Evidence map›Paper›PMID 36398439›Full record

Trial reportJapanese journal of clinical oncology2023

Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial.

Hiroji Iwata, Rikiya Nakamura, Norikazu Masuda, Toshinari Yamashita, Yutaka Yamamoto, Kokoro Kobayashi, Junji Tsurutani, Tsutomu Iwasa, Kan Yonemori, Kenji Tamura and 11 more

Registry-linked trialOpen access · bronzeAbstract readRandomized Controlled TrialClinical Trial, Phase II
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Japanese journal of clinical oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03291886 (Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer), which is not on this map. Cited by 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
2.1field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03291886 phase2completednot on this map

Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer

TypeinterventionalSponsorKyowa Kirin Co., Ltd.Ran2017 to 2021Enrolled133ConditionsAdvanced or Recurrent Breast CancerArmsEntinostat, Entinostat(Placebo), Exemestane
3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.

  1. Pooled it
  2. Clinical progress and functional modalities of HDAC inhibitor-based combination therapies in cancer treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Review
  3. Article
  4. Precision epigenetic therapies in oncology.Cancer metastasis reviews · 2025
    Review
  5. Getting the right combination to break the epigenetic code.Nature reviews. Clinical oncology · 2025
    Review
  6. Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024
    Review
  7. Article
  8. Article
  9. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 13 institutions in 2 countries.

Hiroji IwataDepartment of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan.
Rikiya NakamuraDivision of Breast Surgery, Chiba Cancer Center, Chiba, Japan.
Norikazu MasudaDepartment of Surgery, Breast Oncology, National Hospital Organization, Osaka National Hospital, Osaka, Japan.
Toshinari YamashitaDepartment of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan.ORCID 0000-0002-6479-1660
Yutaka YamamotoDepartment of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Kokoro KobayashiDepartment of Breast Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Junji TsurutaniAdvanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.
Tsutomu IwasaAdvanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.
Kan YonemoriDepartment of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Kenji TamuraDepartment of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Tomoyuki ArugaDepartment of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
Eriko TokunagaDepartment of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
Koji KanekoDepartment of Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
Min-Jung LeeDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Akira YunoDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Azusa KawabataR&D Division, Kyowa Kirin Co., Ltd, Tokyo, Japan.
Toshihiro SeikeR&D Division, Kyowa Kirin Co., Ltd, Tokyo, Japan.
Ayumi KanedaR&D Division, Kyowa Kirin Co., Ltd, Tokyo, Japan.
Yozo NishimuraR&D Division, Kyowa Kirin Co., Ltd, Tokyo, Japan.
Jane B TrepelDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Shigehira SajiDepartment of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
Kyowa Kirin (Japan) · JPNational Institutes of Health · USShowa University · JPAichi Cancer Center · JPChiba Cancer Center · JPFukushima Medical University · JPJapanese Foundation For Cancer Research · JPKanagawa Prefectural Hospital Organization · JPKumamoto University · JPNational Hospital Organization Kyushu Cancer Center · JPNiigata Cancer Center Hospital · JPOsaka National Hospital · JPTokyo Metropolitan Komagome Hospital · JP

Funding

Signal Transduction Events and the Regulation of Cell GrowthZICSC006743 · NCI · DIVISION OF CLINICAL SCIENCES - NCI · PI TREPEL, JANE B · 2009 to 2023
$13.8M
Kyowa KirinNCI NIH HHSNIH HHS
6 · The paper itself

Abstract

backgroundWe aimed to confirm the efficacy and safety of the oral histone deacetylase inhibitor entinostat in Japanese patients with hormone receptor-positive advanced/recurrent breast cancer and to explore potential biomarkers.

methodsThis phase II, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT03291886) was conducted at 28 Japanese sites (September 2017-July 2020; interim analysis cutoff: April 2019). Patients with progression/relapse following non-steroidal aromatase inhibitors were randomized 1:1 to entinostat (5 mg/week) or placebo, plus exemestane (25 mg/day). Primary endpoint was progression-free survival; secondary endpoints included overall survival and safety. Exploratory biomarker outcomes included lysine acetylation, immune cell profiles, estrogen receptor 1 mutations and plasma chemokines.

resultsOf 133 randomized patients, 131 (65 entinostat, 66 placebo) who received study drug were analyzed. Median (95% confidence interval) progression-free survival was 5.8 (3.2-7.8) months for entinostat and 3.3 (3.1-5.8) months for placebo (hazard ratio [95% confidence interval]: 0.75 [0.50 - 1.14]; P = 0.189). Median overall survival was not reached in either group. Entinostat tended to prolong progression-free survival in patients aged ≥65 years, not endocrine resistant, or with estrogen receptor 1 Y537S mutation. Candidate biomarkers of efficacy (progression-free survival) included lysine acetylation in CD3+ cells, plasma interferon gamma-induced protein 10, dendritic cell CD86 expression, and CD4+ cell expression of human leukocyte antigen-DR and inducible T-cell co-stimulator. Safety was similar to non-Japanese populations; however, seven entinostat-treated patients (10.8%) had reversible lung injury.

conclusionsIn Japanese patients, the safety of entinostat plus exemestane was acceptable and progression-free survival was prolonged, although not significantly. Exploratory analyses identified potential biomarkers, including lysine acetylation, of efficacy.

Indexed as

Breast NeoplasmsAndrostadienesAntineoplastic Combined Chemotherapy ProtocolsBenzamidesDouble-Blind MethodEstrogen Receptor alphaFemaleHumansLysineNeoplasm Recurrence, LocalPyridinesReceptors, EstrogenAndrostadienesBenzamidesentinostatEstrogen Receptor alphaexemestaneLysinePyridinesReceptors, Estrogenbiomarkersentinostatepigenomicsexemestanehistone deacetylase inhibitors

Identifiers

PMID36398439
PMCPMC9825728
OpenAlexW4309368428

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.