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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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Xu, H., Chen, K., Jia, X., Tian, Y., Dai, Y., Li, D., Xie, J., Tao, M., & Mao, Y. (2015) · The Oncologist · doi:10.1634/theoncologist.2015-0096 · Cited by 110
Phenformin as prophylaxis and therapy in breast cancer xenografts
Appleyard, M. V. C. L., Murray, K. E., Coates, P. J., Wullschleger, S., Bray, S. E., Kernohan, N. M., Fleming, S., Alessi, D. R., & Thompson, A. M. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.56 · Cited by 108
“…ra n sl a ti o n a l T h e ra p e u ti c s diabetic practice, with clear associations between metformin use in diabetics and the prevention of breast cancer (Evans et al, 2005) and increased efficacy of chemotherapy against breast cancer in the neoadjuvant setting (Jiralerspong et al, 2009).”
BackgroundZhuang, Y., & Miskimins, W. K. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0343 · Cited by 113
“Diabetics taking metformin have a lower risk of cancer (1–3) and metformin has been found to enhance neoadjuvant therapy for diabetic breast cancer patients (4).”
BackgroundMetformin and Cancer Occurrence in Insulin-Treated Type 2 Diabetic Patients
Monami, M., Colombi, C., Balzi, D., Dicembrini, I., Giannini, S., Melani, C., Vitale, V., Romano, D., Barchielli, A., Marchionni, N., et al. (2010) · Diabetes Care · doi:10.2337/dc10-1287 · Cited by 110
“S everal studies have shown that metformin is associated with reduced cancer-related morbidity and mortality (1–4), due to improvement in insulin sensitivity (5) or to the activation of AMP-activated protein kinase (6).”
BackgroundSivalingam, V. N., Myers, J., Nicholas, S., Balen, A. H., & Crosbie, E. J. (2014) · Human Reproduction Update · doi:10.1093/humupd/dmu037 · Cited by 113
“…metformin were shown to have higher rates of pathological complete response to neoadjuvant chemotherapy than those not on metformin, according to a retrospective study of 2529 patients, including 68 and 87 diabetic patients taking and not taking metformin, respectively (Jiralerspong et al., 2009).”
Lee, K., Hsu, E., Guh, J., Yang, M., Wang, D.-S., Kulp, S. K., Shapiro, C. L., & Chen, C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.264598 · Cited by 106
Kłubo-Gwieździńska, J., Costello, J. M., Patel, A. D., Bauer, A. J., Jensen, K. E., Mete, M., Burman, K. D., Wartofsky, L., & Vasko, V. V. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3799 · Cited by 106
“Our observations indicating that metformin use is associated with higher efficacy of cancer treatment among diabetic patients are consistent with previous studies demonstrating that pathological complete response rates in breast cancer patients receiving neoadjuvant chemotherapy were higher in persons with diabetes re…”
ResultWahdan-Alaswad, R. S., Cochrane, D. R., Spoelstra, N. S., Howe, E. N., Edgerton, S. M., Anderson, S. M., Thor, A. D., & Richer, J. K. (2014) · Hormones and Cancer · doi:10.1007/s12672-014-0188-8 · Cited by 104
“These observations have led to a dramatic increase in the number of studies investigating the effect of metformin upon breast cancer as well as the initiation of clinical trials involving metformin [25, 51].”
BackgroundYu, Z., Zhao, G., Xie, G., Zhao, L., Chen, Y., Yu, H., Zhang, Z., Li, C., & Li, Y. (2015) · Oncotarget · doi:10.18632/oncotarget.5405 · Cited by 103
“Epidemiologic data have revealed that MET, a first-line treatment for type-2 diabetes, can reduce cancer incidence and mortality in certain cancers [15, 16], and increase the number of breast carcinoma patients obtaining complete response to neo-adjuvant therapy [17].”
BackgroundIn vitro and in vivo anti-melanoma action of metformin
Janjetović, K., Harhaji-Trajkovic, L. M., Misirkic-Marjanovic, M., Vucicevic, L. M., Stevanović, D., Zogovic, N. S., Šumarac-Dumanović, M., Micić, D., & Trajković, V. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.07.004 · Cited by 110
Obesity, metabolism and the microenvironment: Links to cancer
Makowski, L., Sundaram, S., & Johnson, A. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.119606 · Cited by 106
“cancer incidence and deaths among diabetic patients, hence clinical trials are underway, some focusing on BC,[51‐54] and reviewed in.”
BackgroundLin, C., Yeh, H.-H., Huang, W.-L., Yan, J.-J., Lai, W., Su, W., Chen, H. H. W., & Su, W. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2012-0244oc · Cited by 104
Wang, Z., Wang, N., Liu, P., & Xie, X. (2016) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-319-43589-3_9 · Cited by 104
Metformin use and improved response to therapy in rectal cancer
Skinner, H. D., Crane, C. H., Garrett, C. R., Eng, C., Chang, G. J., Skibber, J. M., Rodrı́guez-Bigas, M. A., Kelly, P., Sandulache, V. C., Delclos, M. E., et al. (2013) · Cancer Medicine · doi:10.1002/cam4.54 · Cited by 103
“In other disease sites, metformin use has been associated with improved response to chemotherapy [15], as well as improved outcomes after treatment [16–18].”
BackgroundMetformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy
Koritzinsky, M. (2015) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2015.06.003 · Cited by 103
“003 epidemiologic data have been followed by a number of retrospective reports suggesting that the population of diabetic metformin users not only have a lower cancer incidence but also have better cancer outcomes across many sites and treatment modalities (4-10).”
BackgroundBreast cancer: Current and future endocrine therapies
Palmieri, C., Patten, D. K., Januszewski, A. P., Zucchini, G., & Howell, S. J. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.08.001 · Cited by 102
Nair, V., Pathi, S. S., Jutooru, I., Sreevalsan, S., Basha, R. M., Abdelrahim, M., Samudio, I. J., & Safe, S. H. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt231 · Cited by 99
Liu, H., Scholz, C. W., Zang, C., Schefe, J. H., Habbel, P., Regierer, A. C., Schulz, C., Possinger, K., & Eucker, J. (2012) · PubMed · Cited by 98
Triggle, C. R., & Ding, H. (2015) · Acta Physiologica · doi:10.1111/apha.12644 · Cited by 101
“…the putative anticancer effects of metformin seem to be more effective against certain types of cancer, notably breast and lung cancer, inferring that metformin may preferentially target a cellular pathway(s) that are specific for certain cancers (Jiralerspong et al. 2009, Tan et al. 2011).”
BackgroundLiu, Q., Tong, D., Liu, G., Gao, J., Wang, L.-A., Xu, J., Yang, X., Xie, Q., Huang, Y., Pang, J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0420 · Cited by 100
“Cell lysates were separated on SDS–PAGE followed by Western blotting assay as described previously (23, 33) with the following primary antibodies: COX2 (1:1,000, Origene) and b-actin (1:5,000, Cell Signaling).”
BackgroundMethodThe Insulin Receptor: A New Target for Cancer Therapy
Malaguarnera, R., & Belfiore, A. (2011) · Frontiers in Endocrinology · doi:10.3389/fendo.2011.00093 · Cited by 98
Karataş, F., Erdem, G. U., Şahin, S., Aytekin, A., Yüce, D., Sever, A. R., Babacan, T., Ateş, Ö., Ozisik, Y. Y., & Altundağ, K. (2016) · The Breast · doi:10.1016/j.breast.2016.05.013 · Cited by 97
Marrone, K. A., Zhou, X. C., Forde, P. M., Purtell, M., Brahmer, J. R., Hann, C. L., Kelly, R. J., Coleman, B., Gabrielson, E. W., Rosner, G. L., et al. (2018) · The Oncologist · doi:10.1634/theoncologist.2017-0465 · Cited by 99
“In a retrospective study of breast cancer patients undergoing chemotherapy, a high frequency of complete pathological responses was noted in diabetic patients treated with metformin in addition to chemotherapy compared with diabetic patients receiving other diabetic treatment while undergoing chemotherapy [8].”
ResultKim, H. J., Kwon, H., Lee, J. W., Kim, H. J., Lee, S. B., Park, H. S., Sohn, G., Lee, Y., Koh, B. S., Yu, J. H., et al. (2015) · Breast Cancer Research · doi:10.1186/s13058-015-0574-3 · Cited by 101
“In particular, metformin treatment has been associated with lower breast cancer incidence among patients with diabetes and higher pathologic complete response in patients with early-stage breast cancer who were receiving neoadjuvant therapy [11].”
BackgroundSehdev, A., Shih, Y. T., Vekhter, B. G., Bissonnette, M. B., Olopade, O. I., & Polite, B. N. (2014) · Cancer · doi:10.1002/cncr.29165 · Cited by 95
Lin, H., Li, N., He, H., Ying, Y., Sunkara, S., Luo, L., Lv, N., Huang, D., & Luo, Z. (2015) · Molecular Pharmacology · doi:10.1124/mol.115.099549 · Cited by 96
Hou, G., Zhang, S., Zhang, X., Wang, P., Hao, X., & Zhang, J. (2013) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2404-y · Cited by 94
“During neoadjuvant chemotherapy, the early breast cancer patients with diabetes predicted a higher pCR rate when additionally treated with metformin than those treated with other antidiabetic drugs [12].”
Fu, Z., Ye, J., Dean, J. W., Bostick, J. W., Weinberg, S. E., Xiong, L., Oliff, K. N., Chen, Z. E., Avram, D., Chandel, N. S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.024 · Cited by 97
“Both metformin and AG311, inhibitors of mitochondrial complex I, have been reported to cooperate with other therapies to resolve cancer regression in some human and mouse tumors (Bastian et al., 2017; Jiralerspong et al., 2009; Wheaton et al., 2014).”
BackgroundThe complexities of obesity and diabetes with the development and progression of pancreatic cancer
Bao, B., Wang, Z., Li, Y., Kong, D., Ali, S. S., Banerjee, S., Ahmad, A., & Sarkar, F. H. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.11.003 · Cited by 94
“One recent study showed that women taking metformin had a pathologic complete response rate of 24 percent as compared to 8 percent of women who were not [169].”
ResultCumulative Metformin Use and Its Impact on Survival in Gastric Cancer Patients After Gastrectomy
Lee, C., Jung, M., Jung, I., Heo, S. J., Jeong, Y. H., An, J. Y., Kim, H., Cheong, J., Hyung, W. J., Noh, S. H., et al. (2015) · Annals of Surgery · doi:10.1097/sla.0000000000001086 · Cited by 92
Insulin-Sensitizing Therapy Attenuates Type 2 Diabetes–Mediated Mammary Tumor Progression
Fierz, Y., Novosyadlyy, R., Vijayakumar, A., Yakar, S., & LeRoith, D. (2009) · Diabetes · doi:10.2337/db09-1291 · Cited by 92
Association Between Metformin Use and Risk of Prostate Cancer and Its Grade
Margel, D., Urbach, D. R., Lipscombe, L. L., Bell, C. M., Kulkarni, G. S., Austin, P. C., & Fleshner, N. E. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt170 · Cited by 91
Type 2 Diabetes and Cancer: What Is the Connection?
Cannata, D., Fierz, Y., Vijayakumar, A., & LeRoith, D. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20167 · Cited by 94
Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2
Biernacka, K. M., Uzoh, C. C., Zeng, L., Persad, R. A., Bahl, A. K., Gillatt, D. A., Perks, C. M., & Holly, J. M. P. (2013) · Endocrine Related Cancer · doi:10.1530/erc-13-0077 · Cited by 90
“This is consistent with the literature that indicates metabolic disturbances, such as hyperglycaemia can compromise the response to chemotherapy in a range of different cancers, such as breast ( Jiralerspong et al. 2009), colorectal (Gribovskaja-Rupp et al.”
ResultCatch it before it kills: progesterone, obesity, and the prevention of endometrial cancer.
Carlson, M. J., Thiel, K. W., Yang, S., & Leslie, K. K. (2012) · PubMed · Cited by 89
Diabetes and cancer II: role of diabetes medications and influence of shared risk factors
Onitilo, A. A., Engel, J. M., Glurich, I., Stankowski, R. V., Williams, G. M., & Doi, S. A. R. (2012) · Cancer Causes & Control · doi:10.1007/s10552-012-9971-4 · Cited by 92
“Furthermore, diabetic patients with breast cancer who received metformin in addition to neoadjuvant chemotherapy had a higher pathologic complete response rate than diabetic patients who did not receive metformin [78].”
MicroRNAs in Tumor Cell Metabolism: Roles and Therapeutic Opportunities
Pedroza‐Torres, A., Romero-Cordoba, S. L., Justo-Garrido, M., Salido-Guadarrama, I., Rodríguez‐Bautista, R., Montaño, S., Muñiz-Mendoza, R., Arriaga-Canon, C., Fragoso‐Ontiveros, V., Álvarez-Gómez, R. M., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01404 · Cited by 93
“One striking example of this oncosuppressive feature is the cooperative effect of metformin and neoadjuvant chemotherapy to achieve complete tumor regression in some breast cancer patients (225).”
BackgroundBost, F., Sahra, I. B., MARCHAND‐BRUSTEL, Y. L., & Tanti, J. (2011) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32834d8155 · Cited by 95
“Along the same line, metformin treatment was associated with a higher pathologic complete response in diabetic patients, compared with nondiabetic patients, treated with neoadjuvant chemotherapy [11].”
ResultCancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients
Bo, S., Ciccone, G., Rosato, R., Villois, P., Appendino, G., Ghigo, E., & Grassi, G. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01480.x · Cited by 87
“Metformin is actually being evaluated as an adjuvant therapy in breast cancer trials, because it seems to enhance chemotherapy and yields higher pathologically complete response rates [13, 27].”
BackgroundLatest insights into the risk of cancer in diabetes
Noto, H., Goto, A., Tsujimoto, T., Osame, K., & Noda, M. (2013) · Journal of Diabetes Investigation · doi:10.1111/jdi.12068 · Cited by 90
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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