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The progesterone-receptor modulator, ulipristal acetate, drastically lowers breast cell proliferation

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Abstract

Purpose

The proliferation of breast epithelial cells increases during the luteal phase of the menstrual cycle, when they are exposed to progesterone, suggesting that ulipristal acetate, a selective progestin-receptor modulator (SPRM), may reduce breast cell proliferation with potential use in breast cancer chemoprevention.

Methods

Women aged 18–39 were randomized 1:1 to ulipristal 10-mg daily or to a combination oral contraceptive (COC) for 84 days. Participants underwent a breast biopsy and breast MRI at baseline and at end of study treatment. Proliferation of breast TDLU cells was evaluated by Ki67 immunohistochemical stain. We evaluated the breast MRIs for background parenchymal enhancement (BPE). All slides and images were masked for outcome evaluation.

Results

Twenty-eight treatment-compliant participants completed the study; 25 of whom had evaluable Ki67 results at baseline and on-treatment. From baseline to end of treatment, Ki67 % positivity (Ki67%+) decreased a median of 84% in the ulipristal group (N = 13; 2-sided p (2p) = 0.040) versus a median increase of 8% in the COC group (N = 12; 2p = 0.85). Median BPE scores decreased from 3 to 1 in the ulipristal group (p = 0.008) and did not decrease in the COC group.

Conclusion

Ulipristal was associated with a major decrease in Ki67%+ and BPE. Ulipristal would warrant further investigation for breast cancer chemoprevention were it not for concerns about its liver toxicity. Novel SPRMs without liver toxicity could provide a new approach to breast cancer chemoprevention.

Trial registration

NCT02922127, 4 October 2016.

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Data availability

The data underlying this article will be shared on reasonable application to the corresponding author.

Abbreviations

BMI:

Body mass index

BPE:

Background parenchymal enhancement

Cl:

Confidence limit

COC:

Combination oral contraceptive

E2:

Estradiol

ERα%+ :

ERα % positivity

FNA:

Fine needle aspirate

IQR:

Interquartile range

Ki67%+ :

Ki67 % positivity

PRA%+ :

PRA % positivity

NICHD:

National Institute of Child Health and Human Development

MRI:

Magnetic resonance imaging

P4:

Progesterone

Rx:

On-treatment

SPRM:

Selective progestin-receptor modulator

TDLU:

Terminal duct lobular unit

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Acknowledgements

We wish to express our sincerest gratitude to the women who volunteered to be part of this study. We also wish to express our thanks to Ariel Allen, Jacqueline Dillon, and Molly Morgan for managing the recruitment and day-to-day study conduct, to Hao Yang for anonymizing the MRIs and arranging for the presentation of only one breast from the MRI to RH for analysis. We also wish to express our thanks to Renu Nandakumar of the Biomarkers Core Laboratory at the Irving Institute for Clinical and Translational Research, home to Columbia University Irving Medical Center’s Clinical and Translational Science Award Program hub, for carrying out the ulipristal and levonorgestrel assays.

Funding

This study was supported by a grant from the National Cancer Institute (5RO1 CA200795; P.I. CLW). MCP was supported in part through the National Institutes of Health/National Cancer Institute Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. The study sponsors had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, PH 16-69, 630 West 168th Street, New York, NY, 10032, USA

    Carolyn L. Westhoff

  2. Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA

    Hua Guo, Zhong Wang & Hanina Hibshoosh

  3. Department of Obstetrics and Gynecology, Weill-Cornell Medical Center, New York, NY, USA

    Margaret Polaneczky

  4. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Malcolm C. Pike

  5. Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA

    Richard Ha

Authors
  1. Carolyn L. Westhoff
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  2. Hua Guo
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  3. Zhong Wang
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  4. Hanina Hibshoosh
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  5. Margaret Polaneczky
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  7. Richard Ha
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Contributions

CLW and MCP conceived the study. CLW, MCP, MP, HH, and RH designed the study. CLW, HH, RH, HG, ZW, and MP acquired the data. HG, ZW, and MCP analyzed the data. All authors contributed to data interpretation as well as critical revision and final approval of the manuscript.

Corresponding author

Correspondence to Carolyn L. Westhoff.

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Westhoff, C.L., Guo, H., Wang, Z. et al. The progesterone-receptor modulator, ulipristal acetate, drastically lowers breast cell proliferation. Breast Cancer Res Treat 192, 321–329 (2022). https://doi.org/10.1007/s10549-021-06503-1

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