AU  - Fujiyama N
AD  - Clinical Research Support Center, Akita University Hospital, Akita, Japan.
FAU - Hatakeyama, Shingo
AU  - Hatakeyama S
AD  - Department of Urology, Hirosaki University School of Medicine, Hirosaki, Japan.
FAU - Kobayashi, Takashi
AU  - Kobayashi T
AUID- ORCID: 0000-0003-1069-2816
AD  - Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
FAU - Kato, Renpei
AU  - Kato R
AD  - Department of Urology, Iwate Medical School of Medicine, Iwate, Japan.
FAU - Naito, Sei
AU  - Naito S
AD  - Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
FAU - Sakatani, Toru
AU  - Sakatani T
AD  - Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
FAU - Kashima, Soki
AU  - Kashima S
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Koizumi, Atsushi
AU  - Koizumi A
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Yamamoto, Ryohei
AU  - Yamamoto R
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Nara, Taketoshi
AU  - Nara T
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Kanda, Souhei
AU  - Kanda S
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Numakura, Kazuyuki
AU  - Numakura K
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Saito, Mitsuru
AU  - Saito M
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
FAU - Obara, Wataru
AU  - Obara W
AUID- ORCID: 0000-0003-2720-9640
AD  - Department of Urology, Iwate Medical School of Medicine, Iwate, Japan.
FAU - Tsuchiya, Norihiko
AU  - Tsuchiya N
AD  - Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
FAU - Ohyama, Chikara
AU  - Ohyama C
AD  - Department of Urology, Hirosaki University School of Medicine, Hirosaki, Japan.
FAU - Ogawa, Osamu
AU  - Ogawa O
AUID- ORCID: 0000-0001-5491-8878
AD  - Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
FAU - Habuchi, Tomonori
AU  - Habuchi T
AD  - Department of Urology, Akita University School of Medicine, Akita, Japan.
LA  - eng
GR  - 16H02679/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 16K10992/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 19K09663/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 19K16706/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 19K18551/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 21K06592/Ministry of Education, Culture, Sports, Science and Technology/
PT  - Journal Article
DEP - 20220924
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
SB  - IM
MH  - Humans
MH  - Alleles
MH  - *Carcinoma, Transitional Cell/genetics/pathology
MH  - Genotype
MH  - Progression-Free Survival
MH  - *Urinary Bladder Neoplasms/genetics/pathology
MH  - *Genes, MHC Class II
MH  - *Genes, MHC Class I
PMC - PMC9746062
OTO - NOTNLM
OT  - HLA evolutionary divergence
OT  - checkpoint blockade immunotherapy
OT  - human leukocyte antigen
OT  - pembrolizumab
OT  - urothelial cancer
COIS- The authors declare no conflicts of interest associated with this manuscript.
EDAT- 2022/07/19 06:00
MHDA- 2022/12/15 06:00
PMCR- 2022/12/01
CRDT- 2022/07/18 04:26
PHST- 2022/06/27 00:00 [revised]
PHST- 2021/12/16 00:00 [received]
PHST- 2022/06/30 00:00 [accepted]
PHST- 2022/07/19 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/07/18 04:26 [entrez]
PHST- 2022/12/01 00:00 [pmc-release]
AID - CAS15488 [pii]
AID - 10.1111/cas.15488 [doi]
PST - ppublish
SO  - Cancer Sci. 2022 Dec;113(12):4059-4069. doi: 10.1111/cas.15488. Epub 2022 Sep 24.