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. 2017 Mar 8;8(33):55582-55592.
doi: 10.18632/oncotarget.16029. eCollection 2017 Aug 15.

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

Fleur Weeber #  1   2 , Geert A Cirkel #  1   3 , Marlous Hoogstraat  1   4 , Sander Bins  1   5 , Christa G M Gadellaa-van Hooijdonk  1   6 , Salo Ooft  2 , Erik van Werkhoven  7 , Stefan M Willems  1   8 , Marijn van Stralen  9 , Wouter B Veldhuis  10 , Nicolle J M Besselink  1   11 , Hugo M Horlings  12 , Neeltje Steeghs  1   3   13   14 , Maja J de Jonge  1   5 , Marlies H G Langenberg  1   3 , Lodewyk F A Wessels  4   15   16 , Edwin P J G Cuppen  1   11   16   17 , J H Schellens  1   13   14   16   18 , Stefan Sleijfer  1   5   16 , Martijn P Lolkema  1   5 , Emile E Voest  1   13   16
Affiliations

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

Fleur Weeber et al. Oncotarget. .

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST The authors report no conflict of interest.

Figures

Figure 1
Figure 1. Evaluability of patients
This figure illustrates the evaluability of patients for the biomarker analyses. A single patient can be evaluable according to both RECIST and TTP ratio. Abbreviations: IC, Informed Consent; PD, Progressive Disease.
Figure 2
Figure 2. Pre-post treatment biopsy
This figure demonstrates the copy number profile of chromosome 7 in patient #2 pre-treatment and post-treatment. Pre-treatment, there is an amplification of MET. This amplification is not present in the post-treatment biopsy. Instead, there is an amplification of BRAF wild-type.
See this image and copyright information in PMC

References

    1. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011–1019. - PMC - PubMed
    1. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819. - PMC - PubMed
    1. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–529. - PMC - PubMed
    1. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523. - PMC - PubMed
    1. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456. - PubMed