Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies
Abstract
:1. Introduction
2. Preclinical Evidence: Findings from In Vitro and In Vivo Models
2.1. Mechanisms of Action
2.2. Metformin: Impact on Breast Cancer Outcomes in Preclinical Models
2.3. Metformin: Anticancer Effects Are Influenced by Glycemic Status/Metabolic Status
2.4. Metformin Dose Modulates Cancer Prevention and Treatment Efficacy
2.5. Membrane Transporters Determine Metformin Efficacy
Study | Model | Metformin Treatment | Impact of Metformin |
---|---|---|---|
Anisimov et al., 2005 [31] | Female Transgenic FVB/N mice carrying HER-2/neu mammary cancer gene | Dose: 1200 mg/L in drinking water; 5 d/wk Duration: from 2 months of age to natural death | ↑ life span by 8% vs. control ↑ tumor latency vs. control ↓ mean tumor diameter vs. control |
Checkley et al., 2017 [32] | Female Wistar rats MNU-induced ER+ mammary tumors Diet: high-fat (45% kcal fat) | Dose: 2 mg/mL in drinking water Duration: 8 wks | 2/3 of tumors had ↓ size ↓ tumor proliferative index (Ki67) |
Giles et al., 2018 [33] | Female Wistar rats; Ovariectomized MNU-induced ER+ mammary tumors Diet: high-fat (45% kcal fat) | Dose: 2 mg/mL in the drinking water Duration: 8 wks | ↓ tumor size vs. control ↓ new tumor formation ↓ aromatase+, CD68+ MΦ in tumor microenvironment vs. control + D4:D6 |
Song et al., 2023 [35] | BALB/c-nu nude mice with MDA-MB-231 cells to form tumors | Dose: 22 mM Duration: 7 days | ↓ tumor size & weight vs. control |
Thompson et al., 2015 [36] | Model 1: Female Sprague Dawley rats MNU-induced ER+ mammary tumors Diet: low fat (8% kcal fat) | Doses (2): 50 or 150 mg/kg BW/d (gavage) Duration: 121 days | No significant effect on tumor outcomes vs. controls |
Model 2: MMTV-Neu+/−/p53 KO+/− mouse model (ER- mammary tumors) Diet: low fat (8% kcal fat) | Dose: 1500 mg/kg diet Duration: 60 days of age until ~11 months of age | No significant effect on tumor outcomes vs. controls | |
Model 3: ER- orthotopic mammary tumors (cells from C3(1)Tag tumor–bearing mice implanted in female SCID mice) | Doses (2): 100 or 150 mg/kg BW/d (i.p. injection) Duration: once tumors reached 125 mg, daily for 14 d | Neither dose significantly inhibited the tumor growth | |
Zhu et al., 2015 [37] | Female Sprague Dawley rats MNU-induced ER+ mammary tumors Diet: AIN-93G | Dose: 9.3 mmol/kg diet Duration: ~6 wks (started MET 1 wk after carcinogen) | No significant effect on tumor outcomes vs. controls |
Bojkova et al., 2009 [38] | Female Sprague Dawley rats MNU-induced ER+ mammary tumors | Dose1: 50 μg/mL Dose2: 500 μg/mL Duration: ~20 wks | No significant effect on tumor outcomes vs. controls |
Zhu et al., 2011 [42] | Female Sprague Dawley rats MNU-induced ER+ mammary tumors Diet: AIN-93G ad libitum or 40% calorie restriction (Expt 3 only) | Experiment 1 Dose1: loading 0.5%, then 0.05% Dose2: loading 1.0%, then 0.25% (w/w) in the diet Duration: 5 d loading + 28 d maintenance dose | Dose1: No significant effect on tumor outcomes vs. controls Dose2: ↓ tumor weight & multiplicity ↑ tumor latency vs. control |
Experiment 2 Dose: 0.3% (w/w) in the diet Duration: started 7 d post carcinogen, for 9 wks | No significant effect on tumor outcomes vs. controls, suggesting that early events in the carcinogenic process are more susceptible to high dose metformin | ||
Experiment 3 Dose: 0.25% (w/w) + 40% calorie restriction Duration1: 10 wks Duration2: 8 wks treatment, last 2 weeks of 10 wks removed from 0.25% (w/w) + 40% calorie restriction | 40% caloric restriction (CR) alone or combined with MET were equally effective in inhibiting mammary carcinogenesis ↓ tumor weight & multiplicity vs. controls ↑ tumor latency vs. control Stopping both CR & MET: - retained benefits on preventing new tumors - lost benefit on suppressing growth of existing tumors | ||
Zhuang et al., 2014 [43] | Female Balb/C mice injected with 4T1 cells Diet: control (24% kcal fat) vs. ketogenic (4.6% pr, 93.4% fat, 2% cho—also calorically restricted) | Dose: 2 mg/d (i.p) Duration: ~2 wks | Control diet: MET had no effect on tumor volume Ketogenic diet: ↓ tumor volume vs. control MET + ketogenic diet: ↓ tumor volume vs. control & vs. ketogenic diet alone |
Marini et al., 2016 [44] | Female BALB/c mice + syngeneic 4T1 cells (TNBC) Diet: chow (12% fat) +/− short-term starvation (2 × 48 h periods on days 5–7 & 12–14) | Dose: 3 mg/mL in the drinking water Duration: 14 days | MET ↓ tumor volume vs. chow control Short-term starvation + MET further ↓ tumor growth |
Zhu et al., 2014 [50] | Female FVB/N-Tg MMTV-ErbB2 transgenic mice Diet: estrogen-free AIN-93G diet | Premalignant stage experiment Dose: 250 mg/kg injected i.p. Duration: 10 weeks | ↓ lateral branching & alveolar structures ↓ CD61high/CD49fhigh tumor-initiating cells |
Syngeneic grafting of MET pretreated 78617 tumor cells (derived from MMTV-ErbB2 tumors) into MMTV-ErbB2 mice | In vitro pretreatment + tumor grafts experiment Dose: 1 mmol/L in the media (in vitro) Duration: 72 h Tumors monitored for 14 d post injection | MET pretreatment ↓ tumor volume | |
Barbieri et al., 2015 [51] | Female NOD-SCID mice (non-obese diabetic severe combined immunodeficient) injected with cancer stem cell like cells from mammary canine tumors. | Dose: 360 mg/Kg BW/day in the drinking water Duration: 6 months | ↓ tumor weight ↓ tumor Ki-67 & mitotic index |
Study | Glucose | Metformin | Outcomes |
---|---|---|---|
Wahdan-Alaswad et al., 2013 [39] | 5 mM 10 mM 17 mM | 5 mM | Most cell lines: ↓ proliferation |
5 mM 10 mM 17 mM | 10 mM | ↓ proliferation in TNBC but no other cell lines | |
Varghese et al., 2019 [40] | 5.5 mM | 25–100 µM | no change: MDA-MB-231 no change: MDA-MB-468 |
500 µM–10 mM | ↓ proliferation: MDA-MB-231: ↓ proliferation: MDA-MB-468: | ||
25 mM | 25 µM | no change: MDA-MB-231 no change: MDA-MB-468 | |
100 µM | ↑ proliferation: MDA-MB-231 ↑ proliferation: MDA-MB-468 | ||
250, 500 uM | ↑ proliferation: MDA-MB-231 ↓ proliferation: MDA-MB-468 | ||
1–10 mM | no change: MDA-MB-231 ↓ proliferation: MDA-MB-468 | ||
Zhu et al., 2011 [42] | Not stated | 0.02–0.2 mM | no change: MDA-MB-468 |
0.02–1 mM | no change: MCF7 | ||
0.02–2 mM | no change: BT-20 no change: MDA-MB-453 | ||
0.02–5 mM | no change: BT-549 no change: MDA-MB-231 | ||
0.02–10 mM | No change: SK-BR-3 | ||
1–20 mM | ↓ proliferation: MDA-MB-468 | ||
2–20 mM | ↓ proliferation: MCF7 | ||
5–20 mM | ↓ proliferation: BT-20 ↓ proliferation: MDA-MB-453 | ||
10–20 mM | ↓ proliferation: BT-549 ↓ proliferation: MDA-MB-231 | ||
20 mM | ↓ proliferation: SK-BR-3 |
2.6. Metformin and Breast Cancer Stem Cells
2.7. Metformin: Modulation of microRNAs and Long Non-Coding RNAs in Breast Cancer
2.7.1. MicroRNAs (miRNAs)
2.7.2. Long Non-Coding RNAs
2.8. Metformin and Immune Modulation
3. Translating Metformin to the Clinic
3.1. Epidemiological Evidence
3.2. Clinical Findings: Window of Opportunity Trials
Study Type | ID ClinicalTrials.gov | Population/Cancer Details | Intervention(s) | Primary Outcome(s) | Related Publications | Key Findings |
---|---|---|---|---|---|---|
Completed Studies | ||||||
RCT | NCT01302379 | Postmenopausal breast cancer survivors w/BMI > 25 kg/m2 | 6-month intervention (4 groups) (1) placebo + lifestyle intervention (2) MET + lifestyle intervention (3) placebo + standard printed dietary guidelines (4) MET + standard printed dietary guidelines MET dosing: wk 1: 500 mg/day (PM) wks 2–4: 1000 mg/day (PM) wks 5+: 1500 mg/day (500 mg AM + 1000 mg PM) | Change (baseline to 6 mos) for: - insulin, - glucose, - C-reactive protein, - bioavailable testosterone, - sex hormone binding globulin | Nwanaji-Enwerem et al., 2021 [110], Bellerba et al., 2022 [111] | MET + Lifestyle Intervention ↓ insulin −21.8% (CI −29.7 to −13.0) ↓ C-reactive protein −21.4% (CI −38.9 to 1.0) MET + Standard Dietary Guidelines ↓ insulin −13.2% (CI −21.7 to −3.7) ↓ C-reactive protein −9.2% (CI −29.0 to 16.1) |
Phase 2 | NCT00930579 | Newly diagnosed early invasive BC | Pre-surgical intervention MET 1500 mg/day for a minimum of 2 wks prior to surgery | Kalinsky et al., 2014 [107], Kalinsky et al., 2017 [112] | No change in tumor proliferation (Ki-67) ↓ BMI, cholesterol, and leptin MET modulated proteins involved in apoptosis/cell cycle, cell signaling, & invasion/motility, including: - ↑ tumor Raptor, C-Raf, Cyclin B1, Cyclin D1, TRFC, and Syk - ↓ tumor pMAPKpT202, Y204, JNKpT183, pT185, BadpS112, PKC.alphapS657, and SrcpY416 | |
NCT02028221 | Premenopausal w/BMI > 25 kg/m2 and metabolic syndrome | BC prevention 12-mo intervention (1) Placebo (2) MET wks 1–4 850 mg/day, wks 5 + 1700 mg/day | Change in breast density at 6 and 12 mos | Martinez et al., 2016 [113], Tapia et al., 2021 [114] | ↓ waist circumference and waist-to-hip ratio No change in % breast density or dense breast volume Non-significant (p = 0.07).↓ in non-dense breast volume | |
NCT01310231 | Metastatic or unresectable locally advanced BC on 1st-4th line chemotherapy w/anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens w/o diabetes | Intervention continued until disease progression (1) placebo + standard chemotherapy (2) MET 850 mg/2× day + standard chemotherapy | Progression-free survival | Pimentel et al., 2019 [115] | No effect on progression-free survival, overall survival, and response rate | |
NCT02431676 | Individuals that have survived solid malignant tumors including breast, prostate, lung, colon, skin melanoma, endometrial, liver, pancreatic, rectal, kidney, other solid malignant tumors. | Secondary prevention study evaluating the effect of the interventions on IGF-1 (1) Self-directed weight loss (2) Coach-directed behavioral weight loss (3) MET up to 2000 mg/day | IGF-1 at 6 mos IGF1/IGFBP3 molar ratio levels at 6 and 12 mos | Juraschek et al., 2018 [116], Mueller et al., 2021 [117], Hu et al., 2021 [118], Tilves et al., 2022a [119], Tilves et al., 2022b [120] | ↓ BMI ↑ butyrate, acetate, and valerate at 6 months Altered microbiota composition: ↑ Escherichia coli and Ruminococcus torques, ↓ Intestinibacter bartlettii, R. faecis and R. intestinalis | |
Phase 3 | NCT01101438 | Women w/o diabetes w/high-risk nonmetastatic BC | 5 Year Intervention (1) Placebo + standard treatment (2) MET + standard treatment MET dosing: wks 1–4 850 mg/day, wks 5+ 850 mg/2× day | Invasive disease-free survival | Goodwin et al., 2022 [121], Goodwin et al., 2023 [122] | No change in invasive disease-free survival or the risk of developing new cancers. |
Window of opportunity | NCT00897884 | w/o diabetes w/newly diagnosed untreated BC | Window-of-opportunity neoadjuvant study, intervention 2–3 wks prior to surgical removal of tumor MET 500 mg/3× day | Tumor proliferation rate (pre vs. post treatment) | Dowling et al., 2015 [123] | ↓ insulin receptor expression in tumors ↓ phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) in tumors |
Phase 2 | NCT01340300 | Stage I-III CRC & BC survivors, >2 mo from completing standard therapy (excluding hormone rx or trastuzumab) | Randomized to 12 wks of: (1) Control educational materials (2) MET (3) Exercise (4) MET + Exercise MET dosing: wks 1–2 1/day, wks 3+ 2/day Exercise: Training w/exercise physiologist 2× wk | Change in fasting insulin (baseline to 3 mos) | Brown et al., 2020 [124], Meyerhardt et al., 2020 [125] | MET ↓ insulin from baseline −1.16 mU/L ± 1.18 ↓ leptin from baseline −2.56 ng/mL ± 1.33 ↓ IGF1 from baseline −2.66 ng/mL ± 3.28 MET + Exercise ↓ insulin from baseline −2.47 mU/L ± 1.07 ↓ leptin from baseline −5.09 ng/mL ± 1.21 ↓ IGF1 from baseline −1.29 ng/mL ± 2.98 |
Early Phase 1 | NCT01980823 | Newly diagnosed operable invasive BC or DCIS No prior treatment | Window-of-opportunity intervention ~2 wks prior to surgical removal of tumor MET 1500 mg/day + Atorvastatin 80 mg/day | Change in tumor Ki-67 (proliferation; baseline to 2 wks) | N/A | No results reported. |
NCT01793948 | Postmenopausal w/elevated risk for breast cancer w/BMI ≥ 25 w/o diabetes | BC prevention study MET (850 mg/ 2× day) for 12 cycles vs. placebo | Changes in protein phosphorylation after MET exposure from baseline to 12 mos | N/A | No results reported. | |
Phase 1 | NCT02882581 | Adults >50 years w/BC | Radiation: 11C-metformin | MET uptake in BC | N/A | No results reported. |
NCT01650506 | TNBC w/o diabetes | Single arm phase 1 study Intervention: Erlotinib + Metformin MET dosing: Dose titrated from 850 mg/2× day to 850 mg/3× day Erlotinib dosing: 150 mg/day | Max tolerated dose of MET in combination with a 150 mg erlotinib/day | N/A | No results reported. | |
NCT02278965 | Pre- and postmenopausal w/history of early stage BC w/BMI ≥ 25 w/o diabetes | Single group assignment, intervention for 12 mos MET 850 mg/2× day + Omega-3 fatty acids 560 mg/2× day | # of participants completing the 1-year intervention | N/A | No results reported. | |
NCT00933309 | Postmenopausal w/history HR+ BC and evidence metastasis w/BMI ≥ 25 | Duration: as long as the disease is stable and/or responding (1) Exemestane 25 mg/day (2) Exemestane 25 mg/day + Avandamet (MET 500 mg + Rosiglitazone 2 mg)/day | Dose-limiting toxicity | N/A | No results reported. | |
NCT00659568 | Metastatic or unresectable solid tumor (breast, endometrial, kidney, lung, unspecified) or lymphoma | Determine max tolerated dose of MET when administered with temsirolimus Intervention: MET + temsirolimus | Max tolerated and recommended dose of MET when administered w/temsirolimus | N/A | No results reported. | |
NCT02145559 | Adults w/solid tumors that is metastatic or unresectable and standard or palliative measures are not an option (breast, lung, liver, lymphoma, kidney) | Evaluate the pharmacodynamic markers sirolimus + metformin therapy (1) MET XR up to 1000 mg/day + Sirolimus (2) Delayed MET (no MET for 2 wks then titrated up to 1000 mg/day) + Sirolimus | Pharmacodynamic biomarker p70S6K | N/A | No results reported. | |
Phase 2 | NCT01266486 | Early stage BC w/o diabetes | Single group assignment Intervention (14–21 days): Extended-release MET 1500 mg/day | Phosphorylation of S6K, 4E-BP-1 and AMPK | Lord et al., 2018 [126] Lord et al., 2020 [108], Ralli et al., 2022 [127] | ↑ in genes that regulate fatty acid oxidation ↓ mitochondrial metabolites, activates mitochondrial metabolic pathways, and ↑ 18-FDG flux in tumors Tumor heterogeneity: - Mitochondrial response to MET dictates response - Identified OXPHOS transcriptional response (OTR) signature in tumors that were resistant to MET - Tumors that ↑ OXPHOS genes had ↑ proliferation score |
NCT04143282 | MBC w/o diabetes | Chemotherapy alone vs MET + chemotherapy | Radiologic response rate at 3 mos Overall & progression-free survival at 6 mos | Rabea et al., 2021 [128] | Improved radiologic response, ↓ mortality & ↓ disease progression but overall survival & progression-free survival not significantly affected | |
NCT04170465 | BC w/o metastasis and w/o diabetes | RCT, intervention 6 mos (1) MET 850 mg/2× day + AC-T neoadjuvant chemotherapy (2) AC-T neoadjuvant chemotherapy alone | Tumor apoptosis and chemotherapy toxicities at 6 mos | Serageldin et al., 2023 [129] | MET + AC-T: ↓ peripheral neuropathy incidence & severity ↓ oral mucositis ↓ fatigue ↓ fatty liver incidence preserved cardiac function | |
NCT05053841 | Postmenopausal women w/BC w/o diabetes | Parallel assignment, 6-mo intervention, randomized: (1) Control: women w/obesity (n = 15) letrozole alone (2) Women w/obesity (n = 15) letrozole + MET 2000 ± 500 mg/day (3) Women w/o obesity (n = 15) letrozole alone | Change in serum biomarkers from baseline to 6 mos | El-Attar et al., 2023 [130] | ↓ estradiol, leptin, fasting glucose, insulin, osteocalcin serum levels, and HOMA-IR | |
NCT02488564 | Patients w/operable BC or locally advanced BC that is HER2+ w/o diabetes | Single group assignment, trial duration 36 mos Intervention: Liposomal doxorubicin + Docetaxel + Trastuzumab + MET 1000 mg/2× day | Pathologic complete response rate | N/A | No results reported. | |
NCT01589367 | Postmenopausal w/ER+ BC w/o diabetes | 1:1 randomized clinical (1) Letrozole 2.5 mg/day + MET (2) Letrozole 2.5 mg/day + placebo MET dosing 1 wk 500 mg/2× day, followed by 1 wk (1000 mg AM|500 mg PM)/day, followed by 22 wks 1000 mg/2× day | Clinical response rate from baseline to 24 wks | Kim et al., 2014 [131] | No results reported. | |
NCT05351021 | Early stage BC w/o diabetes receiving adjuvant paclitaxel | Randomized, parallel assignment study to test MET as a preventive for paclitaxel-induced peripheral neuropathy (1) MET 850 mg/2× day + adjuvant paclitaxel (2) placebo + adjuvant paclitaxel | Incidence of grade II or > peripheral neuropathy at end of paclitaxel treatment | Bakry et al., 2023 [132] | ↓ paclitaxel-induced peripheral neuropathy ↑ quality of life | |
NCT00909506 | Women w/operable BC w/overweight or pre-DM | Randomized, parallel assignment, 24 wk intervention (1) placebo (2) MET 500 mg/day. | Weight loss at 6 mos | N/A | No results reported. | |
NCT01885013 | HER2− MBC w/o diabetes | Randomized, parallel assignment, study 24 mos + 12-mo follow-up (1) MET 1000 mg/2× day + Myocet + Cyclophosphamide (2) Myocet + Cyclophosphamide | Progression-free survival | Gennari et al., 2020 [133] | no effect on IGF-1R expression or circulating tumor cell count | |
Phase 4 | (breast, lung, liver, lymphoma, kidney) NCT05840068 | MBC w/o diabetes | Randomized, parallel assignment, intervention 6 mos (1) MET 500 mg/2× day + chemotherapy (2) Control chemotherapy alone | IGF-1 levels at 6 mos | N/A | No results reported. |
Active—Not Recruiting | ||||||
Phase 2 | NCT04248998 | Stage I-III TNBC w/fasting glucose ≤ 250 mg/dL | Randomized, parallel assignment (1) Chemotherapy + fasting-mimicking diet (2) Chemotherapy + fasting-mimicking diet + MET 1700 mg/day | Rate of pathologic complete responses | N/A | Pathologic complete response is higher in diabetic patients who utilize neoadjuvant chemotherapy and take metformin. |
NCT04300790 | ER+ and/or PgR+, HER2− advanced BC w/centrally confirmed PI3KCAMut on an aromatase inhibitor | Single Group Assignment (1) Normoglycemic patients: Alpelisib + MET (up to 100 mg/2× day) + endocrine therapy (2) Pre-diabetic patients: Alpelisib + MET (up to 100 mg/2× day) + endocrine therapy (3) Insulin naïve type 2 diabetic patients: Alpelisib + MET (up to 100 mg/2× day) + endocrine therapy | Development of treatment-induced hyperglycemia (Alpelisib + Endocrine Therapy) | N/A | No results reported. | |
NCT02874430 | Localized breast, uterine, or cervical cancer | Single Group Assignment, intervention 6 wks Doxycycline + MET | Change in % of stromal cells expressing Caveolin-1 at an intensity of 1+ or greater | N/A | No results reported. | |
Phase 3 | NCT01905046 | Women w/high risk for BC (such as w/atypical hyperplasia, LCIS, DCIS, family history, etc.) | BC prevention, randomized, crossover assignment, (1) MET 850 mg/2× day for 24 mos (2) Placebo 12 mos, may crossover to MET mos 13–24 | Presence or absence of cytological atypia in unilateral or bilateral RPFNA aspirates after 12 and 24 mos | N/A | No results reported. |
Active—Recruiting | ||||||
Observational | NCT02695121 | Adults w/type 2 diabetes exposed to dapagliflozin and other antidiabetic treatments (including MET) | Observational cohort study | Incidence of bladder and breast cancer | N/A | No results reported. |
Phase 1 | NCT03006172 | Locally advanced or metastatic PIK3CA-mutant solid tumors including BC | Non-randomized, sequential assignment (1) Inavolisib single agent (2) Inavolisib + palbociclib + letrozole (3) Inavolisib + letrozole (4) Inavolisib + fulvestrant (5) Inavolisib + palbociclib + fulvestrant (6) Inavolisib + palbociclib + fulvestrant + MET (7) Inavolisib + trastuzumab + pertuzumab | % of participants w/dose limiting toxicities Recommended phase II dose of inavolisib % of participants w/adverse and serious adverse events | N/A | No results reported. |
Phase 2 | NCT05023967 | Early BC w/o diabetes | Randomized, parallel assignment, intervention 4–6 wks (1) Fasting (≥16 h every night) + continuous glucose monitoring + nutritional counseling + MET extended-release (2) Usual dietary pattern + continuous glucose monitoring | Frequency of dose-limiting toxicity Change cell proliferation pre-post treatment (Ki67) | N/A | No results reported. |
NCT05660083 | HER2− metaplastic BC and/or TNBC | Single group assignment Combination of an iNOS inhibitor + nab-paclitaxel + alpelisib To prevent deep venous thrombosis & hypertension: aspirin + amlodipine To reduce risk of severe hyperglycemia: MET up to 1000 mg/2× day | Recommended phase II dose of Alpelisib + standard + nab-paclitaxel + L-NMMA Objective response rate | N/A | No results reported. | |
NCT01042379 | Adults w/BC | I-SPY Trial: Randomized to one of 36 experimental agents (compared to standard therapy) One group contained MET: MET + Ganitumab (AMG 479; an anti-IGF-1R antibody) | Does adding experimental agents to standard neoadjuvant medications ↑ the probability of pathologic complete response over standard neoadjuvant chemotherapy | Wang and Yee 2019 [134], Yee et al., 2021 [135] | Numerous publications, only 1 metformin related Metformin + ganitumab + paclitaxel (PGM) - metformin not sufficient to control drug-induced hyperglycemia | |
Active—Pre-Recruitment | ||||||
Early Phase 1 | NCT05680662 | Early BC, MBC, TNBC | Randomized, parallel assignment (1) Adjuvant quadruple therapy (quercetin 500 mg/day + zinc sulfate 50 mg/day + EGCG 300 mg/day + MET 850 mg/day) + standard chemotherapy (2) Control only standard chemotherapy | Invasive disease-free survival | N/A | No results reported. |
Phase 4 | NCT05507398 | Non-MBC | Randomized, parallel assignment (1) Placebo (2) MET 1000 mg/day (3) Atorvastatin 20 mg/day | Improvement in overall response rate and pathological response | N/A | No results reported. |
Terminated | ||||||
Early Phase 1 | NCT01302002 | Early BC w/o diabetes | Metformin pre-surgery, non-randomized, single-group assignment MET 500 mg/2× day for 3 wks | Cell proliferation (Ki67), apoptosis (TUNEL), fosforilate, AKT, CD1a CD83, CD68, F40/80, arginase, iNOS, T cells [CD4(+),CD45RA(+), CD 45RO, CD4, CD8 and FOXP3(+)] | Withdrawn—no enrollment | No results reported. |
Phase 2 | NCT01477060 | HER2−, ER+ and/or PgR+, MBC w/o diabetes | Randomized, parallel assignment, intervention until disease progression or other circumstance that mitigates termination (1) hormonal therapy + lapatinib 1250 mg/day (2) hormonal therapy + MET 1500 mg/day (3) hormonal therapy + lapatinib 1250 mg/day + MET 1500 mg/day | Progression-free survival | Terminated; low accrual | No results reported. |
NCT01627067 | Postmenopausal w/BMI ≥ 25 w/HR+ BC and metastatic disease | Single group assignment Everolimus 10 mg/day + Exemestane 25 mg/day + MET 1000 mg/2× day | Progression-free survival (compare between overweight and obese patients) | Terminated; funding issues Yam et al., 2019 [136] | MET + everolimus + exemestane - was safe - moderate clinical benefit in patients with both overweight and obesity - 5/22 = partial response; 7/22 = stable disease for ≥24 weeks --> clinical benefit rate of 54.5% | |
NCT02360059 | Adults w/invasive BC w/o diabetes to undergo paclitaxel chemotherapy | MET for paclitaxel neurotoxicity, randomized, parallel assignment (1) MET 1000 mg 2× day for 12 wks during paclitaxel treatment (2) Placebo for 12 wks during paclitaxel treatment | Mean change in neuropathy | Terminated; low accrual | No results reported. | |
NCT02472353 | Adults w/BC w/o diabetes needing neoadjuvant or adjuvant therapy w/doxorubicin | MET to reduce cardiac toxicity in BC, randomized, parallel assignment (1) Standard care w/doxorubicin (2) Standard care w/doxorubicin + MET | # of patients w/≤ 5% ↓ in left ventricle ejection fraction on echocardiogram | Terminated; low accrual | No results reported. | |
NCT04899349 | Adults w/HR+, HER2− advanced BC | Randomized, parallel assignment (1) Alpelisib + fulvestrant + dapagliflozin + MET XR (500–2000 mg/day) (2) Alpelisib + fulvestrant + MET XR (500–2000 mg/day) | # of patients w/hyperglycemia grade ≥ 3 over the 1st 8 wks of alpelisib + fulvestrant | Terminated; low accrual | No results reported. | |
Phase 3 | NCT02201381 | Adults w/cancer | Single group assignment Atorvastatin up to 80 mg/day + MET up to 1000 mg/2× day + doxycycline 100 mg/day + mebendazole 100 mg/day | Overall survival | Withdrawn Agrawal et al., 2023 [137] | No MET BC results reported. |
Phase 4 | NCT04741204 | Non-Hispanic white or black females w/BMI ≥ 25 w/newly diagnosed BC | Non-randomized, single-group assignment, compare outcomes between black & white women MET XR release 750 mg/2× day | Tumor progression | Withdrawn—Staffing issues | No results reported. |
NA | NCT00984490 | Stage I or II BC that can be surgically removed w/o diabetes | Single group assignment, intervention 7–21 days prior to surgery MET 850 mg/2× day | Change cell proliferation (Ki67) from baseline to post-treatment | Terminated; low accrual | No results reported. |
Status Unknown | ||||||
Phase 2 | NCT04559308 | w/o diabetes w/BC receiving neoadjuvant chemotherapy | Randomized, parallel assignment (1) 4 cycles (doxorubicin+cyclophosphamide), then 12 cycles paclitaxel+ MET 1000 mg/2× day, then surgery (2) 4 cycles (doxorubicin + cyclophosphamide), then 12 cycles paclitaxel, then surgery | Clinical benefit rate (tumor size) at 8 mos | N/A | No results reported. |
NCT03238495 | HER2+ BC | Randomized, parallel assignment (1) Chemotherapy only (TCH + P) (2) Chemotherapy (TCH + P) + MET 850 mg/2× day | Pathologic complete response | N/A | No results reported. | |
NCT02506777 | Locally advanced BC | Randomized, parallel assignment (1) Conventional chemotherapy—fluoruracil, doxorubicin, cyclophosphamide (FDC) × 6 cycles + MET 850 mg/2× day (2) Conventional chemotherapy FDC × 6 cycles + melatonin 3 mg/day (3) Conventional chemotherapy FDC × 6 cycles | Response rate and pathomorphological response after 6 mos | N/A | No results reported. | |
NCT03192293 | HR+ HER2− MBC | Single group assignment MET 850 mg/2× day + Simvastatin + Fulvestrant | Clinical benefit rate after 24 wks | N/A | No results reported. | |
NCT02506790 | ER+ locally advanced BC | Randomized, parallel assignment (1) Toremifene 60 mg/day + MET 850 mg/2× day (2) Toremifene 60 mg/day + melatonin 3 mg/day (3) Toremifene 60 mg/day | Response rate and pathomorphological response after 4 mos | N/A | No results reported. | |
NCT01566799 | HR+, HER2− BC w/o diabetes | Single group assignment Standard chemotherapy + MET 500 mg/day for 24 wks | Pathologic complete response after 24 wks | N/A | No results reported. | |
NCT04001725 | Melanoma, lung or BC w/brain metastasis requiring high-dose dexamethasone treatment | Randomized, parallel assignment (1) Dexamethasone min dose of 8 mg/day (2) Dexamethasone min dose of 8 mg/day + MET up to max 2550 mg/day | MET preventing precocious dexamethasone-induced diabetes after 14 days | Green et al., 2022 [138] | No MET BC results reported. | |
NCT01929811 | BC | Randomized, parallel assignment (1) Standard chemotherapy + MET 500 mg/3× day (2) Standard chemotherapy | Pathologic complete response rate after 5 mos | Huang et al., 2023 [139] | No change in pathological complete response or disease outcome w/MET No difference in proliferation (Ki67) w/MET MET prevented the ↑ in total cholesterol and LDL-C after standard treatment | |
Phase 2/3 | NCT04387630 | Early BC w/o diabetes | Randomized, parallel assignment (1) MET max 2550 mg/day + standard treatment (2) Placebo + standard treatment | Clinical response rate after 3 mos of therapy | N/A | No results reported. |
Unknown | NCT01666171 | BC patients concurrently enrolling or previously enrolled in MA.32 study w/breast density ≥ 25% | (1) MET 850 mg/2× day for 5 years (2) placebo | % change mammographic breast density in contralateral (unaffected) breast from baseline to 1 year | N/A | No results reported. |
NCT01286233 | BC patients eligible for randomization to MA.32 study | (1) MET 850 mg/2× day for 5 years (2) placebo | Patient-reported fatigue, stress, sleep, depression, general quality of life, comorbid conditions, and behavioral risks Biological correlates of fatigue DNA polymorphisms Changes in RNA gene expression | N/A | No results reported. |
3.3. Has the Translation of Metformin to the Clinic as an Anticancer Agent Failed?
4. Future Perspectives and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Corleto, K.A.; Strandmo, J.L.; Giles, E.D. Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals 2024, 17, 396. https://doi.org/10.3390/ph17030396
Corleto KA, Strandmo JL, Giles ED. Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals. 2024; 17(3):396. https://doi.org/10.3390/ph17030396
Chicago/Turabian StyleCorleto, Karen A., Jenna L. Strandmo, and Erin D. Giles. 2024. "Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies" Pharmaceuticals 17, no. 3: 396. https://doi.org/10.3390/ph17030396