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Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer

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Abstract

Purpose

Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC).

Methods

In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy.

Results

Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53–2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant.

Conclusion

No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to no approval from the Ethics Committee for sharing data.

Abbreviations

HR:

Hormone receptor

HER2:

Human epidermal growth factor 2

ABC:

Advanced or metastatic breast cancer

PFS:

Progression-free survival

OS :

Overall survival

QOL :

Quality of life

CDK :

Cyclin-dependent kinase

ER :

Estrogen receptor

POETIC :

Perioperative endocrine therapy for individualizing care

IHC :

Immunohistochemistry

AI :

Aromatase inhibitor

cfDNA :

Cell-free DNA

ESMO :

European Society for Medical Oncology

ET :

Endocrine therapy

NGS :

Next-generation sequencing

UMT :

Unique molecular tag

UMI:

Unique molecular identifiers

HR :

Hazard ratios

CI :

Confidence intervals

PR:

Progesterone receptor

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Acknowledgements

We greatly appreciate all women who participated in this trial. We also thank all investigators and their collaborators for their dedication to this study, Mebics for their data entry assistance, TAKARA bio for genomic analysis and the Japan Breast Cancer Research Group (JBCRG) for their administrative assistance.

Funding

This trial was founded by AstraZeneca K.K.

Author information

Authors and Affiliations

  1. Breast and Thyroid Surgery, Kawasaki Medical School Hospital, 577 Matsushima, Kurashiki City, Okayama, 701-0192, Japan

    Takayuki Iwamoto

  2. Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan

    Takayuki Iwamoto

  3. Department of Breast Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan

    Naoki Niikura & Takuho Okamura

  4. Breast Surgery, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan

    Kenichi Watanabe

  5. Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Kumamoto, Japan

    Takashi Takeshita

  6. Department of Breast Surgery, Kansai Medical University Hospital, Hirakata, Osaka, Japan

    Yuichiro Kikawa

  7. Department of Medical Oncology, Saitama Red Cross Hospital, Saitama, Saitama, Japan

    Kokoro Kobayashi

  8. Breast Center, Department of Breast Surgery, Kyushu Medical Center, Fukuoka, Fukuoka, Japan

    Nobutaka Iwakuma

  9. Department of Surgery, Division of Breast and Endocrine Surgery, Tohoku University Hospital, Sendai, Miyagi, Japan

    Hiroshi Tada

  10. Department of Gastrointestinal and Breast Surgery, Hiroshima Prefectural Hospital, Hiroshima, Hiroshima, Japan

    Shinji Ozaki

  11. Department of Breast Surgery, Kobe City Nishi-Kobe Medical Center, Kobe, Hyogo, Japan

    Toshitaka Okuno

  12. Department of Breast Surgery, Kurume University Hospital, Kurume, Fukuoka, Japan

    Uhi Toh

  13. Department of Breast and Endocrine Surgery, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan

    Yutaka Yamamoto

  14. Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan

    Michiko Tsuneizumi

  15. Breast Oncology Service, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan

    Hiroshi Ishiguro

  16. Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

    Norikazu Masuda

  17. Department of Medical Oncology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, Japan

    Shigehira Saji

Authors
  1. Takayuki Iwamoto
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  2. Naoki Niikura
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Contributions

Drafting the work: TI; conception or design of the work: TI, NN, KW, TT, YK, NI, HI, NM, and SS; acquisition of data and samples: KK, TO, HT, SO, TO, UT, YY, and MT; Final approval of the version to be published: all authors.

Corresponding author

Correspondence to Takayuki Iwamoto.

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Conflict of interest

T Iwamoto: research grant from Pfizer; N Niikura: research grant from Chugai, Pfizer, Eisai, Mochida, Daiichi Sankyo and Novartis and honoraria for lectures from Chugai, Eli Lilly, MSD, Daiichi-Sankyo, AstraZeneca and Pfizer; K Watanabe: honoraria for lectures from Chugai, Eli Lilly, Nippon-Kayaku, Kyowa-Kirin, Novartis, Taiho, Eisai, Pfizer, Shionogi, Daiichi-Sankyo and AstraZeneca; Y Kikawa: honoraria for lectures from Eisai, Novartis, Astra Zeneca, Taiho, Pfizer, Daiichi Sankyo, Lilly and Chugai; K Kobayashi: honoraria for lectures from Pfizer, Taiho, Chugai, Astrazeneca, Eli Lilly, Eisai and Novartis; H Tada: research grant from Daiichi Sankyo, Eli Lilly, Kirin, Chugai, Novartis, Taiho; U Toh: research grant from Chugai, Eisai, Taiho, Nippon Kayaku and honoraria for lectures from Pfizer, Kyowa-Kirin, Eli Lilly and Daiichi Sankyo; Y Yamamoto: research grant from Chugai, Kyowa-Kirin, Eisai, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Takeda, Lilly, Pfizer and Novartis, honoraria for lectures from AstraZeneca, Chugai, Kyowa-Kirin, Novartis, Lilly, Pfizer, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Eisai, Takeda, MSD, Sysmex and Exact Science, Advisory Board: AstraZeneca, Chugai, Novartis, MSD, Lilly, Pfizer and Daiichi-Sankyo and Member of the Board of Directors at Japanese Breast Cancer Society and Japan Breast Cancer Research Group; H Ishiguro: research grant from Eisai, Daiichi sankyo, Takeda and Chugai and honoraria for lectures from Eisai, Pfizer, Daiichi sankyo, Chugai and Kyowa Kirin; N Masuda: research grant from Chugai, Eli Lilly, Astra Zeneca, Pfizer, Daiichi-Sankyo, MSD, Eisai, Novartis, Sanofi, Kyowa-Kirin, Nippon-Kayaku and Ono-Pharma, honoraria for lectures from Chugai, Pfizer, Astra Zeneca, Eli Lilly, Daiichi Sankyo and Eisai and Board of Directors at Japanese Breast Cancer Society; S Saji: research grant from Taiho, Eisai, Chugai, Takeda, MSD, Astra Zeneca and Daiichi Sankyo, honoraria for lectures from Chugai, Kyowa Kirin, MSD, Novartis, Eisai, Takeda, Daiichi Sankyo, Eli Lilly, Astra Zeneca, Pfizer, Taiho, Ono and Nipponkayaku, Participation on a Data Safety Monitoring Board or Advisory Board at Chugai/Roche, Astra Zeneca, Eli Lilly, Pfizer, Kyowa Kirin, Daiichi Sankyo and MSD and Executive board member at JBCRG, JBCS, JSMO and BIG. The others have no competing interests.

Ethics approval

This study received an approval from the Ethics Committee of Fukushima Medical University School of Medicine and the respective institution.

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Informed consent was obtained from all individual participants included in the study.

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10549_2023_7144_MOESM1_ESM.tif

Supplementary file1 Supplementary Fig. 1 Individual cfDNA mutations at baseline and day 15 of cycle one after combination treatment. Black: mutation positive; Blank: mutation negative. (TIF 146 KB)

Supplementary file2 (DOCX 17 KB)

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Iwamoto, T., Niikura, N., Watanabe, K. et al. Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer. Breast Cancer Res Treat 203, 225–234 (2024). https://doi.org/10.1007/s10549-023-07144-2

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