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Clinical Studies

p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane

British Journal of Cancer volume 130, pages 613–619 (2024)Cite this article

Subjects

Abstract

Background

To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy.

Methods

Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment.

Results

Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01).

Conclusions

This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice.

Clinical Trial Registration

NCT02444390.

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Fig. 1
Fig. 2: Progression-free survival according to p4EBP1 expression.
Fig. 3: Overall survival according to p4EBP1 expression.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Amélie Vermorel and Laetitia Odeyer for their technical expertise, and Drs Lilian Amrein and Yuki Takahashi who provided medical writing services. This study was supported by fund of the Breast Cancer Research Foundation and a research grant to UNICANCER by Novartis.

Funding

This work was supported by R&D UNICANCER. The SAFIR receives financial support from Novartis and the ARC foundation. Data collection, analysis and publication is managed entirely by R&D UNICANCER independently of the funding organizations.

Author information

Authors and Affiliations

  1. Centre Léon Bérard, Lyon, France

    Hélène Vanacker, Isabelle Treilleux, Camille Schiffler, Valéry Attignon & Thomas Bachelot

  2. Institut Curie, Paris, France

    Ivan Bieche, Paul H. Cottu, Antoine Pinton & Nicolas Servant

  3. Institut de cancérologie de l’ouest Pays de Loire Nantes-Angers, Saint-Herblain, France

    Mario Campone, Anne Patsouris & Alain Morel

  4. Gustave Roussy, Villejuif, France

    Monica Arnedos, Etienne Rouleau & Fabrice Andre

  5. Institut de Cancérologie Lucien Neuwirth, Saint-Priest-En-Jarez, France

    Jean-Philippe Jacquin

  6. ICR, Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France

    Florence Dalenc

  7. Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, F-49000, Angers, France

    Alain Morel

  8. UNICANCER R&D, Paris, France

    François Legrand & Marta Jimenez

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  1. Hélène Vanacker
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Contributions

HV: conceptualisation, investigation, writing–original draft, writing–review and editing. IT: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. CS: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. IB: conceptualisation, investigation, writing–original draft, writing–review and editing. MC: conceptualisation, investigation, writing–original draft, writing–review and editing. AP: conceptualisation, investigation, writing–original draft, writing–review and editing. MA: conceptualisation, investigation, writing–original draft, writing–review and editing. PHC: conceptualisation, investigation, writing–original draft, writing–review and editing. JPJ: conceptualisation, investigation, writing–original draft, writing–review and editing. FD: conceptualisation, investigation, writing–original draft, writing–review and editing. AP: conceptualisation, investigation, writing–original draft, writing–review and editing. NS: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. VA: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. ER: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. AM: conceptualisation, data curation, formal analysis, methodology, software, validation, visualisation, writing–original draft, writing–review and editing. FL: conceptualisation, data curation, formal analysis, methodology, writing–original draft, writing–review and editing. MJ: conceptualisation, data curation, formal analysis, methodology, writing–original draft, writing–review and editing. FA: conceptualisation, investigation, writing–original draft, writing–review and editing. TB: conceptualisation, investigation, writing–original draft, writing–review and editing.

Corresponding author

Correspondence to Thomas Bachelot.

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Competing interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mario Campone reports consulting or advisory role with Astra ZENECA, Novartis, Sanofi, Lilly, Pfizer, Gilead, Daiichi-Sankyo, consulting with Pierre Fabre Oncology, Sanofi, Novartis, Servier, Daiichi-Sankyo, PET- Therapy, Diaccurate, travel accomodation with Pfizer, Novartis, Roche, Astra Zeneca Anne Patsouris reports travel accommodation by Roche, Pfizer, ESAI, Lilly, MUNDIPHARMA. Monica Arnedos reports honoraria with Novartis, Pfizer, Gilead, Astra Zeneca, Roche, Astra Zeneca, Daiichi Sankyo and Pfizer (to institution), and travel accomodation with Novartis, Daiichi Sankyo, Pfizer, Lilly, Astra Zeneca. Paul H. Cottu reports consulting role with Pfizer, Roche, Lilly, Pierre Fabre, Novartis, NanoString Technologies, Seagen. Florence Dalenc reports consulting role with DAICHI, AZ, PFIZER, NOVARTIS, SEAGEN and travel/congress support with DAICHI, PFIZER, NOVARTIS, GILEAD. Etienne Rouleau reports consulting role with AstraZeneca, BMS, Roche,Clovis, MSDGSK and Research funding from AstraZeneca. Alain Morel, reports consulting role and research funding with Astrazeneca, GSK, MSD. Fabrice Andre reports stock and Other Ownership Interest with PEGASCY and institutionnal research fundings from AstraZeneca, Novartis, Pfizer, Lilly, Roche, Daiichi, and travel accommodations, from Novartis, Roche, GlaxoSmithKline, AstraZeneca. Thomas Bachelot reports consulting role and institutional research funding from Seagen, Pfizer, AstraZeneca/Daiichi, Novartis, Lilly, and non-financial support from Pfizer, all outside the submitted work. Hélène Vanacker, Isabelle Treilleux, Camille Schiffler,Ivan Bieche, Jean-Philippe Jacquin, Antoine Pinton, Nicolas Servant, valery Attignon, François Legrand, Marta Jimenez declare no conflict of interest.

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This study was approved by an independent Ethics Committee (Comité De Protection des Personnes Sud-Est II-2014 -036 B). All patients provided written informed consent.

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Vanacker, H., Treilleux, I., Schiffler, C. et al. p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane. Br J Cancer 130, 613–619 (2024). https://doi.org/10.1038/s41416-023-02549-8

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