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 nonresponding 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.

The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer

“…In addition to combining them with chemotherapy, hormonal, and antiHER-2 treatments, some preclinical studies have found synergic effect when added to IGF1R or MEK inhibitors, due to their feedback upregulation of the PI3K/Akt pathway [82][83][84][85][86]. On the other hand, some studies have also started to test predictive factors to PI3K inhibitors in order to find more sensitive BC subpopulations, but the results are insufficient to make conclusions [58, 84,[87][88][89][90][91][92][93][94][95].…”

mTOR inhibitors in breast cancer: A systematic review

“…There were 16 studies evaluating everolimus (1492 patients, 17 articles; one study was described in two distinct articles [22,24]) [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33]. Ten studies described the results of phase I trials [13,17,[20][21][22][23]27,28,31,32], one described those of a phase I/II trial [15], four studies involved a phase II design [10,25,26,33] and one study involved a phase III design [12].…”

“…Three studies were conducted on hormone receptor (HR) positive metastatic breast cancer patients [10,12,28], and three studies were conducted in a HER2-positive metastatic setting [15,20,21], while in six studies the distinction between subtypes of breast cancer patients was not made [13,17,25,27,31,32]. None of the studies reported results regarding OS [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33]. All studies reported detailed outcomes pertaining to efficacy and/or safety [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33].…”

“…None of the studies reported results regarding OS [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33]. All studies reported detailed outcomes pertaining to efficacy and/or safety [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33]. Further details are provided in Tables 1-4. There were seven studies examining temsirolimus (1245 patients, 8 articles; one study was described in two distinct articles [14,16]) [11,14,16,19,29,30,34,35].…”

The role of S6K1 in ER-positive breast cancer

“…Work attempting to identify predictors of response following single-agent everolimus treatment noted gene expression changes in responding vs. resistant tumors, but no clear-cut pattern was observed. 74 S6K1 as a marker of sensitivity to mTORC1 inhibitors. mTOR inhibition was observed to result in the reversal of resistance in a breast cancer cell line rendered cross-resistant to tamoxifen and fulvestrant, accompanied by reduction in ERα phosphorylated on Ser167.…”