Title
Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study
Author
Weeber, Fleur (Center for Personalized Cancer Treatment; Netherlands Cancer Institute)
Cirkel, Geert A. (Center for Personalized Cancer Treatment; University Medical Center Utrecht)
Hoogstraat, Marlous (Netherlands Cancer Institute; Center for Personalized Cancer Treatment)
Bins, Sander (Center for Personalized Cancer Treatment; Erasmus MC)
Gadellaa-van Hooijdonk, Christa G.M. (Center for Personalized Cancer Treatment; University Medical Center Utrecht)
Ooft, Salo (Netherlands Cancer Institute)
van Werkhoven, Erik (Netherlands Cancer Institute)
Willems, Stefan M. (Center for Personalized Cancer Treatment; University Medical Center Utrecht)
van Stralen, Marijn (University Medical Center Utrecht)
Veldhuis, Wouter B. (University Medical Center Utrecht)
Besselink, Nicolle J.M. (University Medical Center Utrecht; Center for Personalized Cancer Treatment)
Horlings, Hugo M. (Netherlands Cancer Institute)
Steeghs, Neeltje (Center for Personalized Cancer Treatment; University Medical Center Utrecht; Netherlands Cancer Institute)
de Jonge, Maja J. (Center for Personalized Cancer Treatment; Erasmus MC)
Langenberg, Marlies H.G. (Center for Personalized Cancer Treatment; University Medical Center Utrecht)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Netherlands Cancer Institute; Cancer Genomics Centre) 
Cuppen, Edwin (University Medical Center Utrecht)
Cuppen, Edwin (University Medical Center Utrecht; Center for Personalized Cancer Treatment; Cancer Genomics Centre; Hubrecht Institute)
Schellens, J.H. (Center for Personalized Cancer Treatment; Netherlands Cancer Institute; Cancer Genomics Centre; Universiteit Utrecht)
Sleijfer, Stefan (Center for Personalized Cancer Treatment; Erasmus MC; Cancer Genomics Centre)
Lolkema, Martijn P. (Center for Personalized Cancer Treatment; Erasmus MC)
Voest, Emile E. (Netherlands Cancer Institute; Center for Personalized Cancer Treatment; Cancer Genomics Centre)
Date
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.
Subject
Biomarkers
Clinical study
Everolimus
Predict response
Time to progression ratio
To reference this document use:
http://resolver.tudelft.nl/uuid:c77b2113-4158-4322-b1bb-a389f12af786
DOI
https://doi.org/10.18632/oncotarget.16029
Source
OncoTarget, 8 (33), 55582-55592
Part of collection
Institutional Repository
Document type
journal article
Rights
© 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