Metformin as an adjuvant option for systemic treatment of breast cancer
DOI:
https://doi.org/10.26641/2307-0404.2023.4.294154Keywords:
breast cancer, metformin, chemotherapy, modification, neoadjuvant treatment, luminal type, medical resistance, survive of patientAbstract
The modification of the used and development of new treatment regimens significantly improved the overall, recurrence-free survival and quality of life of patients with malignant oncological diseases. Recently, drugs used in non-oncological pathology have been introduced into cancer treatment regimens. This phenomenon is associated with a better understanding of the biology of tumor cells and the mutations that can change this biology. Metformin is actively researched in terms of the treatment of various oncological diseases. For the most part, the modification of the neoadjuvant treatment regimen for early or locally advanced stages of breast cancer results in a less traumatic variant of surgical procedure, thereby increasing recurrence-free survival. The aim is to systematize the data on the possibilities of the antitumor metformin usage for neoadjuvant treatment of breast cancer and to study the results of clinical and morphological effectiveness of the treatment by reviewing the literature. A search of PubMed from February 2023 showed 258 results on the antitumor effects of metformin, of which only 159 were published in the last 5 years. On this subject only four clinical studies were carried out, and only one of them pertained to the implementation of metformin in the systemic treatment of breast cancer. For this review, 55 sources of general and specialized information on anticancer effects of metformin were analyzed. It should be noted that approximately 60% of the study results were published more than 5 years ago and primarily focused on the biological, not clinical aspects of metformin usage. Only one study regarding the implementation of metformin for systemic treatment of breast cancer was carried out by Ukrainian scientists. Currently, there are 2 main hypotheses regarding the antitumor effect of metformin. First one is driven by its impact on the metabolic function of cells and energy deficit. Second – the method of regulating the proliferation of tumor cells involves the PIK3 branch of the regulatory cascade of biological reactions in cancer cells. In addition, metformin reduces the development of resistance in breast cancer cells, thus allowing active chemotherapy agents to act in synergism. However, further studies on the effect of metformin used alone or in combination with standard chemotherapy regimens require a more adequate definition of proto-oncogenic mutations and somatic mutation load. However, it should be considered that more aggressive therapy of oncological diseases can be a nosocomial selector of more aggressive clones of the pool of tumor cells. The main questions are whether metformin can be a targeted drug for the treatment of tumor, whether it is appropriate to use it at the time when the manifestation of evolution disturbances of tumor cell is minimal and homogeneity is maximal.
References
Chen YC, Li H, Wang J. Mechanisms of metfor-min inhibiting cancer invasion and migration. Am J Transl Res. 2020 Sep 15;12(9):4885-901. PMID: 33042396; PMCID: PMC7540116.
Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne). 2022 Feb 11;13:800995. doi: https://doi.org/10.3389/fendo.2022.800995
Shahid RK, Ahmed S, Le D, Yadav S. Diabetes and Cancer: Risk, Challenges, Management and Outcomes. Cancers (Basel). 2021 Nov 16;13(22):5735. doi: https://doi.org/10.3390/cancers13225735
Global Burden of Disease Collaborative Network, Global Burden of Disease Study 2019 (GBD 2019). Re-sults (2020, Institute for Health Metrics and Evaluation – IHME). [Internet]. [cited 2022 Nov 20]. Available from: https://vizhub.healthdata.org/gbd-results/.14.02.2023
Jing C, Wang Z, Fu X. Effect of diabetes mellitus on survival in patients with gallbladder Cancer: a systematic review and meta-analysis. BMC Cancer. 2020;20:689.
doi: https://doi.org/10.1186/s12885-020-07139-y
NCCN Breast cancer Evidence Blocks. Version 4/2022 [Internet]. 2022 [cited 2022 Nov 20]. Available from: https://www.nccn.org/professionals/physician_gls/-pdf/breast_blocks.pdf
Spring LM, Fell G, Arfe A, et al. Pathologic Com-plete Response after Neoadjuvant Chemotherapy and Im¬pact on Breast Cancer Recurrence and Survival: A Com¬prehensive Meta-analysis. Clin Cancer Res. 2020 Jun 15;26(12):2838-48. doi: https://doi.org/10.1158/1078-0432.CCR-19-3492
El-Khayat SM, Abouegylah M, Abdallah D, et al. The effect of metformin when combined with neoadjuvant chemotherapy in breast cancer patients. Med Oncol. 2021 Nov 5;39(1):1.
doi: https://doi.org/10.1007/s12032-021-01599-3
Rapoport BL, Barnard-Tidy J, Van Eeden RI, et al. Pathological complete response in early breast cancer patients undergoing neoadjuvant chemotherapy: Focus on Ki-67 and molecular subtypes. Annals of Oncology. 2019;30(Suppl 3):III37. doi: https://doi.org/10.1093/annonc/mdz097.012
Earl H, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, et al. Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT. Health Technol Assess. 2020 Aug;24(40):1-190. doi: https://doi.org/10.3310/hta24400
Loibl S, Sikov W, Huober J, et al. Event-free sur-vival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial. Annals of Oncology. 2021;32(Suppl 5):S407-46. doi: https://doi.org/10.1016/annonc/annonc687
Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): A randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497-509. doi: https://doi.org/10.1016/S1470-2045(18)30111-6
Miglietta F, Dieci MV, Tsvetkova V, et al. Validation of Residual Proliferative Cancer Burden as a Predictor of Long-Term Outcome Following Neoadjuvant Chemotherapy in Patients with Hormone Receptor-Positive/Human Epidermal Growth Receptor 2-Negative Breast Cancer. Oncologist. 2020 Sep;25(9):e1355-62. doi: https://doi.org/10.1634/theoncologist.2020-0201
Abe K, Yamamoto N, Hayashi K, et al. Caffeine citrate enhanced cisplatin antitumor effects in osteosar-coma and fibrosarcoma in vitro and in vivo. BMC Cancer. 2019;19:689.
doi: https://doi.org/10.1186/s12885-019-5891-y
Fang M, Wang D, Coresh J, Selvin E. Undiagno-sed Diabetes in U.S. Adults: Prevalence and Trends. Diabetes Care. 2022 Sep 1;45(9):1994-2002. doi: https://doi.org/10.2337/dc22-0242
Ugwueze CV, Ogamba OJ, Young EE, Onyenekwe BM, Ezeokpo BC. Metformin: A Possible Option in Cancer Chemotherapy. Anal Cell Pathol (Amst). 2020 Apr 27;2020:7180923. doi: https://doi.org/10.1155/2020/7180923
Garcı ́a-Este ́vez L, Corte ́sJ, Pe ́rez S, et al. Obe-sity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status. Front Oncol. 2021;11:705911. doi: https://doi.org/10.3389/fonc.2021.705911
Viollet B, Horman S, Leclerc J, et al. AMPK inhi-bition in health and disease. Crit Rev Biochem Mol Biol. 2010;45(4):276-95. doi: https://doi.org/10.3109/10409238.2010.488215
Jalving M, Gietema JA, Lefrandt JD, de Jong S, Rey¬ners AK, Gans ROB, et al. EGE 'Metformin: Taking away the candy for cancer?' Eur J of Cancer. 2010;46(13):2369-80. doi: https://doi.org/10.1016/j.ejca.2010.06.012
Lebelo MT, Joubert AM, Visagie MH. Warburg effect and its role in tumourigenesis. Arch Pharm Res. 2019 Oct;42(10):833-47. doi: https://doi.org/10.1007/s12272-019-01185-2
Yamaguchi R, Perkins G. Challenges in targeting cancer metabolism for cancer therapy. EMBO Rep. 2012;13:1034-5. doi: https://doi.org/10.1038/embor.2012.176
Stine ZE, Schug ZT, Salvino JM, et al. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21:141-62. doi: https://doi.org/10.1038/s41573-021-00339-6
Saini N, Yang X. Metformin as an anti-cancer agent: Actions and mechanisms targeting cancer stem cells. Acta Biochimica et Biophysica Sinica. 2018;50(2):133-43. doi: https://doi.org/10.1093/abbs/gmx106
Wang Y, An H, Liu T, Qin C, Sesaki H, Guo S, et al. Metformin Improves Mitochondrial Respiratory Acti-vity through Activation of AMPK. Cell Rep. 2019 Nov 5;29(6):1511-23.e5. doi: https://doi.org/10.1016/j.celrep.2019.09.070
Hozumi K, Sugawara K, Ishihara T, et al. Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes. Sci Rep. 2023;13:746. doi: https://doi.org/10.1038/s41598-023-27689-y
Sen S, He Y, Koya D, Kanasaki K. Cancer biology in diabetes. J of Diabetes Investigation. 2014;5(3):251-64. doi: https://doi.org/10.1111/jdi.12208
Hsu, Sheng-Kai, Kai-Chun Cheng, et al. New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway. International Journal of Molecular Sciences. 2021;22(17):9453. doi: https://doi.org/10.3390/ijms22179453
Shi B, Hu X, He H, Fang W. Metformin suppres-ses breast cancer growth via inhibition of cyclooxyge-nase 2. Oncology Letters. 2021;22(2):615. doi: https://doi.org/10.3892/ol.2021.12876
Bao B, Azmi AS, Ali S, Zaiem F, Sarkar FH. Metformin may function as anti-cancer agent via targeting cancer stem cells: The potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers. Ann Transl Med. 2014;2(6):59. doi: https://doi.org/10.3978/j.issn.2305-5839.2014.06.05
Galliote MM, Tamura RE, Sanchez Rubio IG. Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models. Biomolecules. 2022;12(3):357. doi: https://doi.org/10.3390/biom12030357
De A, Kuppusamy G. Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer. 2020 Feb;44(1):100488. doi: https://doi.org/10.1016/j.currproblcancer.2019.06.003
Amjad S, Nisar S, Bhat AA, Shah AR, Fren-neaux MP, et al. Role of NAD+ in regulating cellular and metabolic signaling pathways. Mol Metab. 2021;49:101195. doi: https://doi.org/10.1016/j.molmet.2021.101195
Wardhani BW, Puteri MU, Watanabe Y, Loui-sa M, Setiabudy R, Kato M. TGF-β-Induced TMEPAI Attenuates the Response of Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel. J Exp Pharmacol. 2020 Jan 23;12:17-26. doi: https://doi.org/10.2147/JEP.S235233
Dolhyi V, Avierin D, Hojouj M, Bondarenko I. Tubulin Role in Cancer Development and Treatment. Asp Biomed Clin Case Rep. 2019 Sept 5;2(2):15-22. doi: https://doi.org/10.36502/2019/ASJBCCR.6154
Menendez A, Oliveras-Ferraros C, Cufí S, et al. Metformin is synthetically lethal with glucose withdrawal in cancer cells. Cell Cycle. 2012;11(15):2782-92. doi: https://doi.org/10.4161/cc.20948
Wahdan-Alaswad RR, Fan Z, Edgerton SM, et al. Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle. 2013;12(24):3759-69. doi: https://doi.org/10.4161/cc.26641
Zordoky BN, Bark D, Soltys CL, et al. The anti-proliferative effect of metformin in triple-negative MDA-MB-231 breast cancer cells is highly dependent on glucose concentration: implications for cancer therapy and prevention. Biochim Biophys Acta. 2014 Jun;1840(6):1943-5. doi: https://doi.org/10.1016/j.bbagen.2014.01.023
Oliveras-Ferraros C, Vazquez-Martin A, Cuyas E, et al. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile. Cell Cycle. 2014;13(7):1132-44. doi: https://doi.org/10.4161/cc.27982
Buac D, Kona FR, Seth AK, Ping DQ. Regulation of metformin response by breast cancer associated gene 2. Neoplasia. 2013;15(12):1379-90. doi: https://doi.org/10.1593/neo.131434
Samson SM, Varghese E, et al. Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer. Biomolecules. 2019;9(12):846. doi: https://doi.org/10.3390/biom9120846
Wahdan-Alaswad RS, Edgerton SM, Salem HS, Thor AD. Metformin Targets Glucose Metabolism in Triple Negative Breast Cancer. J Oncol Transl Res. 2018;4(1):129. doi: https://doi.org/10.4172/2476-2261.1000129
Bonanni B, Puntoni M, Cazzaniga M, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J of Clinical Oncology. 2012;30(21):2593-600. doi: https://doi.org/10.1200/JCO.2011.39.3769
He X, Esteva FJ, Ensor J, et al. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Annals of Oncology. 2012;23(7):1771-80. doi: https://doi.org/10.1093/annonc/mdr534
Besic N, Satej N, Ratosa I, Horvat AG, Marinko T, Gazic B, et al. Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients—a retrospective study of clinical and tumor characteristics. BMC Cancer. 2014 Apr 28;14:298. doi: https://doi.org/10.1186/1471-2407-14-298
Min W, Wang B, Guo A, Mao G, Zhao Y, Zhang S, et al. The Effect of Metformin on the Clinicopathological Features of Breast Cancer With Type 2 Diabetes. World J Oncol. 2020 Feb;11(1):23-32. doi: https://doi.org/10.14740/wjon1242
Cejuela M, Martin-Castillo B, Menendez JA, Pernas S. Metformin and Breast Cancer: Where Are We Now? Int J Mol Sci. 2022 Feb 28;23(5):2705. doi: https://doi.org/10.3390/ijms23052705
Mónica C, Martin-Castillo B, Menendez JA, Pernas S. Metformin and Breast Cancer: Where Are We Now? International Journal of Molecular Sciences. 2022;23(5):2705. doi: https://doi.org/10.3390/ijms23052705
Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, et al. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer. 2012 Oct 23;107(9):1608-17. doi: https://doi.org/10.1038/bjc.2012.414
Nasrazadani A, Marti JLG, Kip KE, Marroquin OC, Lemon L, Shapiro SD, et al. Breast cancer mortality as a function of age. Aging (Albany NY). 2022 Feb 8;14(3):1186-99. doi: https://doi.org/10.18632/aging.203881
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: https://doi.org/10.3322/caac.21654 Erratum in: CA Cancer J Clin. 2021 Jul;71(4):359. PMID: 33433946.
Fayanju OM, Ren Y, Thomas SM, Greenup RA, Plichta JK, Rosenberger LH, et al. The Clinical Significance of Breast-only and Node-only Pathologic Com-plete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB). Ann Surg. 2018 Oct;268(4):591-601. doi: https://doi.org/10.1097/SLA.0000000000002953
Ehsan AN, Wu CA, Minasian A, Singh T, Bass M, Pace L, et al. Financial Toxicity Among Patients With Breast Cancer Worldwide: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023 Feb 1;6(2):e2255388. doi: https://doi.org/10.1001/jamanetworkopen.2022.55388
Luangdilok S, Samarnthai N, Korphaisarn K. Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients. J Breast Cancer. 2014 Dec;17(4):376-85. doi: https://doi.org/10.4048/jbc.2014.17.4.376
Janzer A, German NJ, Gonzalez-Herrera KN, Asa-ra JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic interme-diates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA. 2014 Jul 22;111(29):10574-9. doi: https://doi.org/10.1073/pnas.1409844111
Rosin J, Svegrup E, Valachis A, et al. Discordance of PIK3CA mutational status between primary and meta-static breast cancer: a systematic review and meta-ana-lysis. Breast Cancer Res Treat. 2023;201:161-9. doi: https://doi.org/10.1007/s10549-023-07010-1
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