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Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay

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Abstract

Background

Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP’s potential in predicting fulvestrant benefit.

Method

Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP).

Results

For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided p = 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients.

Conclusion

The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.

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Acknowledgements

We thank all patients with contributing data and tissue, we thank all contributing sites and investigators and other personnel, all of which made this study possible. We also wish to thank Knud Nelausen (deceased) for his important contribution to this project in constructing the database and handling incoming data from diverse sources.

Funding

This work was supported by Danish Cancer Society (www.cancer.dk) [R141-A8989-15-S7 to ASKB] and Innovation Fund Denmark (https://innovationsfonden.dk/) [5139-00026B to IKB].

Author information

Author notes

  1. Peter Buhl Jensen and Dorte Nielsen share last authorship.

Authors and Affiliations

  1. Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark

    Troels Dreier Christensen, Anna Sofie Kappel Buhl & Dorte Nielsen

  2. Oncology Venture, Hoersholm, Denmark

    Anna Sofie Kappel Buhl, Ida Kappel Buhl, Annie Rasmussen, Anker Hansen, Steen Knudsen & Peter Buhl Jensen

  3. Department of Pathology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Ib Jarle Christensen & Eva Balslev

  4. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Ida Kappel Buhl

  5. Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Ann S. Knoop & Bent Ejlertsen

  6. Department of Oncology, Nordsjaellands Hospital, Copenhagen University Hospital, Hilleroed, Denmark

    Hella Danø

  7. Department of Oncology, Zealand University Hospital, Naestved, Denmark

    Vesna Glavicic

  8. Department of Oncology, Aalborg University Hospital, Aalborg, Denmark

    Adam Luczak

  9. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

    Sven Tyge Langkjer

  10. Department of Oncology, Regional Hospital West Jutland, Herning, Denmark

    Søren Linnet

  11. Department of Oncology, Vejle Sygehus, Vejle, Denmark

    Erik Hugger Jakobsen

  12. Department of Oncology, Hospital of Southern Jutland, Soenderborg, Denmark

    Jurij Bogovic

  13. The Danish Breast Cancer Cooperative Group, DBCG Secretariat, Rigshospitalet, Copenhagen, Denmark

    Bent Ejlertsen

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  1. Troels Dreier Christensen
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Corresponding author

Correspondence to Troels Dreier Christensen.

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Conflict of interest

Authors IKB, ASKB, AR, AH, SK, PBJ declare current employment or leadership position in Oncology Venture, that has a potential to benefit from these results. Authors IKB (immediate family), ASKB, IJC, AR, AH, SK and PBJ declare ownership in Oncology Venture, that has a potential to benefit from these results. IJC declare consultancy role to Oncology Venture. Author BE has previously received grants from NanoString Technologies, Roche, and Novartis outside the submitted work.

Ethics approval

All procedures performed in the study 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. This was a retrospective non-intervention study and was not associated with any risk for participating patients and the results did not affect future treatment of the patients. The LiPlaCis study (ID H-1–2013-016) and this substudy (ID HGH-2016–097) were approved by The Copenhagen Regional Committee on Health Research Ethics.

Informed consent

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

Data availability statement

Data will be made available through applications to DBCG.

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Christensen, T.D., Buhl, A.S.K., Christensen, I.J. et al. Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay. Breast Cancer 27, 266–276 (2020). https://doi.org/10.1007/s12282-019-01017-7

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