title: Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer.
abstract: There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11-14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E-09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from non-responding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.
authors.affiliation: Endocrine Cancer Group, University of Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK.
authors.forename: Vicky S
authors.initials: VS
authors.lastname: Sabine
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Macaskill
authors.forename: Lorna
authors.initials: L
authors.lastname: Renshaw
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Thomas
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D000068338:Everolimus; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017698:Postmenopause; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000032:analysis*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D000068338:Everolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus