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Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer
Open accessAbstract
Purpose: Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. Patients and Methods: We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using χ 2 tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. Results: The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Conclusion: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
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“Metformin has also been found to cooperate with neo-adjuvant chemotherapy to result in complete tumor regression in some breast cancer patients (Jiralerspong et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Jiralerspong et al., 2009
In the citing paper
“Type 2 diabetic patients receiving neo-adjuvant chemotherapy for breast cancer as well as metformin were more likely to have pathologic complete response (pCR) than patients not receiving it.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [156]
In the citing paper
“However, despite the increase in pCR, metformin did not significantly improve the estimated 3-year relapse-free survival rate [156].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [156]
In the citing paper
“evidence that metformin may also have an adjunctive effect in patients receiving chemotherapy(270)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [270]
In the citing paper
“There is further evidence that metformin may also have an adjunctive effect in patients receiving chemotherapy(270), and there are now more than 100 ongoing trials”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [270]
In the citing paper
“Metformin treatment was associated with higher pathologic complete response among early-stage breast cancer patients receiving neoadjuvant therapy (95).”
From Diabetes and Cancer (2010) · cites this paper as [95]
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Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression
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BackgroundSorafenib synergizes with metformin in NSCLC through AMPK pathway activation
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Insulin, Insulin Resistance, Obesity, and Cancer
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“lowing neoadjuvant chemotherapy was observed among diabetic patients taking metformin.(73) Metformin may be particularly useful in basal type breast cancer because of its known chemoresistance.”
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BackgroundEffects of Sulfonylureas on Tumor Growth: A Review of the Literature
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“A retrospective study of 2529 breast cancer patients who received chemotherapy for early stage disease found that diabetic patients with breast cancer (n = 68) receiving metformin had a complete pathologic response rate threefold higher than that of diabetics not receiving metformin (n = 87).(56) In vitro studies have…”
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New perspectives in ovarian cancer treatment
Schmid, B. C., & Oehler, M. K. (2013) · Maturitas · doi:10.1016/j.maturitas.2013.11.009 · Cited by 67
“Furthermore, a large retrospective review has shown hat rates of complete treatment response were higher in patients aking metformin during neoadjuvant chemotherapy for breast ancer [42].”
BackgroundDiabetes and prognosis in a breast cancer cohort
Schrauder, M. G., Fasching, P. A., Häberle, L., Lux, M. P., Rauh, C., Hein, A., Bayer, C. M., Heusinger, K., Hartmann, A., Strehl, J. D., et al. (2010) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0960-2 · Cited by 67
“…already been suspected by several studies showing for example a higher pathologic complete response rate in BC patients receiving metformin during neoadjuvant chemotherapy, as well as suppressed cancer cell growth by metformin and rosiglitazone in vitro (Jiralerspong et al. 2009; Feng et al. 2010).”
ResultNew Strategies in Prostate Cancer: Targeting Lipogenic Pathways and the Energy Sensor AMPK
Zadra, G., Priolo, C., Patnaik, A., & Loda, M. F. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1955 · Cited by 69
Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma
Donadon, V. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i24.3025 · Cited by 66
Vazquez-Martin, A., López-Bonetc, E., Cufí, S., Oliveras-Ferraros, C., Del Barco, S., Martin-Castillo, B., & Menendez, J. A. (2011) · Drug Resistance Updates · doi:10.1016/j.drup.2011.04.003 · Cited by 66
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript (Jiralerspong et al., 2009).”
BackgroundDiabetes mellitus and metformin in hepatocellular carcinoma
Fujita, K., Iwama, H., Miyoshi, H., Tani, J., Oura, K., Tadokoro, T., Sakamoto, T., Nomura, T., Morishita, A., Yoneyama, H., et al. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i27.6100 · Cited by 68
Sandulache, V. C., Hamblin, J. S., Skinner, H. D., Kubik, M. W., Myers, J. N., & Zevallos, J. P. (2013) · Head & Neck · doi:10.1002/hed.23409 · Cited by 66
“Some studies have shown that metformin improves response to treatment, whereas others have simply demonstrated improved clinical outcomes.(11,12,14,15,17,19) Similar to some previous studies, we found that patients on metformin do exhibit earlier disease stage at presentation, a finding that can clearly impact patient…”
ResultCampagnoli, C., Pasanisi, P., Abbà, C., Ambroggio, S., Biglia, N., Brucato, T., Colombero, R., Danese, S., Donadio, M., Venturelli, E., et al. (2012) · Clinical Breast Cancer · doi:10.1016/j.clbc.2012.03.004 · Cited by 66
Würth, R., Barbieri, F., & Florio, T. (2014) · BioMed Research International · doi:10.1155/2014/126586 · Cited by 69
“These studies showed that diabetic patients suffer higher risk of developing cancer than people without diabetes and that adults with diabetes are more likely to die of cancer than their nondiabetic counterparts [59]; nonetheless cancer patients treated with metformin showed considerably reduced tumor burden and incid…”
ResultIkhlas, S., & Ahmad, M. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.07.029 · Cited by 66
“plete response rates in metformin group in both diabetic and non-diabetic patients [133].”
BackgroundErtel, A., Tsirigos, A., Whitaker‐Menezes, D., Birbe, R., Pavlides, S., Martinez‐Outschoorn, U., Pestell, R. G., Howell, A., Sotgia, F., & Lisanti, M. P. (2012) · Cell Cycle · doi:10.4161/cc.11.2.19006 · Cited by 64
“Conversely, Metformin (a mitochondrial complex I inhibitor)(47) should prevent cancer cells from effectively using mitochondrial fuels by inhibiting OXPHOS in cancer cells, inducing the conventional Warburg effect in cancer cells.(48-52) In fact, all three drugs have been shown to function as anticancer agents and als…”
BackgroundYasin, H. K., Taylor, A. H., & Ayakannu, T. (2021) · Cancers · doi:10.3390/cancers13092149 · Cited by 65
Sayed, R., Saad, A. S., Wakeel, L. M. E., Elkholy, E., & Badary, O. A. (2015) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2015.16.15.6621 · Cited by 62
“The effect of Metformin as a cancer therapeutic was demonstrated by several observational studies (Jiralerspong et al., 2009; Tan et al., 2011; Zhang and Li, 2014).”
BackgroundBhangu, A. A., Wood, G., Mirnezami, A. H., Darzi, A. W., Tekkis, P. P., & Goldin, R. D. (2012) · Surgical Oncology · doi:10.1016/j.suronc.2012.08.003 · Cited by 60
“The use of metformin in breast cancer has been shown in retrospective studies to be associated with the highest rate of complete pathological response (24%), when compared to non-metformin diabetics (8%) and nondiabetics (16%) [64].”
ResultMetformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma
Ma, J., Guo, Y. H., Chen, S., Zhong, C., Xue, Y., Zhang, Y., Lai, X., Wei, Y., Yu, S., Zhang, J., et al. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-172 · Cited by 63
“A recent retrospective analysis examined the effects of metformin on potentiation of chemotherapy in breast cancer patients and found that women with diabetes and breast cancer receiving metformin and neoadjuvant chemotherapy experienced a higher pathologic complete response rate than diabetic patients just receiving…”
BackgroundZhao, Y., Gong, C., Wang, Z., Zhang, J., Wang, L., Zhang, S., Cao, J., Tao, Z., Li, T., Wang, B., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20478 · Cited by 64
“The above studies administered metformin in the neoadjuvant setting at doses between 1500 mg/d-2000 mg/d as a monotherapy or in combination [14, 16, 21, 35, 36].”
BackgroundXu, P., Yin, K., Tang, X., Tian, J., Zhang, Y., Ma, J., Xu, H., Xu, Q., & Wang, S. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109458 · Cited by 61
Metformin: A metabolic disruptor and anti-diabetic drug to target human leukemia
Rosilio, C., Ben‐Sahra, I., Bost, F., & Peyron, J. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.01.006 · Cited by 63
“Similarly, metformin treatment was associated with a higher pathologic complete response in diabetic patients, compared to non-diabetic patients, treated with neoadjuvant chemotherapy for breast cancer [112].”
BackgroundMechanism of the mitogenic influence of hyperinsulinemia
Draznin, B. (2011) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-3-10 · Cited by 60
“Recently, Jiralespong and colleagues [19] have compared the rates of pathologic complete response (pCR) in diabetic patients with breast cancer receiving neoadjuvant chemotherapy and treated with metformin with those not treated with metformin.”
New Strategies in Pancreatic Cancer: Emerging Epidemiologic and Therapeutic Concepts
Li, D., & Abbruzzese, J. L. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1942 · Cited by 61
Metformin: A Dual-Role Player in Cancer Treatment and Prevention
Galal, M. A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S. S., & Aljada, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074083 · Cited by 73
“For instance, there was an observed increase in the complete-response rates among breast cancer patients treated with metformin [149].”
Andújar-Plata, P., Pi-Sunyer, X., & Laferrère, B. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.09.022 · Cited by 59
“[54] studied retrospectively the percentage of pathologic complete response (pCR) in patients with invasive breast cancer treated with neoadjuvant chemotherapy.”
BackgroundMetformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer
Campagnoli, C., Berrino, F., Venturelli, E., Abbà, C., Biglia, N., Brucato, T., Cogliati, P., Danese, S., Donadio, M., Zito, G., et al. (2013) · Clinical Breast Cancer · doi:10.1016/j.clbc.2013.08.012 · Cited by 59
Gerosuppressant Metformin: less is more
Menéndez, J. A., Cufí, S., Oliveras‐Ferraros, C., Vellón, L., Joven, J., & Vázquez‐Martín, A. (2011) · Aging · doi:10.18632/aging.100316 · Cited by 57
“Finally, because many tumor cells retain the ability to senesce, in culture and in vivo, in response to DNA-damaging chemotherapeutic agents [140-142], it might be tempting to suggest that metformin-enhanced cellular senescence in the context of DDR could explain metformin’s ability to increase the rate of pathologica…”
BackgroundZhang, J., Li, G., Chen, Y., Fang, L., Chen, G., Bai, F., Ma, M., Lyu, J., & Meng, Q. H. (2017) · Journal of Cancer · doi:10.7150/jca.19858 · Cited by 58
“Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than similar patients who did not receive metformin [6, 7].”
BackgroundZhang, Y., Storr, S. J., Johnson, K., Green, A. R., Rakha, E. A., Ellis, I. O., Morgan, D. A. L., & Martin, S. G. (2014) · Oncotarget · doi:10.18632/oncotarget.2683 · Cited by 59
“Retrospective studies have found that use of the antidiabetic drug metformin in diabetic patients’ results in a reduced incidence of, and better survival from, breast cancer [12, 37-39].”
BackgroundSoo, J. S.-S., Ng, C., Tan, S. H., Malik, R. A., Teh, Y.-C., Tan, B.-S., Ho, G. F., See, M., Taib, N. A. M., Yip, C. H., et al. (2015) · APOPTOSIS · doi:10.1007/s10495-015-1158-5 · Cited by 58
Guimarães, I. D. S., Ladislau, T., Tessarollo, N. G., dos Santos, D. Z., Gimba, E. R. P., Sternberg, C., Silva, I. V., & Rangel, L. B. A. (2017) · Pharmacological Reports · doi:10.1016/j.pharep.2017.11.007 · Cited by 58
Varghese, S., Samuel, S. M., Varghese, E., Kubatka, P., & Büsselberg, D. (2019) · Biomolecules · doi:10.3390/biom9010016 · Cited by 58
“A “complete response” (no remaining cancer in the affected breast or lymph node(s) was more likely in diabetic breast cancer patients that received chemotherapy and metformin when compared to those who received chemotherapy alone [47].”
BackgroundMetformin Protects Skeletal Muscle from Cardiotoxin Induced Degeneration
Langone, F., Cannata, S. M., Fuoco, C., Lettieri‐Barbato, D., Testa, S., Nardozza, A. P., Ciriolo, M. R., Castagnoli, L., Gargioli, C., & Cesareni, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114018 · Cited by 56
Soliman, P. T., Zhang, Q., Broaddus, R. R., Westin, S. N., Iglesias, D. A., Munsell, M. F., Schmandt, R. E., Yates, M. S., Ramondetta, L. M., & Lu, K. H. (2016) · Gynecologic Oncology · doi:10.1016/j.ygyno.2016.10.011 · Cited by 57
Hoseininezhad-Namin, M. S., Pargolghasemi, P., Alimohammadi, S., Rad, A. S., & Taqavi, L. (2017) · Physica E Low-dimensional Systems and Nanostructures · doi:10.1016/j.physe.2017.04.002 · Cited by 57
The Efficacy of Dandelion Root Extract in Inducing Apoptosis in Drug‐Resistant Human Melanoma Cells
Chatterjee, S. J., Ovadje, P., Mousa, M., Hamm, C. M., & Pandey, S. (2010) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2011/129045 · Cited by 56
“had clinically proven this by determining that diabetics with breast cancer taking Metformin had a higher pathological complete response than diabetic breast cancer patients not taking the drug [13].”
BackgroundPan, J., Chen, C., Jin, Y., Fuentes‐Mattei, E., Velázquez-Torres, G., Benito, J. M., Konopleva, M. Y., Andreeff, M., Lee, M., & Yeung, S. J. (2012) · Cell Cycle · doi:10.4161/cc.20770 · Cited by 56
Inositols in the Treatment of Insulin-Mediated Diseases
Muscogiuri, G., Palomba, S., Laganà, A. S., & Orio, F. (2016) · International Journal of Endocrinology · doi:10.1155/2016/3058393 · Cited by 59
“Patients with early stage breast cancer whowere receivingmetformin along with neoadjuvant therapy experienced a higher pathologic complete response [38].”
BackgroundParikh, A. B., Kozuch, P. S., Rohs, N. C., Becker, D. J., & Levy, B. P. (2017) · Investigational New Drugs · doi:10.1007/s10637-017-0511-7 · Cited by 56
Mondal, S., Samajdar, R. N., Mukherjee, S., Bhattacharyya, A. J., & Bagchi, B. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.7b11928 · Cited by 56
Metformin, an Old Drug, Brings a New Era to Cancer Therapy
He, H., Ke, R., Lin, H., Ying, Y., Liu, D., & Luo, Z. (2015) · The Cancer Journal · doi:10.1097/ppo.0000000000000103 · Cited by 55
“It was observed that the use of metformin as a neoadjuvant increased pathological complete response rates in breast cancer patients with diabetes, compared with either diabetic patients without metformin or nondiabetic patients (24% vs 8% vs 16%), although no significant survival was improved.(24) A smaller study on t…”
ResultLKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells
Li, N., Zou, J., Lin, H., Ke, R., He, X., Lu, X., Huang, D., Luo, L., Lv, N., & Luo, Z. (2015) · Tumor Biology · doi:10.1007/s13277-015-4639-9 · Cited by 57
“Intriguingly, studies have compared the complete pathological response or distant metastasis in diabetic patients complicated with breast cancer who received metformin in neoadjuvant chemotherapy to those without it [7].”
BackgroundKhandekar, M. J., Banks, A. S., Laznik-Bogoslavski, D., White, J. P., Choi, J. H., Kazak, L., Lo, J. C., Cohen, P., Wong, K., Kamenecka, T. M., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717776115 · Cited by 55
“One potential application of these therapeutics is to increase the efficacy of cytotoxic treatments in cancer (10, 20, 21).”
BackgroundContext-Dependent Pharmacological Effects of Metformin on the Immune System
Marcucci, F., Romeo, E. L., Caserta, C. A., Rumio, C., & Lefoulon, F. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.01.003 · Cited by 57
Stebbing, J., Sharma, A., North, B. V., Athersuch, T. J., Zebrowski, A., Pchejetski, D., Coombes, R. C., Nicholson, J. K., & Keun, H. C. (2011) · Annals of Oncology · doi:10.1093/annonc/mdr347 · Cited by 56
“Recently, it has been shown that diabetic patients with breast cancer receiving metformin during neoadjuvant chemotherapy have higher pathologic complete response (pCR) rates compared with diabetics not receiving metformin [9], while in the Women’s Intervention Nutrition Study, women randomly allocated to a low-fat di…”
BackgroundResultHardie, D. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010819 · Cited by 55
“This association has been confirmed in several other retrospective studies, including one in which breast cancer patients already taking metformin for diabetes had a significantly better response to chemotherapy than diabetics not on metformin, as well as nondiabetics (Jiralerspong et al. 2009).”
Result
Metadata
- Authors
- Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M.-C., Hortobagyi, G. N., & Gonzalez-Angulo, A. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- From the Departments of Breast Medical Oncology, Biochemistry and Molecular Biology, Quantitative Sciences, Surgical Oncology, Pharmacy, Molecular and Cellular Oncology, and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Gynecology and Obstetrics, University of Muenster, Muenster, Germany.
- Venue
- Journal of Clinical Oncology
- Published
- 2009-07-10
- Volume
- 27
- Issue
- 20
- Pages
- 3297-3302
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC2736070
- OpenAlex
- W2171998898
- Cited by
- 880
- References
- 42
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 18 · 2023: 34 · 2022: 31 · 2021: 51 · 2020: 43 · 2019: 60 · 2018: 34 · 2017: 42 · 2016: 54 · 2015: 53 · 2014: 73 · 2013: 97 · 2012: 76
- FWCI
- 35.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Association for Cancer Research
- Breast Cancer Research Foundation
- Amgen
- American Society of Clinical Oncology
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5k23ca121994-03)
- National Cancer Institute (1K23CA121994-01), K23-CA121994, 1K23CA121994)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Keywords
- metformin, breast cancer, diabetes mellitus, neoadjuvant chemotherapy, pathological complete response, predictors of treatment response
- MeSH terms
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Diabetes Mellitus, Female, Humans, Hypoglycemic Agents, Metformin, Middle Aged, Remission Induction, Multivariate Analysis, Logistic Models, Survival Analysis, Treatment Outcome, Neoadjuvant Therapy
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