The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics

Awada, Ahmad; Cardoso, Fátima; Fontaine, Christel; Dirix, Luc; Grève, Jacques De; Sotiriou, Christos; Steinseifer, Jutta; Wouters, Carine; Tanaka, Chiaki; Zoellner, Ulrike; Tang, Pui; Piccart, Martine

doi:10.1016/j.ejca.2007.10.003

Cited by 139 publications

(84 citation statements)

References 13 publications

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“…In breast cancer, a beneficial effect of combination treatment with the mTOR inhibitor RAD001 (everolimus) and letrozole has been reported. 16 Moreover, mTOR specific siRNA showed the possibility of an alternative gene therapy approach in one study.…”

Section: Discussionmentioning

confidence: 99%

High expression of mTOR is associated with radiation resistance in cervical cancer

Kim

Sung

et al. 2010

J Gynecol Oncol

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Objective: Mammalian target of rapamycin (mTOR) is known to promote cell proliferation, survival, and resistance to radiation. The aim of this study was to determine whether mTOR expression was associated with survival and the response to radiation in patients with cervical cancer. Methods: After reviewing 119 patients treated by primary radiotherapy for stage IIB-IVA cervical cancer, a case-control study was performed. The cases (n=12) with local recurrence or radiation failure after primary radiation therapy were selected. For each case, two controls that had no recurrence were selected. Using pretreatment paraffin-embedded tissues, the cytoplasmic expression of phosphorylated-mTOR (p-mTOR) was evaluated by immunohistochemistry. Staining was scored based on intensity (intensity score [IS] 0-3) and proportion (proportion score [PS] 0-100). The progression free survival (PFS) was defined from the end of treatment to the day of recurrence by imaging studies or biopsy. The staining distribution and PFS were compared between the two groups. The results were analyzed by the Student t-test, Mann-Whitney U-test, Fisher's exact test, and Cox proportional hazards regression model. Results: The p-mTOR cytoplasmic expression was significantly associated with a poor response to radiotherapy (p ＜0.01). With respect to survival, a higher cytoplasmic expression of p-mTOR was associated with a worse outcome (p=0.02). The hazard ratio for recurrence or radiation failure was 6.18 for mTOR IS and 1.04 for mTOR PS (p＜0.05 for both), indicating that the degree of p-mTOR staining correlated with the recurrence risk. Conclusion: High expression of p-mTOR was associated with radiation resistance; therefore p-mTOR may be a prognostic marker for response to radiotherapy in patients with cervical cancer.

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Section: Discussionmentioning

confidence: 99%

High expression of mTOR is associated with radiation resistance in cervical cancer

Kim

Sung

et al. 2010

J Gynecol Oncol

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“…In preclinical breast cancer studies, rapalogs augmented effects of anti-estrogens, including tamoxifen, fulvestrant, and aromatase inhibitors (letrozole and exemestane) (104)(105)(106). It is not clear why combined temsirolimus and letrozole yielded no improvement over letrozole alone in one trial in metastatic estrogen receptor-positive (ER + ) breast cancer (107), while everolimus appeared to complement letrozole in advanced breast cancer (108,109). Combined aromatase and mTORC1 inhibition is being further evaluated in larger patient cohorts.…”

Section: Rapamycin and Rapalogs As Anticancer Therapiesmentioning

confidence: 99%

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Wander¹,

Hennessy²,

Slingerland³

2011

J. Clin. Invest.

371

363

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“…Everolimus given as a single agent in patients with advanced cancer (n = 55), produced clinical benefit in 7% of patients, which included disease stabilisation in two breast cancer patients for [5 months [14]. In combination with letrozole, everolimus produced one complete response and six stable disease responses [6 months in patients with advanced breast cancer (n = 18) [15] and in the neoadjuvant setting, this combination increased the efficacy of letrozole in newly diagnosed breast cancer patients (n = 138) [16]. In the first clinical study of everolimus administered as a single preoperative agent in primary breast cancer patients, everolimus treatment significantly reduced proliferation (Ki67) and mTOR pathway activation [17].…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

Sabine

Sims

Macaskill

et al. 2010

Breast Cancer Res Treat

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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.

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The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics

Cited by 139 publications

References 13 publications

High expression of mTOR is associated with radiation resistance in cervical cancer

High expression of mTOR is associated with radiation resistance in cervical cancer

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer

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