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

Journal Article (2017)
Author(s)

Fleur Weeber (Center for Personalized Cancer Treatment, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Geert A. Cirkel (University Medical Center Utrecht, Center for Personalized Cancer Treatment)

Marlous Hoogstraat (Center for Personalized Cancer Treatment, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Sander Bins (Erasmus MC, Center for Personalized Cancer Treatment)

Christa G.M. Gadellaa-van Hooijdonk (Center for Personalized Cancer Treatment, University Medical Center Utrecht)

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)

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 (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Center for Personalized Cancer Treatment, University Medical Center Utrecht)

Maja J. de Jonge (Center for Personalized Cancer Treatment, Erasmus MC)

Marlies H.G. Langenberg (Center for Personalized Cancer Treatment, University Medical Center Utrecht)

Lodewyk F.A. Wessels (Cancer Genomics Centre, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, TU Delft - Pattern Recognition and Bioinformatics)

Edwin Cuppen (University Medical Center Utrecht)

Edwin Cuppen (University Medical Center Utrecht, Hubrecht Institute, Center for Personalized Cancer Treatment, Cancer Genomics Centre)

J.H. Schellens (Universiteit Utrecht, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, Center for Personalized Cancer Treatment, Cancer Genomics Centre)

Stefan Sleijfer (Erasmus MC, Cancer Genomics Centre, Center for Personalized Cancer Treatment)

Martijn P. Lolkema (Erasmus MC, Center for Personalized Cancer Treatment)

Emile E. Voest (Cancer Genomics Centre, Center for Personalized Cancer Treatment, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Research Group
Pattern Recognition and Bioinformatics
DOI related publication
https://doi.org/10.18632/oncotarget.16029
More Info
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Publication Year
2017
Language
English
Research Group
Pattern Recognition and Bioinformatics
Issue number
33
Volume number
8
Pages (from-to)
55582-55592
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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.