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 been found to cooperate with neo-adjuvant chemotherapy to result in complete tumor regression in some breast cancer patients.
“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
Type 2 diabetic patients receiving neo-adjuvant chemotherapy for breast cancer as well as metformin were more likely to have pathologic complete response than patients not receiving it.
“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]
Despite an increase in pathologic complete response, metformin did not significantly improve the estimated 3-year relapse-free survival rate.
“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]
Metformin may have an adjunctive effect in patients receiving chemotherapy.
“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]
There is further evidence that metformin may also have an adjunctive effect in patients receiving chemotherapy.
“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]
Metformin treatment was associated with higher pathologic complete response among early-stage breast cancer patients receiving neoadjuvant therapy.
“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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“Jiralerspong et al. (2009) studied pathological complete response (pCR) rates in breast cancer patients receiving neoadjuvant chemotherapy – pCR was significantly higher in diabetics receiving metformin than in diabetics not receiving metformin (24 vs 8%), with intermediate pCR in non-diabetics who…”
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“Furthermore, according to the results of research by Jiralespnog et al on diabetic (n=155) and non-diabetic (n=2,374) patients with breast cancer, pathologic complete remission (pCR) of patients taking metformin along with chemotherapy was higher compared to patients who did not receive metformin.(99) Other related st…”
ResultMetformin in cancer prevention and therapy.
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Cancer drug discovery by repurposing: teaching new tricks to old dogs
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“Clinically, retrospective analyses suggested that metformin may improve patient response following neo-adjuvant chemotherapy for breast cancer.(20)”
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Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer
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“Because of this, it is tempting to suggest that, in the context of DDR, metformin-enhanced cellular senescence may underlie metformin’s ability to increase the rate of pCR in neoadjuvant chemotherapy in diabetic patients with breast cancer [33] and to promote tumor regression and prevent relapse when combined with sub…”
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ResultThe fat side of prostate cancer
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“04).(57) This has prompted clinical trials of metformin, including a trial of neoadjuvant chemotherapy and trastuzumab with or without metformin in women diagnosed with HER2-positive primary breast cancer.”
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“Recently, it has been shown that patients taking metformin have improved responses following neoadjuvant chemotherapy (49) and that metformin is a radiosensitizer in vitro (50).”
Metformin and cancer: new applications for an old drug
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“identified approximately 155 diabetic and 2,374 nondiabetic patients with breast cancer and showed that diabetic patients receiving metformin and neoadjuvant taxane chemotherapy have a higher pathologic complete remission (pCR) rate than do diabetics not receiving metformin [84].”
BackgroundRepositioning metformin for cancer prevention and treatment
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Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells
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Metformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With Diabetes
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“plete response with neoadjuvant chemotherapy among diabetic patients taking metformin as compared with nondiabetic patients.(76)”
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MethodInfluentialMetformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes
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“IGF1R and MRP1 (“Multidrug Resistance-Associated Protein 1”) co-expression is linked to a poorer response to anticancer drugs.(130)”
BackgroundResultPancreatogenic Diabetes: Special Considerations for Management
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“in pancreatic cancer patients, metformin has also been shown to have anti-cancer effectiveness in diabetic breast cancer patients [”
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“In a recent study of patients receiving neoadjuvant chemotherapy for breast cancer, a group of women who were also treated with metformin for coexisting diabetes showed a greater rate of pathologic response.(136) Agents such as metformin that indirectly target the mTOR complex hold great promise, because mTOR serves a…”
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Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer
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Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study
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“In a retrospective analysis, diabetic breast cancer patients taking metformin had a significantly higher rate of response to neoadjuvant chemotherapy than those taking other antidiabetic drugs [5].”
BackgroundMetformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers
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“Epidemiological data have strongly associated metformin usage with improved cancer outcomes in multiple cohorts in numerous different cancers, including OvCa (Decensi et al., 2010; Evans et al., 2005; Ezewuiro et al., 2016; Jiralerspong et al., 2009; Libby et al., 2009; Romero et al., 2012; Wright and Stanford, 2009).”
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“The patients with diabetes with breast cancer receiving metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than did those not receiving metformin (24).”
BackgroundObesity and cancer pathogenesis
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“Interestingly, metformin also increased chemosensitivity of HCC cells, consistent with observation in clinical study and mouse xenografts models (22, 23).”
ResultBrownfoot, F. C., Hastie, R., Hannan, N. J., Cannon, P., Tuohey, L., Parry, L. J., Senadheera, S., Illanes, S. E., Kaitu’u-Lino, T. J., & Tong, S. (2016) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2015.12.019 · Cited by 222 · see citing works
Metformin and breast cancer risk: a meta-analysis and critical literature review
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“It has been shown to reduce pro-growth signaling through EGFR, MAPK and Akt pathway.(29,30,46) It also has been shown to inhibit mammary tumorigenesis using a variety of model systems (reviewed in detail in ref.”
BackgroundMethodDiabetes, Metformin, and Breast Cancer in Postmenopausal Women
Chlebowski, R. T., McTiernan, A., Wactawski‐Wende, J., Manson, J. E., Aragaki, A. K., Rohan, T. E., Ipp, E., Kaklamani, V., Vitolins, M. Z., Wallace, R. B., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.39.7505 · Cited by 214 · see citing works
Metformin: A Therapeutic Opportunity in Breast Cancer
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Self-citationAssociation between Metabolic Syndrome and Cancer
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Diabetes, cancer, and metformin: connections of metabolism and cell proliferation
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Metformin in Breast Cancer: Time for Action
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“Furthermore, retrospective analysis of data from neoadjuvant breast cancer therapy indicated that metformin may potentiate the effect of chemotherapy (7).”
BackgroundMetabolic alterations and targeted therapies in prostate cancer
Flavin, R., Zadra, G., & Loda, M. F. (2010) · The Journal of Pathology · doi:10.1002/path.2809 · Cited by 177 · see citing works
“Recent evidence indicates that: (a) diabetics under treatment with metformin show a reduced cancer incidence [95] and cancer-related mortality, compared to patients exposed to sulphonylureas or insulin [96]; (b) metformin use is associated with a 44% risk reduction in PCa cases compared to controls in Caucasian men [9…”
p53 Regulation of Metabolic PathwaysPreprint
Gottlieb, E., & Vousden, K. H. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001040 · Cited by 178 · see citing works
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Goodwin, P. J., Stambolic, V., Lemieux, J., Chen, B. E., Parulekar, W. R., Gelmon, K. A., Hershman, D. L., Hobday, T. J., Ligibel, J. A., Mayer, I. A., et al. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-1224-1 · Cited by 177 · see citing works
“Additional support for a role of metformin in breast cancer outcomes comes from a retrospective clinical study that reported significantly increased pathologic complete response (pCR) rates to standard neoadjuvant chemotherapy in diabetic breast cancer patients who were receiving metformin (24% pCR) compared to diabet…”
ResultBayraktar, S., Hernadez‐Aya, L. F., Lei, X., Meric‐Bernstam, F., Litton, J. K., Hsu, L., Hortobagyi, G. N., & Gonzalez‐Angulo, A. M. (2012) · Cancer · doi:10.1002/cncr.26439 · Cited by 176 · see citing works
“Age at diagnosis, y Median (range) 53 (30-67) 51 (35-80) 48 (21-87)”
Metformin selectively affects human glioblastoma tumor-initiating cell viability
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“Subsequently, high complete response rate in diabetic breast cancer patients treated with metformin, according to neo-adjuvant protocols, was reported.(19) It was proposed that metformin activity was not due to indirect effects related to the antagonism of pro-tumoral effects induced by diabetic hyperglycemia,(43) but…”
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“In a retrospective study examining the rates of pathologic complete remission (pCR) after neoadjuvant chemotherapy, it was found that 24% of diabetic patients taking metformin achieved pCR, compared with 8% of those who were not receiving metformin.(77) In summary, the use of metformin in diabetic patients is associat…”
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“In a retrospective study in breast cancer patients with diabetes, patients treated with metformin had higher complete pathologic response rates to neoadjuvant therapy than diabetic patients treated with other antidiabetic drugs [27].”
BackgroundAnisimov, V. N., Egormin, P. A., Piskunova, T. S., Popovich, I. G., Тындык, М. Л., Yurova, M. N., Zabezhinski, M. A., Anikin, I. V., Karkach, A. S., & Romanyukha, A. A. (2010) · Cell Cycle · doi:10.4161/cc.9.1.10407 · Cited by 172 · see citing works
PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery
Zhao, Y. D., Wang, W., Guo, S., Wang, Y., Miao, L., Xiong, Y., & Huang, L. (2016) · Nature Communications · doi:10.1038/ncomms11822 · Cited by 171 · see citing works
Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients
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Self-citationImpact of Metformin on the Prognosis of Cirrhosis Induced by Viral Hepatitis C in Diabetic Patients
Nkontchou, G., Cosson, E., Aout, M., Mahmoudi, A., Bourcier, V., Charif, I., Ganne‐Carrié, N., Grando–Lemaire, V., Vicaut, É., Trinchet, J., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2415 · Cited by 165 · see citing works
“Furthermore, women with T2D receiving neoadjuvant chemotherapy for breast cancer were reported to have a higher complete response rate if they were using metformin as compared with women not using metformin (17).”
BackgroundDiabetes increases the risk of breast cancer: a meta-analysis
Hardefeldt, P. J., Edirimanne, S., & Eslick, G. D. (2012) · Endocrine Related Cancer · doi:10.1530/erc-12-0242 · Cited by 164 · see citing works
“New evidence has also indicated that metformin use may improve prognosis (Jiralerspong et al. 2009).”
BackgroundTan, B., Yao, W., Ge, J., Peng, X., Du, X., Zhang, R., Yao, B., Xie, K., Li, L., Dong, H., et al. (2011) · Cancer · doi:10.1002/cncr.26151 · Cited by 161 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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