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

Journal article (2017)

Authors

Fleur Weeber Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Center for Personalized Cancer Treatment
Geert A. Cirkel University Medical Center Utrecht, Center for Personalized Cancer Treatment
Nicolle J.M. Besselink University Medical Center Utrecht, Center for Personalized Cancer Treatment
Hugo M. Horlings Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Neeltje Steeghs Center for Personalized Cancer Treatment, University Medical Center Utrecht, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Maja J. de Jonge Center for Personalized Cancer Treatment, Erasmus MC
Marlies H.G. Langenberg University Medical Center Utrecht, Center for Personalized Cancer Treatment
L.F.A. Wessels Cancer Genomics Centre, Pattern Recognition and Bioinformatics - EEMCS , Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Edwin P.J.G. Cuppen University Medical Center Utrecht
Edwin P.J.G. Cuppen Hubrecht Institute, University Medical Center Utrecht, Cancer Genomics Centre, Center for Personalized Cancer Treatment
J.H. Schellens Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Universiteit Utrecht, Cancer Genomics Centre, Center for Personalized Cancer Treatment
Stefan Sleijfer Cancer Genomics Centre, Erasmus MC, Center for Personalized Cancer Treatment
Marlous Hoogstraat Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Center for Personalized Cancer Treatment
Martijn P. Lolkema Erasmus MC, Center for Personalized Cancer Treatment
Emile E. Voest Cancer Genomics Centre, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Center for Personalized Cancer Treatment
Sander Bins Center for Personalized Cancer Treatment, Erasmus MC
Christa G.M. Gadellaa-van Hooijdonk University Medical Center Utrecht, Center for Personalized Cancer Treatment
Salo Ooft Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Erik van Werkhoven Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis
Stefan M. Willems University Medical Center Utrecht, Center for Personalized Cancer Treatment
Marijn van Stralen University Medical Center Utrecht
Wouter B. Veldhuis University Medical Center Utrecht
Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
Copyright: © 2017 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, L.F.A. Wessels, Edwin Cuppen, Edwin Cuppen, J.H. Schellens, Stefan Sleijfer, Martijn P. Lolkema, Emile E. Voest
DOI: https://doi.org/10.18632/oncotarget.16029
More Info
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Published Date

2017

Language

English

Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

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.