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Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node-positive, hormone receptor-positive, and HER2-negative early breast cancer in the PACS04 and METABRIC studies

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Abstract

Purpose

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) early breast cancer (BC) is the most prevalent BC subtype with substantial biological heterogeneity. Although clinicopathological (CP) characteristics have a clear prognostic value, additional biomarkers could refine survival prediction and guide treatment decision.

Methods

Copy number aberrations and somatic driver mutations were obtained with OncoScan CGH array and sequencing of 36 genes on HR+/HER2− node-positive early BC patients treated with chemotherapy from the PACS04 trial. We built a two-gene genomic score (GS) associated with distant disease-free survival (DDFS), whose prognostic value was assessed on the external METABRIC data (n = 1413) using overall survival (OS) and breast cancer-specific survival (BCSS).

Results

In the PACS04 trial (n = 327), the median follow-up for DDFS (65 events) was 9.6 years. FGFR1 amplifications (\({\text{HR}}_{\text{Amplification}}\) = 2.44, 95% CI [1.25; 4.76], p = 0.009) and MAP3K1 mutations (\({\text{HR}}_{\text{Mutation}}\) = 0.10, [0.01; 0.78], p = 0.03) were associated with DDFS beyond CP characteristics. A prognostic GS combining FGFR1 amplifications and MAP3K1 mutations added more information to CP model (\(\chi_{\text{DDFS}}^{2}\) = 12.97, \(p_{\text{DDFS}}\) < 0.001 and \(\chi_{\text{OS}}^{2}\) = 11.52, \(p_{\text{OS}}\) < 0.001). In the METABRIC study (n = 1413), FGFR1 amplifications (\({\text{HR}}_{\text{Amplification}}\) = 2.00 [1.40; 2.87], p < 0.001) and MAP3K1 mutations (\({\text{HR}}_{\text{Mutation}}\) = 0.58 [0.41; 0.83], p = 0.003) were significantly associated with BCSS beyond CP characteristics. The prognostic GS added significant prognostic information to CP model (\(\chi_{\text{BCSSS}}^{2}\) = 15.39, \(p_{\text{BCSS}}\) < 0.001 and \(\chi_{\text{OS}}^{2}\) = 5.62, \(p_{\text{OS}}\) = 0.02).

Conclusion

In axillary node-positive, HR+, and HER2− early BC, amplifications of FGFR1 gene were strongly associated with increased risk for distant disease, while mutations of MAP3K1 gene were significantly associated with decreased risk.

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Acknowledgements

We thank Yuki Takahashi for some editorial assistance.

Funding

This study was funded by grants from ANR and CGI (RHU MyPROBE and ANR-17-RHUS-0008) and Inca (PAIR SEIN14-049 IDF-ANDRE).

Author information

Author notes

  1. Fabrice André and Stefan Michiels contributed equally to this work.

Authors and Affiliations

  1. Faculté de Médecine, Kremlin-Bicêtre, Université Paris Sud, Villejuif, France

    Dimitri Carene & Fabrice André

  2. INSERM U981, Université Paris Sud, Villejuif, France

    Dimitri Carene, Alicia Tran-Dien, Ludovic Lacroix & Fabrice André

  3. R&D UNICANCER, Paris, France

    Jérôme Lemonnier

  4. Institut Claudius Ragaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France

    Florence Dalenc

  5. Centre François Baclesse, Caen, France

    Christelle Levy

  6. Institut Curie, Paris, France

    Jean-Yves Pierga

  7. Institut régional du Cancer de Montpellier, Montpellier, France

    William Jacot

  8. Grand Hôpital de Charleroi, Charleroi, Belgium

    Jean-Luc Canon

  9. Department of Medical Biology and Pathology, Translational Research Laboratory and BioBank, Gustave Roussy, Villejuif, France

    Catherine Richon & Ludovic Lacroix

  10. Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Cancer Research Center of Lyon (CRCL), Centre Léon Bérard, 69008, Lyon, France

    Christophe Caux

  11. Department of Medical Oncology, Gustave Roussy, Villejuif, France

    Fabrice André

  12. Service de Biostatistique et d’Epidémiologie, Gustave Roussy, Villejuif, France

    Stefan Michiels

  13. CESP, Faculté de médecine, Université Paris Sud, Faculté de médecine UVSQ, INSERM, Université Paris Saclay, Villejuif, France

    Stefan Michiels

  14. Service de Biostatistique et d’Epidémiologie, Gustave Roussy and INSERM U1018, Université Paris Sud, 114 Rue Edouard Vaillant, 94800, Villejuif, France

    Stefan Michiels

Authors
  1. Dimitri Carene
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Correspondence to Stefan Michiels.

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The authors declare no relevant conflict of interest.

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All procedures performed in studies 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.

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Informed consent was obtained from all individual participants included in the PACS04 study.

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Carene, D., Tran-Dien, A., Lemonnier, J. et al. Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node-positive, hormone receptor-positive, and HER2-negative early breast cancer in the PACS04 and METABRIC studies. Breast Cancer Res Treat 179, 387–401 (2020). https://doi.org/10.1007/s10549-019-05462-y

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  • DOI: https://doi.org/10.1007/s10549-019-05462-y

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