Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial

André, Fabrice; O’Regan, Ruth; Özgüroǧlu, Mustafa; Toi, Masakazu; Xu, Binghe; Jérusalem, Guy; Masuda, Norikazu; Wilks, Sharon; Arena, Francis P.; Isaacs, Claudine; Yap, Yoon Sim; Pápai, Zsuzsanna; Làng, István; Armstrong, Anne; Lerzo, Guillermo; White, Michelle; Shen, Kunwei; Litton, Jennifer K.; Chen, David; Zhang, Yufen; Ali, Shyanne; Taran, Tetiana; Gianni, Luca

doi:10.1016/s1470-2045(14)70138-x

Cited by 446 publications

(335 citation statements)

References 36 publications

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“…Several studies have been conducted to analyze the effectiveness of rapamycin and rapalogs alone and in combination with standard chemotherapy, hormonal therapy such as EGFR and anti-VEGF inhibitors in the treatment of several types of cancers such as breast, ovarian, cervical and endometrial [112]. Phase I-II trials are now ongoing with mTOR inhibitors in patients with breast and ovarian cancer.…”

Section: Rapamycin and Its Derivativesmentioning

confidence: 99%

“…Promising results also have been found in a study conducted by Campone et al (2009) [123] to assess the safety and the pharmacokinetic interactions combining everolimus and paclitaxel in patients with breast cancer and ovarian carcinoma. Another phase II clinical study (GOG0268) that evaluates additional effects of the temsirolimus combined with paclitaxel/carboplatin therapy has been conducted in patients with stages III/IV clear cell adenocarcinoma [112,124]. However, some studies failed to show the efficiency of temsirolimus in patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer showing a modest activity of this mTOR inhibitor and the results were insufficient to justify further study in a phase III [125].…”

Section: Rapamycin and Its Derivativesmentioning

confidence: 99%

“…At present, there are several clinical trials focused on the examination of new agents, such as AZD-8055, OSI-027, WYE125132 and INK128, in a variety of human hematological malignancies and solid tumors, including breast cancers [112]. Also some studies were conducted using GSK795 in patients with advanced platinum resistant ovarian and showed interesting results as tumor regressions and CA125 decreases [138].…”

Section: Atp-competitive Inhibitorsmentioning

confidence: 99%

“…In agreement, dual PI3K/mTOR inhibitors have entered clinical trials either as monotherapy as BEZ235/NVP-BEZ235, Novartis (NCT00620594) and BGT226, Novartis (NCT00600275 and NCT00742105) in advanced solid tumors and breast cancer, GDC-0980 (Genentech) (NCT00854126 and NCT00854152) in nonHodgkin lymphoma, PF-04691502, Pfizer (NCT00927823) and GSK2126458, GlaxoSmithKline (NCT00972686) in solid tumors or in combination with other therapeutic agents, for example XL765 (Exelixis) associated with erlotinib (NCT00777699), letrozole (NCT01082068) and temozolomide (NCT00704080) in non-small cell lung cancer, breast cancer and gliomas, respectively [112]. Both BEZ235 and XL765 have shown good tolerability, with adverse effects including diarrhea, anorexia and nausea [160].…”

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

“…There are more than 50 ongoing or upcoming clinical studies investigating metformin in cancer patients as monotherapy or in combined therapy with other antineoplasic agents [112]. For example, two clinical trials (NCT01529593/ NCT02145559) have been initiated aiming the evaluation of the treatment of advanced cancers, including breast cancer, with temsirolimus/sirolimus and metformin.…”

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

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Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Guimarães¹,

Tessarollo²,

Santos³

et al. 2017

J Carcinog Mutagen

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Cancer is one of the leading causes of death worldwide. Every year 8.2 million people die from the disease. In this context, breast and ovarian cancer are the most incidental among women. Elucidation of cell growth pathways and the observation that these pathways are altered in human cancer have encouraged the search for specific inhibitors. The phosphatidylinositol-3cinase (PI3K)/Protein kinase b (AKT)/Mammalian Target of Rapamycin (mTOR) is an important pathway involved in cell growth, tumorigenesis, cell invasion, and resistance to therapies. This pathway is often activated in breast and ovarian cancers and the deregulation of its signaling can contribute to tumor growth, angiogenesis and metastasis. Metformin is one of the most commonly prescribed antidiabetic drugs in the world whose anticancer effects, mediated by reduced mTOR signaling, have become notable. Therefore, this review provides an overview of signaling pathway PI3K/AKT/mTOR in the ovarian and breast cancers as well as for target therapies of mTOR signaling, with an emphasis on its mechanisms, clinical applicability and future perspectives.

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Section: Rapamycin and Its Derivativesmentioning

confidence: 99%

Section: Rapamycin and Its Derivativesmentioning

confidence: 99%

Section: Atp-competitive Inhibitorsmentioning

confidence: 99%

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

Section: Dual Mtor/ Pi3k Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Guimarães¹,

Tessarollo²,

Santos³

et al. 2017

J Carcinog Mutagen

View full text Add to dashboard Cite

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Changing Treatment Paradigms in Metastatic Breast Cancer

Santa-Maria

Gradishar

2015

JAMA Oncol

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Advances in understanding tumor biology, particularly signaling pathways, have led to the development and approval of many novel agents and have changed the landscape of therapy for patients with metastatic breast cancer. This review highlights some of the recent successes and failures in breast cancer drug development, including strategies to overcome endocrine and human epidermal growth factor 2-neu (HER2) resistance, targeting triple-negative breast cancers (which do not express the HER2, estrogen, and progesterone receptors) through novel receptors, harnessing the immune system, and new ways of targeting angiogenesis. For patients with metastatic breast cancer, expanding therapeutic options through clinical trial participation is a crucial part of modern oncology practice. As we continue to learn how to use targeted therapies in the context of genomic medicine, analysis of the tumor in real-time may become increasingly important, giving researchers the information needed to start combining therapies in a biologically informed manner.

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ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

et al. 2017

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We previously reported that micro RNA ‐205 (miR‐205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR‐205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR‐205 downregulation. In ErbB2‐overexpressing breast epithelial cells, miR‐205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD 98059, Raf‐1 inhibitor ZM ‐336372, and ERK inhibitor SCH 772984, but PI 3K inhibitor LY 294002 and p38 MAPK inhibitor SB 203580 had no effect. We established breast epithelial cells overexpressing Raf CAAX , a constitutively active form of Raf‐1, and showed that overexpression of Raf CAAX dramatically reduced miR‐205 expression. In Raf CAAX ‐overexpressing cells, miR‐205 expression was also significantly increased by SCH 772984. Moreover, miR‐205 expression was significantly increased by treatment with DNA methyltransferase ( DNMT ) inhibitor 5‐aza‐2′‐deoxycytidine and expression of several DNMT family members was increased in both ErbB2‐ and Raf CAAX ‐overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR‐205 promoters were predominantly hypermethylated in both ErbB2‐ and Raf CAAX ‐overexpressing cells. Reporter activity of the putative miR‐205 promoters was reduced in both ErbB2‐overexpressing and Raf CAAX ‐overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR‐205 transcription via the Ras/Raf/ MEK / ERK pathway.

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Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial

Cited by 446 publications

References 36 publications

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Changing Treatment Paradigms in Metastatic Breast Cancer

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

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