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Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival

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Abstract

Objective

To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially.

Method

This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints.

Result

The median follow-up time was 56.9 months (IQR 49.5–72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50–2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54–2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3–14.7) months and 10.3 (95% CI 8.2–12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59–1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64–1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups.

Conclusion

For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation and survival outcomes that were no worse than simultaneous use. The application of GnRHa can probably be delayed until menstruation resumption after chemotherapy.

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Acknowledgements

This work was supported by the Shanghai Committee of Science and Technology, China (grant 12DZ2260100), the Shanghai United Developing Technology Project of Municipal Hospitals (SHDC12010116), and the Key Clinical Program of the Ministry of Health (2010–2012). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Ying Zhang, Yajie Ji, Jianwei Li, Li Lei, and Siyu Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui, 200032, Shanghai, People’s Republic of China

    Ying Zhang, Jianwei Li, Siyu Wu, Wenjia Zuo, Xiaoqing Jia, Yujie Wang, Zhenzhou Shen, Jiong Wu, Zhimin Shao & Guangyu Liu

  2. Department of Oncology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Xuhui, 200032, Shanghai, People’s Republic of China

    Ying Zhang, Jianwei Li, Siyu Wu, Wenjia Zuo, Xiaoqing Jia, Yujie Wang, Miao Mo, Zhenzhou Shen, Jiong Wu, Zhimin Shao & Guangyu Liu

  3. Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Xuhui, Shanghai, People’s Republic of China

    Yajie Ji

  4. Department of Breast Surgery, Calmete Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China

    Li Lei

  5. Clinical Statistics Center, Fudan University Shanghai Cancer Center, Xuhui, Shanghai, People’s Republic of China

    Miao Mo

  6. Department of Medical Oncology, Shanghai Fengxian District Central Hospital, Fengxian, Shanghai, People’s Republic of China

    Na Zhang

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  1. Ying Zhang
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  2. Yajie Ji
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Corresponding author

Correspondence to Guangyu Liu.

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The authors have declared no conflicts of interest.

Ethical approval

This trial was approved by the review boards in Fudan University Shanghai Cancer Center (No. 090875-3). All patients provided written informed consent.

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Zhang, Y., Ji, Y., Li, J. et al. Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival. Breast Cancer Res Treat 168, 679–686 (2018). https://doi.org/10.1007/s10549-018-4660-y

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  • DOI: https://doi.org/10.1007/s10549-018-4660-y

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