Oncotarget

Clinical Research Papers:

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study

Fleur Weeber, Geert A. Cirkel, Marlous Hoogstraat, Sander Bins, Christa G.M. Gadellaa-van Hooijdonk, Salo Ooft, Erik van Werkhoven, Stefan M. Willems, Marijn van Stralen, Wouter B. Veldhuis, Nicolle J.M. Besselink, Hugo M. Horlings, Neeltje Steeghs, Maja J. de Jonge, Marlies H.G. Langenberg, Lodewyk F.A. Wessels, Edwin P.J.G. Cuppen, J.H. Schellens, Stefan Sleijfer, Martijn P. Lolkema and Emile E. Voest _

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Oncotarget. 2017; 8:55582-55592. https://doi.org/10.18632/oncotarget.16029

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Abstract

Fleur Weeber1,2,*, Geert A. Cirkel1,3,*, Marlous Hoogstraat1,4, Sander Bins1,5, Christa G.M. Gadellaa-van Hooijdonk1,6, Salo Ooft2, Erik van Werkhoven7, Stefan M. Willems1,8, Marijn van Stralen9, Wouter B. Veldhuis10, Nicolle J.M. Besselink1,11, Hugo M. Horlings12, Neeltje Steeghs1,3,13,14, Maja J. de Jonge1,5, Marlies H.G. Langenberg1,3, Lodewyk F.A. Wessels4,15,16, Edwin P.J.G. Cuppen1,11,16,17, J.H. Schellens1,13,14,16,18, Stefan Sleijfer1,5,16, Martijn P. Lolkema1,5 and Emile E. Voest1,13,16

1 Center for Personalized Cancer Treatment, The Netherlands

2 Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

3 Department of Medical Oncology, UMC Utrecht Cancer Center, Utrecht, The Netherlands

4 Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

5 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

6 Department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands

7 Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

8 Department of Pathology, UMC Utrecht Cancer Center, Utrecht, The Netherlands

9 Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands

10 Department of Radiology, UMC Utrecht Cancer Center, Utrecht, The Netherlands

11 Department of Genetics, UMC Utrecht Center for Molecular Medicine, Utrecht, The Netherlands

12 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

13 Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

14 Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

15 Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands

16 Cancer GenomiCs.nl, Utrecht, The Netherlands

17 Hubrecht institute, Utrecht, The Netherlands

18 Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

* These authors have contributed equally to this work

Correspondence to:

Emile E. Voest, email:

Keywords: everolimus; biomarkers; predict response; time to progression ratio; clinical study

Received: January 02, 2017 Accepted: February 07, 2017 Published: March 08, 2017

Abstract

Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type.

Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation.

Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher’s exact test).

Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.


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