A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy

Pimentel, Isabel; Lohmann, Ana Elisa; Ennis, Marguerite; Dowling, Ryan J.O.; Cescon, David W.; Elser, Christine; Potvin, Kylea; Haq, Rizwan Ul; Hamm, Caroline; Chang, Martin C.; Stambolic, Vuk; Goodwin, Pamela J.

doi:10.1016/j.breast.2019.08.003

Cited by 82 publications

(73 citation statements)

References 14 publications

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“…Of remaining 20 potentially eligible studies, 11 were further excluded by the inclusion or exclusion criteria. Eventually, nine randomized, clinical trials fulfilling the eligibility criteria were included in the meta-analysis [20][21][22][23][24][25][26][27][28]. Table 1 summarizes the major characteristics and clinical outcomes of the nine included studies.…”

Section: Results Of Searchmentioning

confidence: 99%

“…Based on these results, several randomized controlled trials have been conducted to investigate the effect of adding metformin to anticancer agents in patients with various types of cancer [20][21][22][23][24][25][26][27][28][29][30]. Contrary to the observational studies, the most randomized trials failed to demonstrate a significant improvement of clinical outcomes in patients treated with metformin in combination with systemic anticancer treatment [20][21][22][23][24][25][26][27]. However, the results were inconclusive because most studies were phase II trials with a small sample size.…”

Section: Ivyspringmentioning

confidence: 99%

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The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials

Kim

Jang

et al. 2020

Int. J. Med. Sci.

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Preclinical studies have demonstrated that metformin has anticancer properties and act in additive or synergistic way when combined with anticancer agents. We conducted this meta-analysis of randomized clinical trials to evaluate the effect of metformin added to systemic anticancer therapy in patients with advanced or metastatic cancer. A computerized systematic electronic search was performed using PubMed, PMC, EMBASE, Cochrane Library, and Web of Science databases (up to June 2020). From nine randomized clinical trials, 821 patients were included in the pooled analyses of odds ratios (ORs) with 95% confidence intervals (CIs) for overall response rate (ORR) and hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). The concomitant use of metformin with systemic anticancer therapy did not increase tumor response (the pooled OR of ORR = 1.23, 95% CI: 0.89-1.71, p = 0.21), compared with anticancer therapy alone. In terms of survival, metformin added to anticancer agents failed to prolong PFS (HR = 0.95, 95% CI: 0.75-1.21, p = 0.68) and OS (HR = 0.97, 95% CI: 0.80-1.16, p = 0.71). In conclusion, this meta-analysis of randomized clinical trials indicates that the addition of metformin to systemic anticancer therapy has no clinical benefits in patients with advanced or metastatic cancer.

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Section: Results Of Searchmentioning

confidence: 99%

Section: Ivyspringmentioning

confidence: 99%

The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials

Kim

Jang

et al. 2020

Int. J. Med. Sci.

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“…Mitochondria and energy metabolism disruption play an important role in cell death. This is a hot topic, and nowadays, several therapeutic approaches are exploiting and targeting it, as is the case of metformin, currently under clinical trials [16,17]. In this regard, TFP-treatment demonstrates a great anticancer effect because it is able to target mitochondria and induce metabolic-driven cell death.…”

Section: Discussionmentioning

confidence: 99%

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Huang

Lan

Fraunhoffer

et al. 2019

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

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“…84,85 Metformin, an oral biguanide commonly used to treat type 2 diabetes, has been associated with reduced incidence of breast cancer as well as improved breast cancer outcomes in observational studies largely conducted in individuals with diabetes. 86,87 Preclinical data suggest that metformin might act synergistically with certain chemotherapy; 88,89 however, recent phase II randomized studies failed to provide evidence in support of an anticancer activity of metformin when added to standard chemotherapy in women without diabetes and with metastatic breast cancer. 88,90 In vivo evidence from window studies shows an antiproliferative effect of metformin in breast cancer.…”

Section: Can the Treatment Of Endocrinopathies Reduce Recurrence Overmentioning

confidence: 99%

“…86,87 Preclinical data suggest that metformin might act synergistically with certain chemotherapy; 88,89 however, recent phase II randomized studies failed to provide evidence in support of an anticancer activity of metformin when added to standard chemotherapy in women without diabetes and with metastatic breast cancer. 88,90 In vivo evidence from window studies shows an antiproliferative effect of metformin in breast cancer. 91,92 A neoadjuvant "window of opportunity" study of metformin in women without diabetes with operable breast cancer showed that short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.…”

Section: Can the Treatment Of Endocrinopathies Reduce Recurrence Overmentioning

confidence: 99%

Endocrine Therapy-related Endocrinopathies—Biology, Prevalence, and Implications for the Management of Breast Cancer

Brown

Andreopoulou

2020

Oncology &Amp; Hematology Review (US)

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A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy

Cited by 82 publications

References 14 publications

The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials

The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Endocrine Therapy-related Endocrinopathies—Biology, Prevalence, and Implications for the Management of Breast Cancer

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