Observational Study

. 2025 Jul;32(4):841-856.

doi: 10.1007/s12282-025-01713-7. Epub 2025 May 20.

Real-world evidence from Japan regarding survival outcomes and treatment sequence in patients receiving CDK4/6 inhibitor plus endocrine therapy as first- or second-line treatment for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Tetsuhiro Yoshinami¹, Yuko Takano², Yukinori Ozaki³, Yukiko Kajiwara⁴, Mitsugu Yamamoto⁵, Ken-Ichi Watanabe⁵, Masami Tsukabe⁶, Fumie Fujisawa⁷, Shigenori E Nagai⁸, Nobuhiro Shibata⁹, Chiya Oshiro¹⁰, Hiroko Bando¹¹, Nobuyuki Tsunoda¹², Kazuhiko Yamagami¹³, Kei Koizumi¹⁴, Masahiro Takada¹⁵, Naoko Toriguchi¹⁶, Nobuyuki Sekine¹⁶, Tsutomu Kawaguchi¹⁶, Shigehira Saji¹⁷, Yasuaki Sagara¹⁸, Satoshi Morita¹⁹, Norikazu Masuda²⁰

Affiliations

¹ Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita, Osaka, 565-0871, Japan. yosinami-te@onsurg.med.osaka-u.ac.jp.
² Department of Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan.
³ Department of Breast Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan.
⁴ Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
⁵ Department of Breast Oncology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido, Japan.
⁶ Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁷ Department of Medical Oncology, Shiga General Hospital, Moriyama, Shiga, Japan.
⁸ Division of Breast Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, Japan.
⁹ Department of Clinical Oncology, Kansai Medical University Hospital, Hirakata, Osaka, Japan.
¹⁰ Department of Breast Surgery, Kaizuka City Hospital, Kaizuka, Osaka, Japan.
¹¹ Department of Breast and Endocrine Surgery, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
¹² Department of Breast Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi, Japan.
¹³ Department of Breast Surgery and Oncology, Shinko Hospital, Kobe, Hyogo, Japan.
¹⁴ Department of Surgery 1, Division of Breast Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
¹⁵ Department of Breast Surgery, Kansai Medical University, Hirakata, Osaka, Japan.
¹⁶ Department of Japan Drug Development and Medical Affairs, Eli Lilly Japan K.K, Kobe, Hyogo, Japan.
¹⁷ Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
¹⁸ Department of Breast and Thyroid Surgical Oncology, Social Medical Corporation Hakuaikai Sagara Hospital, Kagoshima, Japan.
¹⁹ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²⁰ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

PMID: 40392524
PMCID: PMC12174191
DOI: 10.1007/s12282-025-01713-7

Observational Study

Real-world evidence from Japan regarding survival outcomes and treatment sequence in patients receiving CDK4/6 inhibitor plus endocrine therapy as first- or second-line treatment for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Tetsuhiro Yoshinami et al. Breast Cancer. 2025 Jul.

. 2025 Jul;32(4):841-856.

doi: 10.1007/s12282-025-01713-7. Epub 2025 May 20.

Authors

Affiliations

¹ Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita, Osaka, 565-0871, Japan. yosinami-te@onsurg.med.osaka-u.ac.jp.
² Department of Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Aichi, Japan.
³ Department of Breast Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan.
⁴ Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
⁵ Department of Breast Oncology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido, Japan.
⁶ Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, 2-2-E10 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁷ Department of Medical Oncology, Shiga General Hospital, Moriyama, Shiga, Japan.
⁸ Division of Breast Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, Japan.
⁹ Department of Clinical Oncology, Kansai Medical University Hospital, Hirakata, Osaka, Japan.
¹⁰ Department of Breast Surgery, Kaizuka City Hospital, Kaizuka, Osaka, Japan.
¹¹ Department of Breast and Endocrine Surgery, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
¹² Department of Breast Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi, Japan.
¹³ Department of Breast Surgery and Oncology, Shinko Hospital, Kobe, Hyogo, Japan.
¹⁴ Department of Surgery 1, Division of Breast Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
¹⁵ Department of Breast Surgery, Kansai Medical University, Hirakata, Osaka, Japan.
¹⁶ Department of Japan Drug Development and Medical Affairs, Eli Lilly Japan K.K, Kobe, Hyogo, Japan.
¹⁷ Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
¹⁸ Department of Breast and Thyroid Surgical Oncology, Social Medical Corporation Hakuaikai Sagara Hospital, Kagoshima, Japan.
¹⁹ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²⁰ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

PMID: 40392524
PMCID: PMC12174191
DOI: 10.1007/s12282-025-01713-7

Erratum in

Correction: Real‑world evidence from Japan regarding survival outcomes and treatment sequence in patients receiving CDK4/6 inhibitor plus endocrine therapy as first‑ or second‑line treatment for hormone receptor-positive, HER2‑negative advanced or metastatic breast cancer.
Yoshinami T, Takano Y, Ozaki Y, Kajiwara Y, Yamamoto M, Watanabe KI, Tsukabe M, Fujisawa F, Nagai SE, Shibata N, Oshiro C, Bando H, Tsunoda N, Yamagami K, Koizumi K, Takada M, Toriguchi N, Sekine N, Kawaguchi T, Saji S, Sagara Y, Morita S, Masuda N. Yoshinami T, et al. Breast Cancer. 2025 Sep;32(5):1157-1158. doi: 10.1007/s12282-025-01736-0. Breast Cancer. 2025. PMID: 40549070 Free PMC article. No abstract available.

Abstract

Background: A cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is a current standard first-/second-line treatment for hormone receptor (HR)-positive, HER2-negative advanced/metastatic breast cancer (AMBC). We aimed to provide real-world evidence regarding CDK4/6i therapy in this population.

Methods: In this multicenter observational study, data from patients who had started CDK4/6i therapy between January 1, 2019, and December 31, 2021, as first-/second-line treatment for AMBC were used; real-world progression-free survival (rwPFS), chemotherapy-free survival, and overall survival were analyzed using the Kaplan-Meier method. Additionally, data were analyzed by separating patients with treatment-free interval (TFI) < 12 months (deemed resistant to ET) from the first-line treatment group (hereafter, the exclusive first-line treatment group).

Results: Data from 745 patients were analyzed. Compared with palbociclib, abemaciclib was used in younger patients and those with expected poor prognosis. Median rwPFS was 36.8, 17.8, and 31.4 months in patients with de novo stage IV disease, TFI < 12 months, and TFI ≥ 12 months, respectively, in the first-line treatment group, and 17.4 months in the second-line treatment group. In the exclusive first-line treatment group, median rwPFS of the subsequent treatment after initial CDK4/6i plus ET was < 7 months, regardless of the type of subsequent treatment; prognosis was especially poor in those who were switched to chemotherapy.

Conclusions: The real-world survival outcomes found in this study for patients receiving first-/second-line CDK4/6i therapy were consistent with those of randomized phase 3 studies. As outcomes of subsequent treatment after initial CDK4/6i plus ET remain insufficient, further improvement in treatment is necessary.

Keywords: Abemaciclib; Advanced or metastatic breast cancer; Cyclin-dependent kinase 4/6 inhibitor; Palbociclib; Real-world evidence.

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Conflict of interest statement

Declarations. Conflict of interest: TY reports receiving payment/honoraria from Eli Lilly Japan, AstraZeneca, Chugai Pharmaceutical, Kyowa Kirin, Pfizer, MSD, Eisai, and Novartis Pharma. YT reports grant/contract from Eli Lilly; receiving payment/honoraria from Eli Lilly Japan, Pfizer, Chugai Pharmaceutical, Daiichi Sankyo, MSD, and AstraZeneca. YO reports receiving honoraria from Daiichi Sankyo, Pfizer, Eli Lilly Japan, and Kyowa Kirin. KW reports receiving payment/honoraria from Chugai Pharmaceutical, Eli Lilly Japan, Nippon Kayaku, Kyowa Kirin, Novartis Pharma, Taiho Pharmaceutical, Eisai, Pfizer, Shionogi Pharmaceutical, Daiichi Sankyo, and AstraZeneca. SEN reports receiving payment/honoraria from Eli Lilly Japan, Pfizer, Daiichi Sankyo, Chugai Pharmaceutical, Eisai, MSD, Gilead Sciences, and Kyowa Kirin; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and Chugai Pharmaceutical. NS (Shibata) reports research grants to institution from Daiichi Sankyo, AstraZeneca, and MSD; receiving consulting fees from Kyowa Kirin; receiving lecture honoraria from Kyowa Kirin, MSD, Daiichi Sankyo, Chugai Pharmaceutical, Pfizer, Eisai, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Nippon Kayaku, Merck Biopharma, and Bristol Myers Squibb; participation on an Advisory Board for Kyowa Kirin and Daiichi Sankyo. CO reports receiving payment/honoraria from Eli Lilly Japan. HB reports receiving payment/honoraria from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Eisai, Kyowa Kirin, AstraZeneca, Pfizer, and MSD. NT (Tsunoda) reports receiving payment/honoraria from Eli Lilly Japan, Pfizer, Chugai Pharmaceutical, AstraZeneca, and Eisai. KK reports receiving payment/honoraria from Pfizer and Chugai Pharmaceutical. MT (Takada) reports grants to institution from Yakult and Guardant Health Japan; receiving payment/honoraria from Daiichi Sankyo, AstraZeneca, Taiho Pharmaceutical, Eli Lilly Japan, MSD, Pfizer, Eisai, Chugai Pharmaceutical, Devicor Medical Japan, and Mitaka Kohki. NT (Toriguchi), NS (Sekine), and TK report being employees of Eli Lilly Japan and minor shareholders of Eli Lilly and Company. SS reports grants to institution from Taiho Pharmaceutical, Eisai, Takeda Pharmaceutical, Chugai Pharmaceutical, and Daiichi Sankyo; contracted clinical trials for MSD, AstraZeneca, Gilead Sciences, Eli Lilly Japan, Sanofi, Chugai Pharmaceutical, and Daiichi Sankyo; receiving payment/honoraria from Chugai Pharmaceutical, Kyowa Kirin, MSD, Novartis Pharma, Eisai, Takeda Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, AstraZeneca, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, Nippon Kayaku, Gilead Sciences, and Exact Sciences; participation on a Data Safety Monitoring Board or Advisory Board for Chugai/Roche, AstraZeneca, Eli Lilly Japan, Pfizer, Kyowa Kirin, Daiichi Sankyo, and MSD; being an executive board member for Japan Breast Cancer Research Group (JBCRG), Japanese Breast Cancer Society (JBCS), Japanese Society of Medical Oncology (JSMO), and Breast International Group (BIG). YS reports receiving payment/honoraria from Pfizer, Daiichi Sankyo, Eli Lilly Japan, MSD, Kyowa Kirin, Celltrion Healthcare Japan, AstraZeneca, Eisai, Chugai Pharmaceutical, Nippon Kayaku, and Sysmex. SM reports grants to institution from Eisai; receiving payment/honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, and Ono Pharmaceutical. NM grants to institution from Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca, Pfizer, Daiichi Sankyo, MSD, Eisai, Novartis Pharma, Gilead Sciences, and Ono Pharmaceutical; receiving payment/honoraria from Chugai Pharmaceutical, Pfizer, AstraZeneca, Eli Lilly Japan, Daiichi Sankyo, and Eisai; being a representative/member of Board of Directors (unpaid) for JBCRG, JBCS, Japan Society of Clinical Oncology (JSCO), and Japan Association of Breast Cancer Screening (JABCS). YK, MY, MT (Tsukabe), FF, and KY report no conflict of interest regarding this manuscript. Research involving human participants: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The present study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice (ICH-GCP) Guideline, and Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The protocol [no. 23136 (T34)] was approved by the institutional review board of Osaka University Hospital (Osaka, Japan). Informed consent: Patients provided consent to the use of their data by either providing written informed consent or on an opt-out basis.

Figures

**Fig. 1**
Patient disposition. *ABE* abemaciclib; *CDK4/6i* cyclin-dependent kinase 4/6 inhibitor; *PAL* palbociclib

**Fig. 2**
Survival outcomes in patients in the first- and second-line treatment groups: real-world progression-free survival (A), chemotherapy-free survival (B), and overall survival (C). *AMBC* advanced or metastatic breast cancer; *CDK4/6i* cyclin-dependent kinase 4/6 inhibitor; CI confidence interval; *TFI* treatment-free interval

**Fig. 3**
Overall survival by subsequent treatment after initial CDK4/6i plus ET in the exclusive first-line treatment group (A) and expanded second-line treatment group (B). *AMBC* advanced or metastatic breast cancer; *CDK4/6i* cyclin-dependent kinase 4/6 inhibitor; CI confidence interval; ET endocrine therapy. ^aTreatment was provided with or without ET

**Fig. 4**
Real-world progression-free survival (rwPFS) in patients who received subsequent treatment after initial CDK4/6i plus ET by treatment type: rwPFS of initial CDK4/6i plus ET, defined as time from the start of first-line CDK4/6i therapy, in the exclusive first-line treatment group (A), rwPFS of subsequent treatment, defined as time from the start of subsequent treatment after initial CDK4/6i plus ET, in the exclusive first-line treatment group (B), and rwPFS of subsequent treatment, defined as time from the start of subsequent treatment after initial CDK4/6i plus ET, in the expanded second-line treatment group (C). *AMBC* advanced or metastatic breast cancer; *CDK4/6i* cyclin-dependent kinase 4/6 inhibitor; CI confidence interval; ET endocrine therapy. ^aTreatment was provided with or without ET

See this image and copyright information in PMC

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Real-world evidence from Japan regarding survival outcomes and treatment sequence in patients receiving CDK4/6 inhibitor plus endocrine therapy as first- or second-line treatment for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Affiliations

Real-world evidence from Japan regarding survival outcomes and treatment sequence in patients receiving CDK4/6 inhibitor plus endocrine therapy as first- or second-line treatment for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

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Medical

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