Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute

Yardley, Denise A.; Bosserman, Linda D.; O’Shaughnessy, Joyce; Harwin, William N.; Morgan, Susan; Priego, Victor; Peacock, N. W.; Bass, J. David; Burris, Howard A.; Hainsworth, John D.

doi:10.1007/s10549-015-3599-5

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…Yardley and colleagues [18] recently published the results of a randomized phase II trial in which patients were randomized to receive paclitaxel and bevacizumab with or without everolimus as first-line treatment for HER2 -MBC. The vast majority of patients enrolled had luminal BC (79% for both arms).…”

Section: Clinical Development Of Mtor and Pi3k Inhibitors In Luminal Mbcmentioning

confidence: 99%

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

et al. 2017

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Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in luminal breast cancer (BC). Despite the efficacy of endocrine agents, many patients with luminal BC do not respond to endocrine therapy and many others develop endocrine resistance over time, due to the activation of escape pathways such as the PI3K/AKT/mTOR signaling. Several clinical trials have demonstrated the efficacy of mTOR and PI3K inhibitors in overcoming endocrine resistance in hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic BC (MBC) patients. Nevertheless, to date, everolimus is the only agent targeting the PI3K/mTOR pathway that has been approved for clinical use. Recently, the introduction of CDK 4/6 inhibitors into clinical practice has significantly changed the therapeutic scenarios in luminal MBC. In the absence of direct comparisons among the new treatment combinations and predictive biomarkers of response, the choice of optimal therapeutic algorithms is very challenging. Future trials should focus on identifying more effective and safe combination therapies and defining the best treatment sequences in luminal BC.

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Section: Clinical Development Of Mtor and Pi3k Inhibitors In Luminal Mbcmentioning

confidence: 99%

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

et al. 2017

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“…Paclitaxel (PTX) is the first-line agent for breast cancer, especially for metastatic or HER2-negative breast cancer [13,14]. It possesses multiple anti-tumor activities [15].…”

Section: Introductionmentioning

confidence: 99%

Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model

Liu

et al. 2016

The FEBS Journal

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Paclitaxel is the most commonly used chemotherapeutic agent in breast cancer treatment. In addition to its well-known cytotoxic effects, recent studies have shown that paclitaxel has tumor-supportive activities. Importantly, paclitaxel levels are not maintained at the effective concentration through one treatment cycle; rather, the concentration decreases during the cycle as a result of drug metabolism. Therefore, a comprehensive understanding of paclitaxel's effects requires insight into the dose-specific activities of paclitaxel and their influence on cancer cells and the host microenvironment. Here we report that a low dose of paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of paclitaxel. We also investigated the effects of low doses of paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-jB. Furthermore, low doses of paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dosedependent effects of paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of paclitaxel during treatment.

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“…The remaining four RCTs reported no FAEs in either the everolimus or control arms, and this selection may have introduced bias into this analysis [27,29,33,35]. Several studies were not included in this analysis because of lack of adequate FAE reporting with their preliminary data [19][20][21][22][23][24][25]. Two studies provided rates of fatal adverse events but did not have absolute numbers that were needed to perform accurate analysis [22,25].…”

Section: Discussionmentioning

confidence: 99%

“…Sixteen of the remaining studies were thoroughly evaluated and 7 trials were excluded because of lack of FAE reporting [19][20][21][22][23][24][25]. The abstracts for the BOLERO-3 and RECORD-3 trials presented only the percentage of FAEs in each arm and did not report the actual number of deaths and were therefore excluded [22,25].…”

Section: Population Characteristicsmentioning

confidence: 99%

Treatment-Related Mortality With Everolimus in Cancer Patients

et al. 2014

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Introduction. The overall incidence and odds of fatal adverse events (FAEs) after exposure to everolimus are not well defined. We performed a comprehensive meta‐analysis of published randomized controlled trials (RCTs) to determine the role of everolimus in treatment‐related mortality in patients with cancer. Methods. PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs of everolimus either alone or in combination with another agent compared with the control arm without everolimus and that reported deaths from an adverse event from January 1966 to July 2013. The primary objective was to determine the difference of FAEs between everolimus‐treated patients and control group patients. Results. In total, 2,997 patients with multiple solid tumors from nine RCTs were included. The overall incidence of FAEs in cancer patients treated with everolimus was 0.7% (95% CI 0.3%–1.1%) compared with 0.4% (95% CI 0.0%–0.7%) in cancer patients who did not receive everolimus. The odds ratio of FAEs was greater in everolimus‐treated patients (Peto odds ratio = 3.80, 95% CI 1.59–9.07, p = .003). In subgroup analyses, no significant difference was found in the incidence or odds of FAEs by everolimus administration (alone or in combination) or tumor type (breast cancer vs. nonbreast cancer; p = .63). Conclusion. In patients with cancer, everolimus is associated with a small but significant increase in the odds of a treatment‐related fatal events.

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Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute

Cited by 21 publications

References 27 publications

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model

Treatment-Related Mortality With Everolimus in Cancer Patients

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