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Introduction

Breast Cancer (BC), a disease characterized by clinical, morphological, and molecular heterogeneity, is currently the most commonly diagnosed cancer among women with more than 1.6 million new cases of BC reported worldwide in 2020 (Sung H, et al., 2021). This disease is classified into three subtypes based on immunohistological markers and transcriptomic signatures: Luminal phenotype defined by the expression of hormone receptors (HR+) (estrogen with or without progesterone) HER2-positive cancers characterized by the overexpression of Human Epidermal Receptor protein-2 (HER2+), and Triple-Negative (TN) cancers that do not express any of immunohistological markers (Eroles P, et al., 2012; Yersal O and Barutca S, 2014). Such classification is critical in the selection of appropriate therapeutic strategies for BC patients.

Literature Review

Metastatic Breast Cancer (MBC) is incurable and systemic therapy remains the standard-of-care in these cases. Optimal management includes anti-HER2 targeted agents (HER-2+ cancers), endocrine therapy combined with targeted therapy, especially Cyclin-Dependent Kinases 4/6 inhibitors (Luminal cancers) or chemotherapy used for Triple Negative Breast Cancer (TNBC) with optional combination of locoregional treatments according to the disease status. New predictive biomarkers have emerged and are validated in clinical practice: Germline BRCA1/2 mutation (gBRCAm) status in HER2-negative MBC, Programmed Cell Death Ligand 1 (PD-L1) status in TNBC and Phosphatidylinositol-4,5-bisphosphate 3-Kinase Catalytic subunit Alpha (PIK3CA) in luminal metastatic breast cancer (NCCN, 2023; Cardoso F, et al., 2020). Moreover, in early stages, surgical resection is the standard of care. The choice and the timing of systemic treatments depend on prognosis factors for distant recurrence and phenotypic subtypes (Burstein HJ, et al., 2021).

Type 2 diabetes accounts for 90%-95% of all diabetes. This form encompasses individuals who have relative rather than absolute insulin deficiency and have peripheral insulin resistance (ElSayed NA, et al., 2023).

Biologically, metabolic changes in the type 2 diabetes have an impact on the mammary gland. The insulin resistance observed in type 2 diabetes, overweight or obesity; generate a hyperinsulinism that can stimulate the growth of breast cells expressing insulin receptors (Singh B, et al., 2014). The mechanism entails the involvement of Insulin-like Growth Factor-1 Receptor (IGF- 1R), independent of any direct effects of hormone receptors. In addition, adipose cells, which are more abundant in overweight or obese women, harbor aromatase, leading to local hyperestrogenism that is recognized to contribute to the development of BC (Samavat H and Kurzer MS, 2015).While the incidence of BC is known to be higher in post-menopausal women with DT2 (Michels KB, et al., 2003), determining whether diabetes represents an independent risk factor for this malignancy or the two conditions share the same risk factors is challenging. The association between diabetes and BC arises from shared risk factors, including overweight/obesity, qualitative and quantitative dietary imbalances, and physical inactivity, as well as biological alterations and the impact of endocrine therapies (Bernard L, et al., 2016). The data concerning the involvement of some antidiabetic treatments in the occurrence of breast cancer remains controversial.

Metformin, also known as 1,1 dimethylbiguanidehydrochloride, is a widely used oral medication for the DT2 treatment (Cabello P, et al., 2016). This drug is available as a low-cost generic option and has been used in Europe and USA since 1957 and 1995 respectively, earning the distinction of being the most frequently prescribed anti-diabetic agent worldwide (NICE, 2009). As a result, metformin has been associated with most cancer treatments without significant drug interactions (Coyle C, et al., 2016). Furthermore, toxicity data for metformin in individuals without DT2 mellitus are available from clinical trials investigating its potential role in managing polycystic ovarian syndrome (Costello MF, et al., 2007).

Epidemiological investigations have indicated that metformin exerts a protective effect against tumors, diminishing their incidence and enhancing the prognosis of individuals with cancer (Libby G, et al., 2009; Quinn BJ, et al., 2013). Although the precise mechanisms underlying the protective properties of metformin are not fully elucidated, numerous publications have demonstrated that metformin may execute its antineoplastic effect by modulating various pathways, such as Adenosine Monophosphate-activated Protein Kinase/ mammalian Target of Rapamycin (AMPK/mTOR), anti-inflammatory, cell cycle/apoptosis, insulin/IGF-1R, and angiogenesis pathways in cancer (Viollet B and Foretz M, 2011; Anisimov VN, et al., 2005; Martin-Castillo B, et al., 2010). In vitro, studies have shown that metformin has a direct impact on the growth of cancer cells, reducing the proliferation of different cancer cell lines derived from breast, colon, ovarian, pancreatic, prostate, kidney, and leukemia tissues (Ben Sahra I, et al., 2010; Green AS, et al., 2010). The sensitivity of tumor cells to metformin varies according to their origin and the antiproliferative effects of metformin are observed in most studies only for high concentrations ranging between 5 and 30 mmol/l-1. The plasma metformin concentrations observed in diabetic patients treated with metformin are of 10-40 μmol/l-1 (Viollet B and Foretz M, 2011).

Discussion

Metformin has emerged as a noteworthy compound owing to its pleiotropic effects, as it acts as a metabolic inhibitor, modulating both whole-body and cellular energy metabolism (Pernicova I and Korbonits M, 2014). By inhibiting mitochondrial complex I, metformin restricts the production of reactive oxygen species, oxidative stress, and DNA damage (Algire C, et al., 2012), thereby decreasing the risk of mutagenesis, most likely via activation of the ataxia telangiectasia mutated pathway (Harries LW, et al., 2011). Metformin had also an antineoplastic potential when used in combination with chemotherapy and radiotherapy (Chen G, et al., 2012; Song CW, et al., 2012).

Metformin has demonstrated anti-breast cancer activity in both in vivo and in vitro studies. In vitro, metformin effectively decreases breast cancer cell viability through upregulation of miR-26a expression and downregulation of its targets such as PTEN (Phosphatase and Tensin homolog) (Cabello P, et al., 2016). In vivo, metformin demonstrate a reduction of cell proliferation markers, Ki67, on biopsy samples obtained from non-diabetic women with breast cancer (Hadad S, et al., 2011).

A recent review based on preclinical and clinical trials data, indicates that metformin may have a significant impact on tumor proliferation markers showed an immunomodulatory effect on cancer cells, particularly by increasing the effect on the memory T cell population via the phenotype switching CD8+ Tumor-Infiltrating Lymphocytes (TILs). Moreover, when associated with chemotherapeutic agents such as anthracyclines, platinum, taxanes, or capecitabine, metformin enhances their effectiveness reduces adverse effects and drug resistance (De A and Kuppusamy G, 2020).

Although laboratory evidence of the antimitotic action of metformin is favorable, the results from epidemiological studies remain controversial. While many observational and meta-analysis studies have suggested a reduced risk of cancer in patients treated with metformin (Faillie JL and Bringer J, 2014), a population-based analysis failed to establish an association between improved survival and metformin use in diabetic patients with breast cancer aged over 65 years (Lega IC, et al., 2013). These findings are consistent with several other studies (Suissa S and Azoulay L, 2012; Niraula S, et al., 2013).

Diabetic patients treated with metformin monotherapy exhibit a lower risk of developing cancer compared to those treated with sulfonylureas or insulin (Niraula S, et al., 2013). The combination of metformin with insulin also showed a significant reduction in the risk of colon and pancreatic cancer risk while this protective effect has not been verified for breast and prostate cancers (Currie CJ, et al., 2009).

Prolonged use of metformin has been linked to effective protection against breast cancer in women with diabetes (Renehan AG, 2009). Additionally, metformin therapy has been associated with a higher response rate in patients with breast cancer who undergo neoadjuvant chemotherapy (Jiralerspong S, et al., 2009). In diabetic patients treated with metformin, the response rate was 24%, compared to 16% in non-diabetic patients treated with metformin and 8% in diabetic patients not treated with metformin. As adjuvant therapy in breast cancer, metformin has shown a trend towards improvement in recurrence-free survival according to data from two studies. However, there was no effect on overall survival, as cancer-specific survival was only available for one study including 1774 women; no meta-analysis was possible for this outcome (Coyle C, et al., 2016).

Metformin showed an improvement in the prognosis of patients with HER2-positive, hormone receptor-positive breast cancer and diabetes mellitus. In the phase III randomized Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial, including patients with surgically resected early-stage HER2-positive breast cancer, the adjuvant trastuzumab and lapatinib was evaluated. In this study, patients with breast cancer and diabetes mellitus treated by metformin had a better prognosis compared to metformin non-users (Sonnenblick A, et al., 2017). Disease-free survival, distant disease-free survival, and overall survival were significantly improved. This benefice was limited to hormone receptor-positive patients. However, insulin treatment was associated with a deleterious effect (Sonnenblick A, et al., 2017). Other antidiabetic drugs-thiazolidinedione or sulfonylurea-were not associated with significant breast cancer outcome, although numbers were small. These data support that metformin had salutary effect in patients with diabetic with HER2-positive and hormone receptor–positive breast cancer as by previous preclinical and observational clinical studies. In HER2-positive breast cancer cell lines, metformin decreases HER2/neu oncogene tyrosine kinase activity and expression, which may explain its protective effect in improving the outcome of patients with diabetes and HER2-positive breast cancer (Alimova IN, et al., 2009). Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2- STAT3) and protein kinase B (Akt)-mTOR pathway activation confere also resistance to trastuzumab ; thus, it is possible that the inhibitory effect of metformin on the JAK2-STAT3 and Akt-mTOR pathways overcomes trastuzumab resistance (Berns K, et al., 2007; Chung SS, et al., 2014). The potential differences in insulin use between the diabetic groups (metformin vs. non metformin) may explain his detrimental effect.

These findings are consistent with those published by (He X, et al., 2012), indicating that diabetes mellitus type 2 can further accelerate the growth of HER2+ breast cancer, given that AKT/mTOR signaling is already active in these tumors (Esteva FJ, et al., 2002). Therefore, the choice of antidiabetic pharmacotherapy may influence the prognosis of this group (He X, et al., 2012). If the benefit of metformin appears clear in this tumor subgroup, the results in breast tumors without overexpression of HER2 are contradictory. A randomized phase II study did not demonstrate a benefit in Progression-Free Survival (PFS) when adding metformin to chemotherapy for patients with stage IV, HER2 negative breast cancer (Gennari A, et al., 2016); Noteworthy, a significantly shorter PFS was observed in insulin-resistant patients where Homeostatic Model Assessment (HOMA) index ≥ 2.5, without significant interaction with metformin. The MYME (Myocet^®-Metformin) trial has weaknesses, it is a phase study limited to 122 non-diabetic women (Gennari A, et al., 2016). Similarly, this publication does not give enough information about population characteristics (percentage of triple negative for example). These data must be carefully analyzed. A new meta-analysis has shown that metformin use is associated with better overall survival (HR: 0.53) and better cancer-specific survival (HR: 0.89) of breast cancer patients with diabetes independently of tumor stage and hormone receptor expression (Xu H, et al., 2015).

An American prospective study evaluated the relation between Type 2 diabetes and risk of occurrence of triple negative breast cancer data from a population of 44,541 patients aged 35 to 74 included between 2003 and 2009 in the Sister Study cohort. After a median follow-up of 8.6 years, 2,678 cases of breast cancer were reported. Respectively, 7.2% and 5.3% of women had prevalent and incident type 2 diabetes, with among whom 61% were ever treated with metformin. Type 2 diabetes with metformin use was associated with decreased risk of Estrogen Receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple negative breast cancer (HR 1.74; 95% CI, 1.06-2.83).This correlation was more marked when taking metformin for more than ten years (Park YM, et al., 2021). This observational study therefore confirms that diabetes increases the risk of occurrence of triple-negative breast cancer, and suggests that taking metformin (especially when it is prolonged) reduces the risk of (ER)-positive breast cancer. These results concerning metformin should however be interpreted with caution, because even if the cohort of patients is large, only 177 patients received metformin for their diabetes and this number fell to 20 in patients with triple negative breast cancer.

During the San Antonio Breast Cancer Symposium in 2021, the CTCGMA.32 phase 3 randomized double-blind adjuvant trial was presented. The study randomized 3,649 non-diabetic patients to either metformin (850 mg twice daily for 5 years) or placebo after standard treatment. The results showed that metformin did not improve Invasive Disease-Free Survival (IDFS) or overall survival in both Hormone Receptor (HR)-positive and HR-negative moderate/high-risk, early-stage breast cancer patients. However, the researchers stratified patients by HER2 status before randomization and conducted an exploratory analysis among the 620 HER2-positive patients, of whom the majority were positive for ER/PR (69.2%). The analysis revealed that IDFS in HER2-positive patients was significantly improved with metformin compared to placebo (Hazard Ratio (HR)=0.64), as was overall survival (HR=0.53).In an exploratory analysis,HER2-positive patients with at least one C allele of the ATM-associated rs11212617 single nucleotide polymorphism (SNP) derived a significant IDFS and OS benefit from metformin versus placebo. SNP is known as associated with metformin benefit on glucose control in diabetes. This trial confirms that the use of metformin is useful as an adjuvant treatment in breast cancer in unselected patients (Goodwin PJ, et al., 2021).

Conclusion

In conclusion, there was a growing interest on the benefit of metformin in multiple tumor locations, especially in the breast cancer. In addition to the epidemiological data showing a reduced incidence of breast cancer on metformin, a solid biological rational support the benefits of metformin by the limitation of tumor cell proliferation by downregulating the insulin/ IGF-1 axis and phosphorylation of mTOR. However, the available data are not sufficient to support the use of metformin in breast cancer as an anti-tumor therapy. Ongoing trials are evaluating the benefit of metformin in different stages of breast cancer. More additional research including potential biomarkers is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.

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