Metformin and its derivatives in breast cancer: from glycaemic control to tumor-intrinsic pathways.

Introduction
Metformin, a biguanide-class oral hypoglycaemic agent, is widely prescribed as first-line therapy for type 2 diabetes mellitus [1]. Its primary mechanism of action involves the inhibition of hepatic gluconeogenesis and the enhancement of peripheral insulin sensitivity, leading to reduced circulating glucose and insulin levels [2]. These metabolic actions have gained renewed attention in oncology due to the emerging recognition that hyperinsulinemia and insulin resistance can promote tumour growth through mitogenic signaling. Numerous epidemiological and clinical studies have demonstrated a strong association between hyperinsulinemia, insulin resistance, and adverse BC outcomes. Insulin contributes to tumorigenesis not only through direct mitogenic effects on mammary epithelial cells but also via modulation of insulin-like growth factors (IGFs), sex hormones, and adipokines, all of which contribute to BC progression [3].
Population-based studies have consistently reported that diabetic patients treated with metformin exhibit a lower incidence of various malignancies, including BC, and reduced cancer-specific mortality compared to those receiving other antidiabetic therapies [4]. These observations have provided a strong rationale for exploring metformin’s potential repurposing as an anticancer agent. Preclinical investigations further support this potential, demonstrating that metformin inhibits the proliferation of BC cells, including those resistant to conventional cytotoxic agents [5]. Mechanistically, metformin exerts anticancer effects through both indirect and direct pathways. Indirectly, it reduces systemic insulin and insulin-like growth factor 1 (IGF-1) levels, thereby attenuating proliferative signalling cascades such as the phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR) pathway [6]. Metformin’s well-established metabolic benefits, coupled with its ability to modulate key oncogenic pathways, underscore its promise as a therapeutic agent in BC prevention and treatment. Yet, major knowledge gaps remain regarding the concentration required for anticancer activity, its bioavailability within tumour tissue, and the identity of patients most likely to benefit [7].
This review addresses these gaps by critically examining epidemiological evidence linking metformin to reduced BC incidence, mortality, and improved survival. We will explore the molecular mechanisms underlying its anticancer effects, encompassing both insulin-dependent and insulin-independent pathways. Additionally, we will evaluate metformin’s activity across different BC subtypes, its potential to enhance responses to chemotherapy, targeted, and endocrine therapies, and highlight findings from recent clinical trials. Finally, we will address current limitations, including variable clinical trial outcomes and the need for refined patient stratification and predictive biomarkers, and propose future research directions aimed at optimizing the integration of metformin into BC management strategies.

Epidemiological evidence linking metformin use to breast cancer risk and survival
Epidemiological evidence indicates that metformin use among diabetic patients is associated with a reduced risk of BC incidence and improved survival outcomes [8]. Multiple meta-analyses and large cohort studies have reported that metformin lowers the risk of developing BC by up to 24% in BMI-adjusted analyses, and by as much as 56% with long-term use in some populations [9]. In terms of survival, diabetic BC patients taking metformin have demonstrated significantly better outcomes: one meta-analysis of over 5,000 patients found that metformin use was associated with a 47% reduction in all-cause mortality (HR 0.53; 95% CI, 0.39–0.71) and a 65% improvement in overall survival after adjusting for hormone receptor status (HR 0.35; 95% CI, 0.15–0.84) [10]. The five-year overall survival rates of 91.9% in the metformin group versus 59.1% in non-metformin users, and relapse-free survival rates of 82.8% versus 39.3%, respectively [11], appear strikingly high and warrant critical contextualisation. The higher survival rates are reported from a prospective cohort of diabetic breast cancer patients [10, 12], whereas lower survival outcomes in other studies derive from retrospective analyses of more heterogeneous or non-diabetic populations [13]. Moreover, contradictory findings have been observed in non-diabetic patients, where survival benefits associated with metformin were less pronounced or not statistically significant, highlighting the variability in outcomes across different patient subgroups. Additionally, metformin use has been linked to higher pathologic complete response rates to neoadjuvant chemotherapy in BC patients with diabetes (odds ratio 2.95; 95% CI, 1.07–8.17) [11], though these results also primarily reflect prospective diabetic cohorts. However, not all studies have found a significant association between metformin and reduced BC incidence or mortality, and results in non-diabetic or metastatic populations remain inconsistent [10, 14]. These discrepancies highlight a critical gap, the metabolic and molecular contexts that determine whether metformin exerts a protective or neutral effect remain poorly characterised. Overall, most observational data support a protective association between metformin use and improved BC outcomes, particularly in diabetic patients [8]. But the evidence remains inconclusive regarding causality and the generalisability of these effects to non-diabetic populations.

Structure and its potential role in breast cancer
Metformin is a small, highly polar molecule classified within the biguanide family, with the molecular formula C4H11N5. Structurally, it consists of two guanidine groups linked via a central nitrogen atom, forming a biguanide backbone, and is substituted with two methyl groups at the terminal nitrogen position, hence designated as 1,1-dimethylbiguanide. The molecule contains five nitrogen atoms (Fig. 1), which are critical to its physicochemical and pharmacological properties [7]. These nitrogen atoms enable hydrogen bonding and electrostatic interactions with negatively charged cellular constituents such as mitochondrial membranes. At physiological pH, the terminal nitrogen is readily protonated, conferring a cationic state that provides excellent aqueous solubility but poor membrane permeability, necessitating transport via organic cation transporters (OCTs), particularly OCT1 [7, 15].

Once internalized, metformin inhibits mitochondrial complex I, resulting in reduced ATP production, an elevated AMP/ATP ratio, and activation of AMPK, a central regulator o cellular energy homeostasis. While these mechanisms are well established in diabetes therapy, they are increasingly recognized as critical in the suppression of tumor metabolism, growth, and survival in BC [17, 18]. However, the extent to which these mitochondrial and transporter-dependent mechanisms translate into selective antitumour effects remains unclear [6]. Notably, metformin preferentially accumulates in OCT1-overexpressing malignant and BC stem cells, and synergistic effects are observed when combined with other pharmacologic agents, such as in salt forms with NSAIDs, to enhance cellular uptake and anti-cancer efficacy [5, 19]. Its core structure, nitrogen composition (biguanide), and use of specialised transporters help clarify how metformin works and why it is gaining importance in breast cancer treatment (Table 1).

Metformin derivatives in breast cancer treatment
Metformin derivatives, including phenformin, buformin (Fig. 1), sulfonamide analogues, Schiff-base metal complexes, and newer synthetic biguanides, have attracted considerable interest for their potential in BC [21–33]. Preclinical evidence indicates that these compounds exhibit stronger antiproliferative, metabolic, and tumor-microenvironmental effects than standard metformin, with notable sensitivity in triple-negative (TNBC) and HER2-positive subtypes [26, 28–30, 32–34]. Metabolic mechanisms remain central to their activity, extending beyond canonical AMPK activation, mTOR inhibition, and mitochondrial complex I blockade. These derivatives further modulate insulin/IGF signalling, suppress glycolytic flux, and restore metabolic homeostasis within tumour cells.
Microenvironmental and immune-modulatory actions include inhibition of epithelial–mesenchymal transition, suppression of angiogenesis, regulation of autophagy, and remodelling of the immune milieu to favour antitumor responses [26, 27, 29, 34–36]. This expanding mechanistic profile suggests that chemical modification of the biguanide scaffold could overcome pharmacokinetic limitations of parent metformin, yet comparative in vivo data remain scarce [37, 38].
Synthetic-lethal interactions have also been observed, notably when metformin analogues are combined with Src or fatty-acid oxidation inhibitors in TNBC, and with PARP inhibitors in homologous-recombination–deficient tumours [28, 31, 36, 39]. These findings suggest that structural modifications to the biguanide scaffold may overcome metformin’s pharmacokinetic limitations and expand its therapeutic scope.
However, most of these data derive from preclinical studies, and clinical validation remains limited. The translation of these promising mechanistic findings into meaningful patient benefit is still uncertain, largely due to pharmacokinetic constraints, toxicity concerns (e.g., with phenformin, a more potent but also more toxic biguanide than metformin), and a lack of human efficacy data [40–42].
Translational and early clinical studies have provided preliminary evidence of metformin derivatives’ biological activity, including reduced residual cancer burden in neoadjuvant settings, altered transcriptomic and metabolomic profiles in breast tissue, and subtype-specific responses among HER2 + and TNBC patients [21, 22, 24, 25]. Comparative analyses indicate that phenformin generally demonstrates greater potency than metformin in vitro and in vivo, though its clinical development is constrained by the risk of lactic acidosis. In contrast, buformin and other derivatives exhibit variable efficacy across models, largely dependent on dose and exposure [27, 29, 32, 33]. To overcome metformin’s limited tumor bioavailability, formulation innovations such as nanoplatforms, prodrugs, and targeted conjugates have been developed, enabling enhanced tumor uptake, dual-drug delivery, and even imaging capability [23–25, 30, 34].
Collectively, metformin derivatives represent a promising class of metabolic and immunomodulatory agents for breast cancer therapy. Phenformin shows the strongest anticancer activity among metformin derivatives, particularly in TNBC and HER2-positive models, due to its potent metabolic inhibition. However, its use is limited by lactic acidosis risk. Thus, new-generation biguanides and nanocarrier-based formulations that combine high potency with improved safety offer the most promising direction for future clinical development. However, their translation from bench to bedside remains limited by the lack of comprehensive pharmacokinetic, pharmacodynamic, and toxicological evaluations. Rigorous, biomarker-driven early-phase clinical trials are required to establish safety, optimize patient selection, and confirm therapeutic efficacy, as illustrated in Fig. 2 [43].

Metformin’s mechanism of action: from diabetes to breast cancer and potency across subtypes
Metformin is widely recognized as a first-line pharmacological agent for the treatment of type 2 diabetes mellitus. Its antihyperglycemic activity is primarily mediated through the inhibition of mitochondrial complex I in hepatocytes [44], leadingto reduced ATP production and increased AMP levels. This activates AMP-activated protein kinase (AMPK), a central metabolic regulator that suppresses gluconeogenic genes, reduces hepatic glucose output, and enhances insulin sensitivity [44, 45]. Metformin also antagonizes glucagon-mediated signalling pathways, further contributing to its glucose-lowering effects [46].
Beyond its metabolic role, metformin exhibits both indirect and direct anticancer actions in BC [45]. Indirectly, by lowering systemic insulin levels, it reduces mitogenic stimulation through insulin and insulin-like growth factor 1 (IGF-1) pathways, which are often upregulated in hyperinsulinemic and insulin-resistant states associated with tumour progression [45]. Directly, Metformin inhibits mitochondrial complex I in cancer cells, inducing energetic stress that activates AMPK and suppresses mTOR signalling, thereby limiting cell growth, promoting apoptosis [47, 48]. Metformin also downregulates lipogenic and growth-promoting factors such as sterol regulatory element-binding protein 1 (SREBP-1) and fatty acid synthase (FASN) while upregulating tumour suppressor pathways, reducing cancer cell viability [49]. Additionally, AMPK/mTOR pathway activation contributes to reduced invasion and migration via regulation of epithelial-mesenchymal transition (EMT) markers [45, 48]. Together, these findings demonstrate that metformin disrupts both systemic metabolic drivers and intrinsic oncogenic signaling in BC.
A major unresolved issue is whether the drug reaches sufficient concentrations in tumour tissue to reproduce their direct mitochondrial effects in vivo [50–52]. Preclinical cytotoxic concentrations often exceed those achievable with standard therapeutic dosing, suggesting that systemic metabolic modulation rather than direct tumour cell toxicity may be the dominant mechanism in patients [50–52].
Across BC subtypes, preclinical studies show that metformin inhibits proliferation and induces apoptosis with triple-negative (TNB) and HER2-positive cells demonstrating the greatest sensitivity [53]. TNBC cells display lower IC₅₀ values (mean ~ 17.2 mM) than luminal (non-TNBC) subtypes (mean ~ 31.2 mM), while HER2-positive BC cell lines exhibit significant growth inhibition and apoptosis at concentrations above 0.5 mM [53]. However, these concentrations are substantially higher than those attainable in patients, as plasma levels achieved clinically are 10–100 times lower than the millimolar concentrations required to induce cancer death in vitro [7]. This pharmacokinetic gap likely explains why clinical benefits are more consistent in diabetic patients or when metformin is combined with other anticancer therapies.
Metformin’s anticancer potential in BC arises from its dual ability to modulate systemic metabolism and directly inhibit tumour growth through AMPK–mTOR signaling. Its greatest experimental efficacy occurs in TNBC and HER2-positive models, though limited tumour bioavailability highlights the need for optimized dosing strategies and drug formulations that enhance delivery to tumour tissue.

Metformin and insulin modulation
Metformin enhances insulin sensitivity mainly by reducing hepatic glucose production and improving peripheral insulin signaling. Its primary mechanisms involve mild inhibition of mitochondrial complex I, leading to AMPK activation and downstream modulation of IRS-PI3K-Akt and GLUT4 pathways. By suppressing hepatic gluconeogenesis and promoting glycogen synthesis, metformin lowers fasting glucose and circulating insulin [54, 55]. In skeletal muscle and adipose tissue, it augments insulin-mediated glucose uptake through improved vascular delivery and restored insulin signaling [56, 57]. At the molecular level, metformin increases insulin receptor β expression and IRS2/PI3K/Akt phosphorylation, enhancing glycogen synthase activity and insulin responsiveness [58]. AMPK activation and subsequent ACC phosphorylation link cellular energy balance to reduced gluconeogenesis and improved insulin action [54, 59]. Furthermore, metformin promotes GLUT4 expression and translocation while restoring PKB/Akt activity in peripheral cells [59]. It also exerts anti-inflammatory and redox effects by inhibiting stress kinases such as JNK, upregulating IκBα, and mitigating oxidative and inflammatory pathways; modulation of gut microbiota and LPS signaling may further contribute to improved AMPK and PKB activity [54, 56, 57].

Experimental evidence of metformin’s effects across breast cancer subtypes
Metformin exerts subtype-specific antitumor effects in BC, with distinct mechanisms and efficacy profiles across different molecular subtypes (Table 2). In hormone receptor positive (estrogen receptor and progesterone receptor positive -ER+/PR+) BC cell lines, such as MCF-7 [60]. Metformin has been shown to significantly inhibit cellular proliferation through activation of AMP-activated protein kinase (AMPK) and subsequent suppression of the mTOR signalling pathway [48, 60]. Moreover, its efficacy is enhanced when used in combination with hormonal therapies, suggesting a synergistic interaction that may improve treatment outcomes in this subtype [48].
In HER2-positive BC, both preclinical models and early-phase clinical data support the potential of metformin to suppress HER2 overexpression and enhance the efficacy of targeted therapies [61]. Notably, combination therapy with trastuzumab has demonstrated increased antitumor activity, with a phase II clinical trial reporting a pathological complete response (pCR) rate of 38.3%, underscoring metformin’s ability to potentiate anti-HER2 treatment responses [62].
In TNBC, which has a poor prognosis and limited targeted treatment options, metformin has shown marked antitumor activity [7]. It significantly reduces tumour growth, colony formation, and stemness-associated phenotypes, in part by downregulating critical markers of cancer stemness, including BMI1, CD44, and c-MET, and by impairing cancer stem cell self-renewal capacity [63, 64]. These effects are particularly relevant given the role of cancer stem cells in therapy resistance and tumour recurrence [63]. Nevertheless, across all subtypes, uncertainty persists regarding which molecular or metabolic features predict sensitivity to metformin [65]. Factors such as OCT1 expression, mitochondrial dependence, and AMPK activation status have been proposed but lack consistent validation in clinical settings [65]. Table 2 summarizes the experimental studies on metformin’s anticancer effects in BC subtypes.

Collectively, these findings highlight metformin’s therapeutic potential across multiple BC subtypes, with especially notable efficacy in TNBC, where it targets stemness pathways, and in HER2-positive disease, where it enhances the effectiveness of existing targeted therapies [63, 64]. These subtype-specific responses support further investigation into metformin as a component of combination regimens tailored to molecular BC profiles. The absence of reliable predictive markers, however, continues to hinder precision application, representing a key gap in translational progress.

Clinical and experimental perspectives on Metformin combination therapy in breast cancer
Clinical evidence regarding the use of metformin in combination therapy for BC remains complex and highly context dependent. Randomized controlled trials (RCTs) and meta-analyses in non-diabetic BC patients indicate that adding metformin to standard chemotherapy does not significantly improve progression-free survival (PFS), overall survival (OS), or objective response rates [70]. For example, a meta-analysis of RCTs reported no benefit in PFS (hazard ratio [HR] = 1.00; 95% confidence interval [CI]: 0.79–1.25) or OS (HR = 0.91; 95% CI: 0.69–1.20) with metformin addition [71]. Similarly, prospective studies in metastatic non-diabetic BC showed no significant difference in tumour response or progression rates between metformin plus chemotherapy versus chemotherapy alone [71]. These results underscore the need to distinguish between populations in which metformin exerts metabolic versus direct tumour effects, as blanket combination approaches may dilute measurable benefits.
Despite limited tumoricidal benefit, metformin may improve treatment tolerability. Clinical data suggest reductions in paclitaxel-induced peripheral neuropathy and improvements in quality of life metrics during chemotherapy [72].
In contrast, diabetic BC patients appear to derive greater benefit. Retrospective analyses show higher pathological complete response (pCR) rate among diabetic patients on metformin compared to diabetic patients not receiving it (24% vs. 8%, p = 0.007) during neoadjuvant therapy [11]. This underscores the influence of metabolic context on metformin’s anticancer activity.
Emerging evidence suggests potential synergy with statins [73]. Observational studies indicate that combined metformin and statin use may reduce BC risk, particularly in metabolically dysregulated populations (HR after five years = 0.88; 95% CI: 0.83–0.93 among statin users), while this protective association was attenuated among non-statin users [73]. These findings suggest that the co-administration of metformin and statins may be a promising strategy for risk reduction and tumour suppression, particularly in individuals with metabolic comorbidities [73]. However, the evidence remains largely observational, and whether these effects reflect direct tumour modulation or improved metabolic control is unclear. When taken together with statins clinical outcomes suggest that metabolic health status critically determines metformin responsiveness, yet most trails fail to stratify patients by insulin resistance, obesity, or lipid profile, representing a major design flaw that may mask true therapeutic benefit [73]. Further prospective, stratified clinical trials are warranted to clarify metformin’s role in combination therapy and to identify patient subgroups most likely to benefit.

Clinical trials of metformin in breast cancer
Multiple phase I–III clinical trials have evaluated the efficacy of metformin in both early-stage and metastatic BC. In the neoadjuvant setting, several studies have reported encouraging results (Table 3). For example, a retrospective analysis found that diabetic BC patients who received metformin during neoadjuvant chemotherapy had a significantly higher pCR rate compared to those not on metformin (24% vs. 8%, p = 0.007) [11]. The phase II METEOR trial (NCT01042379) investigated metformin as an adjunct to neoadjuvant chemotherapy in non-diabetic women with early-stage BC, reporting a non-significant trend toward higher pCR rates in the metformin group (22% vs. 8%, p = 0.11) [74].
In the adjuvant and metastatic settings, large, randomized phase III trials such as the MA.32 trial (NCT01101438) have been conducted. The MA.32 trial enrolled over 3,600 non-diabetic women with high-risk operable BC and randomized them to receive metformin or placebo for five years. After a median follow-up of 8.7 years, the study found no significant improvement in invasive disease-free survival or overall survival with metformin compared to placebo [75]. Similarly, the METTEN trial (NCT00659568), a phase II study in HER2-positive BC, found that adding metformin to trastuzumab and chemotherapy did not significantly increase pCR rates, though the combination was well tolerated [76].

These large-scale trials underscore a persistent gap between preclinical promise and clinical efficacy. Most notably, many pivotal studies enrolled metabolically healthy, non-diabetic women, potentially underestimating metformin’s benefit in insulin-resistant or hyperinsulinemia subgroups, the very populations where preclinical and observational evidence suggest the strongest effects [7].
Overall, while early-phase and retrospective studies suggested potential benefits of metformin, particularly in diabetic patients and in the neoadjuvant setting, large, randomized trials in non-diabetic populations have not confirmed a clear survival benefit. This inconsistency highlights the urgent need for stratified trial designs incorporating metabolic and genomic profiling to identify responsive subgroups rather than evaluating metformin in unselected populations. Ongoing and future trials continue to explore specific subgroups, such as those with metabolic syndrome or insulin resistance, to better define the role of metformin in BC therapy.

Challenges and considerations in metformin clinical trials for breast cancer
Despite compelling preclinical evidence supporting the anticancer potential of metformin, findings from RCTs in BC have been inconsistent, with clinical benefits not uniformly demonstrated across patient populations or BC subtypes. Notably, large-scale trials such as the Phase III MA.32 study reported no significant improvement in invasive disease-free survival (IDFS) or overall survival (OS) when metformin was added to standard therapy in both ER + and ER– BC cohorts [75]. While exploratory subgroup analyses from these and other studies have indicated potential benefits in specific populations such as HER2-positive patients with particular genetic variants, these findings remain preliminary and require independent validation in future trials.
Several key uncertainties continue to limit the clinical translation of metformin in oncology. Foremost is the lack of consensus regarding the optimal therapeutic context: Is metformin primarily effective as a systemic metabolic modulator, or can it achieve meaningful intratumoral concentrations for direct cytotoxicity? Additionally, questions persist about optimal dosing, timing, and patient selection. Clinical trials have employed a wide spectrum of dosing strategies, with reported regimens spanning from as low as 250 mg daily up to 2550 mg daily, administered either once daily, twice daily (BID), or three times daily (TID), and often titrated to the maximum tolerated dose or an anti-diabetic dose. For example, BC trials have tested metformin at 500 mg PO BID, escalating to 1000 mg BID or 850 mg BID, sometimes up to 850 mg TID, while other studies have used continuous or intermittent schedules across various combination therapies. Many of these regimens deviate from the standard 500–2000 mg/day typically used in diabetes [80].
Furthermore, the pharmacologically active concentration of metformin in tumour tissues as discussed earlier, remains poorly characterized. Preclinical studies indicate that the concentrations necessary for direct anti-neoplastic effects (notably on AMPK-mTOR pathway signalling) are 10–100 times higher than serum levels typically achieved in humans taking standard oral doses [81]. This pharmacokinetic mismatch undermines the mechanistic rationale for its direct antitumour effects and highlights a need for drug delivery innovations or high-bioavailability analogues. Some clinical trials are now incorporating pharmacokinetic sub-studies to address this gap, but results remain limited.
Another critical barrier is the biological heterogeneity of BC and the absence of reliable predictive biomarkers to identify patients most likely to benefit from metformin. Emerging evidence suggests that metabolic responses to metformin, such as reductions in systemic insulin levels or activation of AMPK, may serve as pharmacodynamic indicators of drug activity. Additionally, genetic factors, including the presence of the minor allele of single-nucleotide polymorphism (SNP) rs11212617 near the ATM gene, have been associated with enhanced treatment response, particularly in HER2-positive patients [82]. Despite these promising leads, biomarker validation remains preliminary, and most ongoing trials do not include metabolic or genomic stratification, representing a missed opportunity for precision therapy development [83].
Metformin remains a promising, low-cost adjunctive therapy in breast cancer, particularly among metabolically dysregulated populations. However, its broad clinical adoption is limited by uncertainties in optimal dosing, patient selection, and clinical trial design. Bridging this translational gap requires a move from generalized, population-wide studies toward mechanism-based, biomarker-enriched trials that align treatment response with underlying metabolic and molecular profiles. Future investigations integrating metabolic, genomic, and pharmacokinetic data will be crucial to define metformin’s true therapeutic value and guide its personalized application in oncology. This review provides a comprehensive synthesis of the evolving role of metformin and its derivatives in breast cancer, highlighting their mechanistic diversity, translational potential, and rational strategies for next-generation drug development and clinical implementation.

Future directions for metformin in breast cancer research
Future research on metformin in BC should focus on identifying the optimal patient populations that are most likely to benefit from its use. This includes individuals who are insulin-resistant, obese, or diabetic, as these metabolic conditions may enhance metformin’s anticancer effects. However, this hypothesis as discussed earlier, remains largely untested in rigorously stratified clinical trials, representing of the most pressing research gaps There is a pressing need to discover and validate predictive biomarkers-such as baseline insulin levels, AMPK activation status, or specific genetic variants (e.g., SNPs near the ATM gene)-that can help tailor metformin therapy to those most likely to respond.
Additionally, further studies should aim to determine the most effective combination regimens, integrating metformin with various chemotherapeutic, targeted, or endocrine therapies to maximize synergistic effects. Mechanism-guided design, where combinations are chosen based on complementary metabolic or signaling pathways, may yield more reproducible clinical benefits than empiric co-administration.
Ultimately, the advancement of personalized medicine approaches, using metabolic and genomic profiling, could enable clinicians to individualize metformin use in oncology, improving outcomes for selected BC patients while minimizing unnecessary exposure for those unlikely to benefit. Future directions should, therefore, prioritize:

Defining intratumoral pharmacokinetics,

Validating predictive metabolic and genomic biomarkers, and.

Developing high-bioavailability derivatives or delivery systems that overcome current pharmacologic limitations.