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Predicting everolimus treatment efficacy in patients with advanced endometrial carcinoma: a GINECO group study

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Abstract

This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer. Tumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6 months for response. Thirty-six blocks were available for analysis of ER, PR, HER2, LKB1, PI3K, PTEN, pAKT, 4E-BP1, p4E-BP1, and S6RP expression by immunohistochemistry, PTEN deletion by FISH, and mutational status of K-RAS, PIK3CA, PTEN, and AKT1 genes. Twelve of 34 evaluable patients had partial response or stable disease (PR, SD) and 22 had progressive disease (PD). Immunohistochemistry showed that no protein expression could predict response to everolimus. Neither could loss of PTEN expression or PTEN deletion or PTEN mutation predict patient outcome. Thirty-one samples were assessable for K-RAS mutations (ten for PR+SD and 21 for PD). There are only four patients with K-RAS mutations and none of them responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12 ± 1.7 months versus 1.05 ± 0.4 months, p < 0.001; OS 9.28 ± 2.0 months versus 2.30 ± 1.4 months, p = 0.034). In conclusion, the level of expression of proteins of the PI3K/mTOR pathway tested in this study cannot predict response to everolimus. However, endometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment.

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Acknowledgments

The authors wish to thank MC Chapeau, L Arnould, M Gelly-Marty, L Arnould, F Collin, S Mercier, S Alvernhe, Helie, S Isaac, B Marie, C Lauro, A Corrand Faure, C Pasquiou-Mege, M Maisonneuve, M Faysse, A Buenerd, M Neyra, F Ettore, C Delfour, J Simony Lafontaine, F Guihaume, P Tranbaloc, and D Piron (Pathology staff from each institution) for their work and useful advice, as well as MD Reynaud, C Chemin Airiau, and M Rogasik for editing assistance. This study has been supported by Novartis Pharma.

Conflict of interest

The following authors declare a conflict of interest: Isabelle Ray-Coquard—relevant financial relationships with Novartis and Roche (Consultant/Advisory Board for Novartis), Olivier Tredan—relevant financial relationships with Novartis and Roche (Consultant/Advisory Board for Novartis), and Thierry PETIT— relevant financial relationships with Novartis Consultant/Advisory Board. The following authors of this paper declare that there is no conflict of interest involved in this paper that could inappropriately influence (bias) their work: Isabelle Treilleux, Qing Wang, Nicolas Gane, Daniel Pissaloux, Nathalie Bonnin, Jacques Cretin, Nathalie Bonichon-Lamichhane, Franck Priou, Sandrine Lavau-Denes, Véronique Mari, Gilles Freyer, Daniela Lebrun, and Jérôme Alexandre.

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Authors and Affiliations

  1. Department of Medical Oncology, Léon Bérard Cancer Center, 28 rue Laennec, Lyon, 69008, France

    Olivier Trédan, Nathalie Bonnin & Isabelle Ray-Coquard

  2. Department of Pathology, Centre Léon Bérard, 28 rue Laennec, 69008, Lyon, France

    Isabelle Treilleux & Daniel Pissaloux

  3. Translational Research Laboratory, Centre Léon Bérard, 28 rue Laennec, Lyon, 69008, France

    Qing Wang

  4. ARCAGY, 1 place du parvis Notre Dame, 75181, Paris, France

    Nicolas Gane

  5. Department of Medical Oncology, Centre Paul Strauss, 3 Rue de la Porte de l’Hopital, 67065, Strasbourg, France

    Thierry Petit

  6. Department of Radiotherapy and Oncology, Clinique Bonnefon, 45 Avenue Carnot, 30100, Ales, France

    Jacques Cretin

  7. Department of Radiotherapy and Oncology, Clinique Tivoli, 220 Rue Mandron/91 Rue de Riviere, 33000, Bordeaux, France

    Nathalie Bonichon-Lamichhane

  8. Department of Medical Oncology, Centre Hospitalier Departemental Les Oudairies, Boulevard Stephane Moreau, 85925, La Roche-sur-Yon, France

    Frank Priou

  9. Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, 2 Avenue Martin Luther King, 87042, Limoges, France

    Sandrine Lavau-Denes

  10. Department of Medical Oncology, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189, Nice, France

    Véronique Mari

  11. Department of Medical Oncology, Centre Hospitalier Lyon-Sud, 165 Chemin de Grand Revoyet, 69495, Pierre-Benite, France

    Gilles Freyer

  12. Department of Medical Oncology, Institut Jean Godinot, 1 Avenue du Général Koenig, 51056, Reims, France

    Daniela Lebrun

  13. AP-HP, Hôpitaux Universitaires Paris Centre, Université Paris Descartes, Site Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75181, Paris, France

    Jérôme Alexandre

Authors
  1. Olivier Trédan
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  2. Isabelle Treilleux
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  3. Qing Wang
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  4. Nicolas Gane
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  5. Daniel Pissaloux
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  6. Nathalie Bonnin
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  7. Thierry Petit
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  8. Jacques Cretin
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  9. Nathalie Bonichon-Lamichhane
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  10. Frank Priou
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  11. Sandrine Lavau-Denes
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  12. Véronique Mari
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  13. Gilles Freyer
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  14. Daniela Lebrun
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  15. Jérôme Alexandre
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  16. Isabelle Ray-Coquard
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Correspondence to Isabelle Ray-Coquard.

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Trédan, O., Treilleux, I., Wang, Q. et al. Predicting everolimus treatment efficacy in patients with advanced endometrial carcinoma: a GINECO group study. Targ Oncol 8, 243–251 (2013). https://doi.org/10.1007/s11523-012-0242-9

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  • DOI: https://doi.org/10.1007/s11523-012-0242-9

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