Oral vinorelbine in metastatic breast cancer: A review of current clinical trial results

Aapro, Matti; Fínek, Jindřich

doi:10.1016/j.ctrv.2011.05.005

Cited by 44 publications

(36 citation statements)

References 39 publications

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“…fl/fl cells with or without restored IRS-2 expression were stimulated with IGF-1 after treatment with nocodazole and vinblastine. An additional Vinca alkaloid drug, vinorelbine, which is used to treat breast cancer patients (23,28), was also assayed (29). As observed previously ( Fig.…”

Section: Igf-1r Signaling Is Dependent On the Microtubule Cytoskeletonmentioning

confidence: 68%

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

Mercado-Matos

Clark

Piper

et al. 2017

Journal of Biological Chemistry

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The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2-but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment.Insulin receptor substrate 1 (IRS-1) 2 and IRS-2 are cytoplasmic adaptors for the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R), and they play a major role in determining the cellular response to stimulation of these receptors (1). Notably, the IRS proteins are required for the activation of PI3K downstream of the IR and IGF-1R, which activate AKT and mechanistic target of rapamycin (mTOR) to promote proliferation, survival, motility, protein synthesis, and glucose metabolism (2-5). IRS-1 and IRS-2 are expressed ubiquitously in humans, including in the normal and malignant mammary epithelium (1). Despite their considerable sequence homology, IRS-1 and IRS-2 play divergent roles in breast cancer. In vitro, studies to assess IGF-1-dependent signaling through the IRS proteins in breast carcinoma cells have revealed that IRS-1 primarily regulates proliferation and survival, whereas IRS-2 regulates motility, invasion, and glycolysis (6 -10). In vivo, overexpression of either IRS-1 or IRS-2 in the mouse mammary gland promotes mammary tumorigenesis (11). However, metastasis is diminished in the absence of Irs-2 expression and increased in the absence of Irs-1 expression (9, 12).Differential localization patterns of IRS-1 and IRS-2 in human breast tumors suggest one explanation for their divergent functions in breast cancer (13). In normal breast tissue, ductal carcinoma in situ, and invasive breast tumors, IRS-1 is primarily localized in the nucleus a...

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Section: Igf-1r Signaling Is Dependent On the Microtubule Cytoskeletonmentioning

confidence: 68%

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

Mercado-Matos

Clark

Piper

et al. 2017

Journal of Biological Chemistry

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“…Over the last few years, a number of oral schedules for single-agent and combined treatments have been developed and are widely used to improve tolerability and compliance in patients with metastatic breast cancer [115], and similar efforts should be made for patients with NSCLC.…”

Section: Expert Opinionmentioning

confidence: 99%

An evaluation of the pharmacokinetics and clinical use of vinorelbine for NSCLC treatment

Caffo

Dipasquale²,

Murgia³

et al. 2013

Expert Opinion on Drug Metabolism & Toxicology

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In the first-line treatment of advanced NSCLC, the use of vinorelbine-based regimens may be less efficacious in controlling disease than other combinations. However, since their activity is not related to histology, vinorelbine still has potential as a first-line treatment for NSCLC patients in whom histology has failed to distinguish non-squamous from squamous histotypes. The use of an oral formulation may furthermore improve tolerability and patient compliance. Vinorelbine should be the drug of choice in the adjuvant setting as the vinorelbine/cisplatin doublet is the only regimen so far that has led to a survival gain in two Phase III trials. In patients aged > 70 years, vinorelbine (together with gemcitabine) should furthermore be the reference drug for first- and second-line therapy when single-agent chemotherapy is the treatment of choice. However, new efforts still need to be made to develop oral schedules for NSCLC.

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“…Пероральная форма винорелбина в качестве монотера-пии может быть оптимальным режимом лечения у паци-енток, где основной целью является контроль медленно прогрессирующей болезни, в том числе у пациенток без агрессивных висцеральных метастазов, либо у пациен-ток, резистентных к гормональной терапии. Такое ле-чение может сохранить качество жизни этой категории больных [5]. В данной ретроспективной работе был проведен анализ только лишь 1-годичной выживаемости, что было про-диктовано недостаточностью первичных данных.…”

Section: дискуссияunclassified

“…Целью лечения пациенток с метастатическим РМЖ является улучшение качества и увеличение длительности ремиссии при сохранении качества жизни пациенток [5]. Для пациенток с метастатическим РМЖ, которым продол-жение терапии таксанами или антрациклинами противо-показано, на сегодняшний день не существует стандартов режимов лечения [4], так как план лечения таких пациенток должен строиться на индивидуальном подходе и принимать во внимание такие факторы, как безрецидивная продолжи-тельность жизни, предыдущие режимы лечения, биология и распространенность опухоли, наличие висцеральных мета-стазов, сопутствующая патология и предпочтения пациента [5], которые зачастую играют не последнюю роль [6]. Таким образом, на настоящий момент имеется необходимость под-бора монотерапии для данной категории больных.…”

Section: Introductionunclassified

“…Их противоопухолевая активность была сравнима, но профили токсичности различались. Так при терапии винорелбина чаще отмечалась гемотоксичность, а при терапии капецита-бином -диарея и пальмарно-плантарный синдром [5]. Винорелбин показал свою эффективность и хорошую пе-реносимость в режиме монотерапии при метастатическом РМЖ с частотой ответа на лечение в 40-60% у пациентов, ранее не получивших какого-либо лечения [7].…”

Section: Introductionunclassified

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Vinorelbine as a monotherapy in metastatic breast cancer treatment

Хисамов¹,

Простов²,

Бяхов³

2017

Zlokač. opuholi

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СОБСТВЕННЫЕ ИССЛЕДОВАНИЯ • OWN INVESTIGATIONSЖурнал «Злокачественные опухоли» • № 1 -2017 г. (22) • www.malignanttumours.org Резюме Цель: проанализировать результаты лечения винорелбином у пациентов с метастатическим раком молочной железы (РМЖ). Пациенты и методы: Всего в 2015 г. в г. Москве было выявлено 5943 случaев установления диагноза РМЖ. С IV стадией заболевания наблюдалось 2378 пациентов. Из них лечение винорелбином получили 113 пациентов, получили другие виды химиотерапии -1056 пациентов, не проводилось никакого лечения 1209 пациентам. В качестве 1-й линии терапии препарат получили 13,5% больных, 2-й линии -59,7%, 3-й линии -26,8%. Результаты: При расчете доверительных интервалов 1-летней выживаемости между группой больных, получивших лечение винорелбином (ДИ 95%; 0.25-1.0), получивших другие виды лечения (ДИ 95%; 0.47-1.0) и не получивших лечения вообще (ДИ 95%; 0.32-0.49), достоверной разницы получено не было, однако, отмечена четкая тенденция к появлению разницы между группой больных, получивших винорелбин и группой пациентов, не получивших никакого лечения. Заключение: Винорелбин является эффективным и хорошо переносимым препаратом при лечении больных с метастатическим РМЖ, однако необходимо проведение рандомизированных мультицентровых исследований с целью оценить его эффективность в качестве монотерапии у больных с метастатическим РМЖ. Abstract Aim: to analyze the results of treatment with vinorelbine in patients with metastatic breast cancer (BC).Patients and methods: There were 5943 of new cases of BC in Moscow and there were 2378 patients with IV stage of the disease. 113 patients were treated with vinorelbine as a monotherapy, 1056 had other options of chemotherapy and 1209 patients had no treatment. As a first-line therapy vinorelbine was used in 13.5% of patients, as a second-line -in 59.7% and as a third-line -in 26.8%. Results: There were no significant difference in 1-year survival between group of treatment with vinorelbine (CI 95%; 0.25-1.0), group of other options of chemotherapy (CI 95%; 0.47-1.0) and group with no treatment (CI 95%; 0.32-0.49). But there were a clear tendency of increasing of difference between vinorelbine group and group without treatment. Conclusion: Vinorelbine is an effective and well-tolerated agent in patients with metastatic BC. But randomized multicenter trials are needed to evaluate efficacy of vinorelbine as a monotherapy.

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Oral vinorelbine in metastatic breast cancer: A review of current clinical trial results

Cited by 44 publications

References 39 publications

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

An evaluation of the pharmacokinetics and clinical use of vinorelbine for NSCLC treatment

Vinorelbine as a monotherapy in metastatic breast cancer treatment

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