Effect of Metformin vs Placebo on and Metabolic Factors in NCIC CTG MA.32

Goodwin, Pamela J.; Parulekar, Wendy R.; Gelmon, Karen A.; Shepherd, Lois E.; Ligibel, Jennifer A.; Hershman, Dawn L.; Rastogi, Priya; Mayer, Ingrid A.; Hobday, Timothy J.; Lemieux, Julie; Thompson, Alastair; Pritchard, Kathleen I.; Whelan, Timothy J.; Mukherjee, Som D.; Chalchal, Haji; Oja, Conrad D.; Tonkin, Katia; Bernstein, Vanessa; Chen, Bingshu E.; Stambolic, Vuk

doi:10.1093/jnci/djv006

Cited by 121 publications

(91 citation statements)

References 20 publications

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“…In agreement with these findings, elevated pretreatment insulin levels in TNBC patients enrolled in our study were associated with a worse PFS (5-year survival rate: 33%; median time to progression: 13 months) compared with TNBC patients with low insulin levels (5-year survival rate: 80%; median time to progression: 34 months; p 5 .002), but the rate of TNBC was too small and the statistical power too low to draw any conclusion (HR: 2.27; 95% CI: 0.63-8.20). Nonetheless, the findings reported here allow us to speculate that lifestyle interventions and insulin-targeting drugs, namely metformin, may prove beneficial not only for the treatment of early BC stages, as recently suggested on the basis of the positive metabolic effects of metformin in this particular cluster of patients [19], but also in subsets of patients characterized by more aggressive tumor phenotypes, such as HER2-negative hormone-resistant tumors, or TNBC, in which treatments are still challenging.…”

Section: Discussionsupporting

confidence: 56%

“…These experimental findings are strengthened by indirect observations that metformin, a biguanide oral hypoglycemic agent capable of lowering insulin levels and improving IR, also might The Oncologist 2016;21:1041-1049 www.TheOncologist.com ©AlphaMed Press 2016 be effective in reducing BC incidence [8] and may beneficially act on proliferation and apoptosis markers in early BC stages [16][17][18]. Accordingly, metformin is being investigated in an adjuvant trial investigating invasive cancer-free survival in nondiabetic women with early breast cancer (National Cancer Institute of Canada Clinical Trials Group MA.32); the primary outcome measure is expected to be released late in 2017 [19].…”

Section: Introductionmentioning

confidence: 99%

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Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

et al. 2016

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Background. Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients. Patients and Methods. Fasting blood glucose, insulin and HbA 1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated. Results. Fasting blood glucose level (mean 6 SD: 99 6 26 vs. 85 6 15 mg/dL), insulin level (median: 10.0 vs. 6.8 mIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA 1c level, were

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

et al. 2016

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“…Metformin is a Food and Drug Administration-approved drug used for the treatment of diabetes that inhibits glycolysis and glycogen synthesis and is currently undergoing phase III clinical trials for cancer therapy (40). We found that metformin treatment of mice bearing orthotopic PDAC tumors decreased levels of glucose metabolites involved in glycolysis and glycogen synthesis.…”

Section: Combined Bptes-np and Metformin Treatment Provides Enhancedmentioning

confidence: 78%

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary

Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

195

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

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“…There have been five recent clinical trials of metformin intervention in breast cancer patients [16][17][18][19][20]. Although a placebo-controlled trial is necessary to compare pre-and post-treatment effects since breast cancer patients after breast surgery usually lose weight due to the operation and voluntarily change their behaviors and lifestyles toward a healthy lifestyle pattern, two trails did not use placebo group [16,17].…”

Section: Discussionmentioning

confidence: 99%

Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial

Hyun

Yang

et al. 2015

Breast Cancer Res Treat

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Previous observational studies have suggested that metformin in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications. This randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients. Female breast cancer patients (N = 105), at least 6 months post-mastectomy, with obesity (≥25 kg/m(2)) and/or pre-diabetes (fasting blood sugar levels ≥100 mg/dL), were randomly assigned to three groups (placebo, metformin 500 mg, and metformin 1000 mg) stratified by tamoxifen use. A linear mixed model for repeated measurements among three groups and ANOVA for profile differences during 6 months of treatment were used for the intention-to-treat analysis. The metformin 1000 mg group had a significantly greater decline in glucose and HbA1c levels between treatment weeks 0 and 6 month (p = 0.008 and 0.009, respectively), and the declines increased with an increase in body mass index (BMI) level (p interaction with BMI = 0.007 and 0.067, respectively). A marginally significant different effect from the metformin 1000 mg treatment was detected for glucose and HbA1c levels (p interaction = 0.084 and 0.063, respectively) in the intention-to-treat analysis. Metformin 1000 mg treatment had a favorable effect on controlling glucose and HbA1C levels in obese non-diabetic breast cancer patients, indicating prognostic importance. Further trials are needed to elucidate the risk-benefit ratio of long-term use of metformin.

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Effect of Metformin vs Placebo on and Metabolic Factors in NCIC CTG MA.32

Abstract: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.

Cited by 121 publications

References 20 publications

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial

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