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BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy

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Abstract

Purpose

Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment.

Methods

We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR.

Results

In the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS.

Conclusions

We confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

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Abbreviations

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

DFS:

Disease-free survival

ER:

Estrogen receptor

NAC:

Neoadjuvant chemotherapy

pCR:

Pathological complete response

PgR:

Progesterone receptor

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Acknowledgments

We thank the members of the Remagus02 group (S Delaloge, M Espié, S Giacchetti, E Brain, JY Pierga) for their contribution to this work. We thank K Tran-Perennou, C Barbaroux, and S Vacher for their helpful technical contribution. We thank Y de Rycke for his expert biostatistics contribution and helpful discussions. This work was supported by Academic Grants (PHRC AOM/2OO2/02117) and Industrial Grants from Pfizer Inc., Roche, Sanofi- Aventis ISRCTN100599. AS Hamy-Petit was supported by an ITMO-INSERM-AVIESAN cancer translational research Grant.

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    Authors and Affiliations

    1. Department of Biostatistics, Institut Curie, Paris, France

      A. S. Hamy & B. Asselain

    2. Pharmacogenomics Unit, Department of Genetics, Institut Curie, Paris, France

      I. Bieche & F. Spyratos

    3. APHP Molecular Oncology Unit, Hôpital Saint Louis, Paris Diderot University, 1 Avenue Claude Vellefaux, 75010, Paris, France

      J. Lehmann-Che & P. de Cremoux

    4. Biology Department, Institut Gustave Roussy, Villejuif, France

      V. Scott

    5. APHP Pathology Department, Hôpital Saint Louis, Paris Diderot University, Paris, France

      Ph. Bertheau

    6. Pathology Department, Hôpital René-Huguenin, Institut Curie, Saint-Cloud, France

      J. M. Guinebretière

    7. Pathology Department, Institut Gustave Roussy, Villejuif, France

      M. C. Matthieu

    8. Pathology Department, Institut Curie, Paris, France

      B. Sigal-Zafrani

    9. APHP, Centre for Therapeutic Innovation, Saint-Louis Hospital, Paris, France

      O. Tembo & M. Marty

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    1. A. S. Hamy
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    Correspondence to P. de Cremoux.

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    F. Spyratos and P. de Cremoux have contributed equally to the study

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    Hamy, A.S., Bieche, I., Lehmann-Che, J. et al. BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy. Breast Cancer Res Treat 159, 499–511 (2016). https://doi.org/10.1007/s10549-016-3961-2

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