Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials

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Although breast cancer is the type of cancer where metformin was most extensively-studied through randomized clinical trials (RCTs), none of the previous reviews in this field provided a comprehensive overview of the landscape of RCTs taking into account the phenotype of breast cancer, its staging, and treatment modalities. This scoping review sought to comprehensively map the literature of RCTs focusing on the use of metformin in the treatment of breast cancer and followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Extension for Scoping Reviews guidelines. The eligibility criteria encompassed all RCTs involving metformin for adult patients with breast cancer, with no constraints regarding context, language, publication date, or outcomes. We included 122 reports from 40 RCTs comprising a total of 5,623 participants and 107 distinct outcomes. The results showed that most studies did not present results by phenotype of breast cancer and highlighted critical gaps and opportunities in the literature. Notably, limited evidence from subgroup analyses within a large RCT suggested potential benefits of metformin in improving overall and disease-free survival among HER2+ participants but not among patients with other phenotypes. Our findings highlight the potential for considerably expanding the current knowledge base in this field through the retrospective determination of participant phenotypes, facilitating cost-effective and time-efficient individual participant data meta-analyses. Furthermore, we recommend that funding agencies and journals mandate the comprehensive presentation of results from RCTs on breast cancer based on phenotype. Metformin Breast cancer Review Clinical trial Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction According to the most recent Global Cancer Statistics report, female breast cancer was the second leading cancer worldwide in 2022, accounting for 11.6% of all cancer cases, an estimated 2.3 million new cases, and 666,000 deaths[1]. Breast cancer accounts for approximately one in four cancer cases and one in six cancer deaths among women in the world. In addition, there are predictions for the year 2040 that the burden of breast cancer will increase to more than 3 million new cases and 1 million deaths every year due to population growth and aging alone[2]. Breast cancer treatments are expensive, and chemotherapy treatments are associated with major toxicity. In the USA, breast cancer has the highest treatment cost of any cancer, accounting for 14% of all cancer treatment costs[3]. In 2020, the cost of medical services for breast cancer patients was $26.2 billion, with an additional $3.5 billion spent on prescription drugs. Furthermore, chemotherapy is a common treatment for breast cancer and has been shown to improve survival. However, it often leads to adverse effects, including nausea, dysgeusia, peripheral neuropathy, loss of appetite, myalgia, and peripheral edema, which can significantly impact various aspects of quality of life[4]. Due to the high cost and toxicity associated with various treatments, less aggressive and more affordable breast cancer treatments are desirable. Metformin is one of the most common medications used worldwide and has been used for more than 60 years because of its efficacy and safety[5]. It is a synthetic biguanide often prescribed as the first-line drug to treat type 2 diabetes mellitus (T2DM). In addition, it is an extremely inexpensive medication, costing approximately 15 cents per tablet[5]. Currently, it is used daily by more than 200 million diabetic patients around the world as monotherapy or in combination with other medications. Nevertheless, the precise mechanisms responsible for its therapeutic benefits are still not fully understood[6]. There are several public health interests in the repurposing of generic drugs for new therapeutic targets, as it represents a unique and cheaper strategy of innovation with several advantages compared with the long and costly process of developing new drugs from scratch[7]. With their initial indication, generic drugs have already passed all the phases required by regulatory agencies to be approved for commercialization. They have well-established pharmacodynamic and pharmacokinetic profiles with well-mapped adverse effects. Over the past decades, besides treating T2DM, several other beneficial effects of metformin have been identified, such as preventing diabetes, and treating polycystic ovarian syndrome[8]. Importantly, metformin has shown promising effects against certain types of cancers and is being investigated in several studies, including observational studies[9], in vitro and/or in vivo experimental studies[10], and clinical trials[11]. The number of Randomized Clinical Trials (RCTs) of metformin for the treatment of breast cancer has been growing, but the landscape of this field remains unclear[12]. Moreover, breast cancer is a heterogeneous disease with great variation in its morphological and molecular characteristics, as well as in its clinical response. Furthermore, different stages of breast cancer are associated with distinct treatment modalities, which are associated with a variety of specific outcomes. Importantly, a recent systematic review attempted to assess the evidence from RCTs on the effectiveness of metformin in the treatment of breast cancer[11]. However, that study was restricted to a limited range of outcomes and did not consider the different phenotypes, stages of breast cancer, or treatment modalities examined in the original studies. These factors are central to the appropriate interpretation of the effectiveness of any breast cancer treatment. To date, metformin does not have an established role in breast cancer therapy. Given the sources of clinical heterogeneity underlying breast cancer and the many clinical trials conducted or planned to be initiated in this field, a scoping review is needed to show the extent of the landscape of existing studies and inform future directions and opportunities for research. Therefore, our goal with this scoping review was to map the literature on RCTs of metformin for the treatment of breast cancer. 2. Methods 2.1 Registration of the scoping review protocol This scoping review was conducted according to the recommendations of the Joanna Briggs Institute guidance for systematic scoping reviews[13]. We registered the protocol with the Open Science Framework[14] (osf.io/yquba), and we published it elsewhere[15]. 2.2 Scoping review questions We pursued answers to the following research questions: 1. What is the extent of the randomized clinical trials literature on the use of metformin in the treatment of breast cancer? 2. What phenotypes and stages of breast cancer were examined in those studies? 3. What treatment modalities, regimens, and comparators were used in those studies? 4. What outcomes were evaluated in those studies and what were their main findings? 2.3 Eligibility criteria We delineated the eligibility criteria following the ‘population, concept, and context’ (PCC) framework. 2.3.1 Population We included 18-year-old adult patients of both sexes with any phenotype and stage of breast cancer. We considered the reports to belong to the same study when the investigated population was the same. We considered those studies that used a subset of the population of a larger study as substudies. 2.3.2 Concept We accepted RCTs that included any intervention for treating breast cancer using metformin. Regarding the unit of randomization of the trials, we included both individuals and clusters of individuals in the population. We included trials in which patients were treated with metformin either alone or in combination with other systemic pharmacological treatments (e.g., hormone therapy or chemotherapy), local radiological treatments, surgical procedures, or behavioral interventions such as weight loss, exercise training, or nutritional interventions. We included studies that used a placebo, standard treatment, or other behavioral interventions as long as they did not include metformin as a comparator/control. Those studies involving the use of metformin combined with other treatments must include a comparator using the same treatments without metformin so that the drug effect could be identified. For those studies that investigated metformin alone, we also included control groups with no treatment. We did not limit the outcomes evaluated in the selected studies. Specifically, we intended to map the outcomes of the clinical trials that proposed the use of metformin for breast cancer treatment. 2.3.3 Context There were no restrictions related to the context, language, or date of publication of the studies identified to be included in the scoping review. 2.4 Literature Search On April 2021, we searched the following databases for potential studies: MEDLINE through PubMed, EMBASE, LILACS, Web of Science, and CENTRAL. The electronic search strategies are shown in Supplement 1 . Additionally, we conducted a gray literature search in two databases: the System for Information on Grey Literature in Europe (OpenGrey) and the National Library of Medicine Bookshelf. In addition to looking for relevant studies in databases, we also searched some registers. We screened ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). We further extended our search efforts through other methods. We searched websites via Google Scholar, and we also hand-searched reference lists of relevant publications, conference abstract books, and specialist referrals. Finally, during the analysis of the data in this review, we updated our search for references in September 2023 and verified whether the results of ongoing studies included in this review had already been published. 2.5 Selection of studies The study selection process followed careful identification steps. First, two researchers (CFMA and LCN) independently screened and reviewed the titles and abstracts of all records indexed in the databases using Rayyan software[16]. Second, they separately examined the full versions of the selected records from the first step. Third, the reviewers independently selected the first 200 results found via Google Scholar through Publish or Perish software[17] and screened them using the Rayyan software again. Finally, the investigators hand-searched the included reports as they extracted data for the review. A third reviewer (EIOV) resolved any disagreements that arose between the first two reviewers during the process. 2.6 Data charting process We developed a data extraction form to collect information from the included studies. We subsequently refined the standardized form according to the progress of the data charting process. All the extractions were performed independently and in duplicate by the two reviewers. Disagreements about the extracted data were resolved by discussion and consensus, and an independent third reviewer (EIOV) was consulted when conflicts and doubts persisted. We did not appraise the methodological quality of the included articles in alignment with the methodological expectations for scoping reviews. Extracted data included: first author; study title; reports used for the data extraction; complete reference; is this a secondary report from a larger study? ; the time period when the study was conducted; the geographical location where the study took place; study design; is the study protocol available? ; type and frequency of breast cancer phenotypes, type and frequency of histological subtypes, type and frequency of other genetic characteristics (e.g. single nucleotide polymorphisms [SNP]); type and frequency of breast cancer stage under investigation; were other types of cancer included?; inclusion/exclusion criteria; sample size; characteristics of the population (e.g., mean age, mean Body Mass Index (BMI), frequency of obesity/overweight, menopause, physical activity, presence of comorbidities such as diabetes, hypertension, hyperlipidemia, and metabolic syndrome, frequency of treatment line chemotherapy provided in palliative care); details of the interventions, including treatment modality (i.e., neoadjuvant or adjuvant; palliative, or unclear), metformin dose, frequency and duration of metformin treatment, cointerventions; details of comparators, including type, dose, frequency, and duration; follow-up; outcome measures with the definitions used by the study authors; statistical analyses; results; adverse events; conclusions reported by the study authors; research limitations; funding sources; and references cited in studies’ reports to be evaluated for possible inclusion in our review. In addition, there was a field for free registration of other information deemed relevant by the reviewers. Published articles with results were chosen to guide the full filling of extraction forms because they show the most recent and complete data related to the study. Reports such as study protocols and conference abstracts supported the charting of the data. Commonly, researchers make the results of their studies available in more than one article. To better organize one study’s data that are spread across multiple published articles, we filled out one form per article with results. When no published articles reported the results of included studies, we used data from study protocols and/or abstracts presented in conference proceedings to complete the extraction forms. We stored the data extracted from each study in digital word-processing documents. At the same time, we organized the same data in digital spreadsheets in a summarized format while filling out the standardized forms. This approach facilitated a comprehensive overview of all studies and allowed for effective data synthesis. 2.7 Collating, summarizing, and reporting the results We structured the presentation of our results around the different phenotypes of breast cancer, their stages, treatment modalities, types of interventions with metformin, comparators, outcomes evaluated in the primary studies, and their main findings. Because none of the studies whose population was restricted to participants with estrogen and/or progestogen receptor positive breast cancer presented their results separated by Luminal A and B phenotypes, we presented those studies under a single Luminal phenotype category. We constructed figures to present the results of the most relevant clinical outcomes evaluated by more than one included study. For these figures, we adopted the criterion of signaling statistically significant results favoring either the metformin group or the control group if at least one aspect of the outcome assessed by the study was positive. For example, if a significantly better overall survival (OS) was observed for patients with the HER2+ phenotype of breast cancer taking metformin in comparison to placebo, but no difference was observed for patients with other phenotype subgroups, the OS outcome was marked as favoring the metformin group for that study in the figure dedicated to that specific outcome. The reporting of results was guided by the PRISMA-ScR statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews)[18]. Our PRISMA-ScR checklist comprising our review is available in Supplement 2 . 3. Results 3.1 Selection of studies and reports We identified 40 studies based on eligibility criteria outlined by our PCC framework. Our searches identified 122 reports related to the 40 studies that were included in the scoping review after screening titles and abstracts and examining full versions of potentially relevant studies. Figure 1 outlines the flowchart for inclusion of reports in this review[19]. Supplement 3 lists the reports that were evaluated in full and excluded from databases, the ICTRP, and Google Scholar, along with the reasons for their exclusion. The reasons for exclusion were based on incompatibilities with our previously mentioned eligibility criteria. These included duplicate studies, incorrect study designs, mismatched populations, and incorrect comparators. 3.2 Nature of reports Of the 122 reports, 39 were full articles, 42 were protocols, 37 were conference abstracts, two were statistical analysis plans (SAP), only one was a thesis related to the study with the protocol number EudraCT 2007-000306-70[20], and only one was a feasibility study whose results were available in the European Union Clinical Trials Registry (EUCTR) [21]. In addition, our review encompassed four large studies, each of which included several substudies: the MYME Trial[22, 23], the METTEN Trial[24–27], the NCIC CTG MA.32 (National Cancer Institute of Canada - Clinical Trials Group MA.32)[28–34], and a trial with the protocol number EudraCT number 2008-004912-10[35–38]. 3.3 Availability of studies’ results The dissemination of results from the included studies exhibited a heterogeneous and often incomplete pattern. Out of the 40 identified studies, 25 had some form of published results, with 19 [26,28,32,39, 43–57] of them appearing as full articles and six[21, 54–58] having results published solely in the form of conference abstracts. In contrast, 15 of the included studies did not have published results; for 11 of them, only their protocols were available[59–69], and four were terminated prematurely without their results being published[70–73]. In addition, the characteristics of the included studies with published results are available in Table 1 . Similarly, the characteristics of the included studies without published results are available in Supplement 4 . 3.4 Breast cancer and other tumors Of the 40 clinical trials included, 35 focused exclusively on patients with breast cancer, while five[50–52, 59, 62] included participants with multiple types of cancer. Two of these trials[59, 62] were available only in the form of a conference abstract and a trial registry without results or detailed research protocols. Although the other three studies[50–52] published their results, they did not report them separately by type of cancer. 3.5 General characteristics of participants from the included studies In total, the 25 studies with published results focused on individuals with breast cancer and included 5,623 participants. The participant counts ranged from 40 to 3,649 (median 73 and interquartile range [IQR] 51 to 121). While most studies involved female participants, four studies[28, 52, 59, 73] included both men and women with breast cancer in their samples, with the majority comprised by women. The three studies[50–52], which included individuals with multiple types of cancer and had some form of published results, did not offer separate data for the 176 patients with breast cancer. The total population enrolled in the four studies[70–73] that were terminated without publishing their results was 244 patients. Finally, the total number of participants planned to enroll according to the research protocols of ongoing studies[59–69] was 2,090. 3.6 The distribution of comorbidities among participants in the included studies The level of reporting on participants’ comorbidities in the included studies was heterogeneous. The most frequently reported comorbidities included obesity, overweight status, hypercholesterolemia, hypertension, diabetes, prediabetes, and metabolic syndrome. 3.6.1 Obesity/overweight Liubota’s trial[43] was the only study in which all participants were obese (BMI > 30). In three other studies[41, 48, 51], participants were either overweight or obese (BMI > 25). In contrast, the METTEN Trial [24] was the only study that excluded any potential participants with a BMI above 30. For the remaining studies with published results [22, 45, 47, 54, 58], the prevalence of overweight and/or obesity among participants ranged from 13% to 43%. Fifteen studies[20, 21, 28, 39, 40, 42, 44, 46, 47, 50, 52, 55–58] did not report any data on that characteristic of their samples. 3.6.2 Diabetes and prediabetes Of the 25 studies with published results, 18[20–22, 24, 28, 35, 40, 42, 44, 45, 47, 50, 53–58] exclusively recruited participants without diabetes. Five[39, 43, 46, 48, 52] of these studies did not provide information about the diabetes status of their samples. Only two studies did not exclude participants with diabetes or prediabetes. In one study[41], 1% of participants had diabetes, while in the other study[51], 17% of participants had prediabetes. 3.6.3 Metabolic syndrome Among the studies reviewed, only three[35, 43, 54] provided data regarding the frequency of metabolic syndrome among their participants. Notably, one[43] of these studies exclusively included participants with metabolic syndrome. In the remaining two[35, 54] studies, the prevalence of metabolic syndrome among participants ranged from 26% to 58%. It is worth noting that 22[20–22, 24, 28, 39–42, 44–48, 50–53, 55–58] of the studies did not include any data related to this particular characteristic of their samples. 3.6.4 Menopause status Among the 25 studies with published results, one study[47] exclusively involved a postmenopausal population. Additionally, five studies[21, 42, 46, 48, 57] specifically focused on postmenopausal women. Ten studies[22, 24, 28, 35, 39, 41, 43–45, 49] examined a mixed population, encompassing pre, peri-, and postmenopausal women. Moreover, nine studies[40, 50–56, 58] did not provide information about the menopausal status of the participants. 3.7 Characteristics of breast cancer 3.7.1 Histological type Only five studies[35, 39, 41, 43, 49] provided information on the frequencies of histological types of breast cancer among their participants. In these studies, the frequencies of ductal, lobular, mixed, or other histological types ranged from 3% to 90%, 4% to 10%, 3% to 8%, and 3% to 3.5%, respectively. 3.7.2 Breast cancer phenotype Figure 2 presents an overview of the studies included in the scoping review according to four aspects: phenotypes, stages of breast cancer, treatment modalities, and status of publication results. The reporting of breast cancer phenotypes varied considerably among the 25 studies with published results. Six studies[21, 42, 50–52, 56] did not mention the phenotypic classification of breast cancer. Five studies[20, 46, 47, 54, 57] explicitly included only participants with the luminal phenotype. A single study[24], consisting of three substudies[25–27], included only HER2+ breast cancer patients. Thirteen studies[22, 28, 35, 39–41, 43–45, 48, 53, 55, 58] included participants with mixed phenotypes. In this group, the frequencies of luminal, HER2+, and triple-negative phenotypes ranged from 62% to 84%, 6% to 40%, and 9% to 12%, respectively. Six mixed studies[22, 28, 35, 44, 53, 58] only provided information about the frequency of the hormonal and HER2 receptors of breast cancers in isolation, without explicitly determining the frequency of each phenotype. Figure 3 illustrates the clinical and nonclinical outcomes of the 13 studies involving mixed breast cancer phenotypes. While all of these studies traditionally presented results according to intervention arms, six studies[28, 35, 39–41, 45] segmented some outcome results by subgroups based on phenotypes, receptors, or stages of breast cancer. Ahmed’s study[39] provided pathological complete response (pCR) results according to phenotypes, and Bonanni’s study[35] reported ki67 results for the luminal phenotype. Six studies [28, 38–41, 45] reported relevant clinical outcomes, such as pCR, objective response rate (ORR), invasive disease–free survival (IDFS), and overall survival (OS), according to hormone and HER2 receptor subgroups. Finally, two studies[40, 45] reported results for clinical and nonclinical outcomes based on subgroups of breast cancer stages. 3.7.3 Stages of breast cancer The stages of breast cancer investigated were also heterogeneous among the 25 studies with some published results (Figure 2). Two studies[20, 35] included participants with stages I and II disease. Six studies[28, 40–42, 48, 50] included participants with breast cancer stages ranging from I to III. Six other trials[24, 43, 45, 55, 57, 58] included patients with stages II to III disease. Three studies[39, 47, 54] included only stage III patients. One study[44] involved a stage interval from IIa to IV. Three studies[22, 46, 53] were restricted to participants with stage IV breast cancer. Finally, four studies[21, 51, 52, 56] did not provide any information regarding the stage of breast cancer among their participants. 3.8 Interventions and Comparators The RCTs included in this review examined metformin as a standalone intervention or in combination with various oncological treatments, employing a variety of comparators. The dosages of metformin investigated in these trials ranged from 850 mg to 2550 mg per day. Of the 25 studies with published results, four trials[28, 35, 41, 42] administered metformin as a single intervention and compared it with placebo. In Sadighi's study[56] and the NeoMet Trial[49], metformin was given to participants in the experimental group, while the participants in the control group received no medication. Furthermore, among the same set of studies, three trials[48, 50, 51] combined metformin with behavioral interventions such as weight loss or exercise training, aiming to prevent recurrence after cancer treatment. The SPIRIT trial[51] had three intervention arms: metformin alone, coach-directed weight loss, and self-directed weight loss. The Reach for Health trial[48], a 2 by 2 factorial randomized trial, included groups receiving metformin alone and weight loss with metformin interventions and compared them with placebo groups and weight loss with a placebo. Meyerhardt's study[50] compared metformin with training exercises, exercise training alone, and metformin alone, and the results were compared with those of an educational information group without treatment. Of the 25 studies with published results, 16 incorporated metformin in combination with standard care systemic therapy, which could involve chemotherapy, hormone therapy, or a combination of both. Specifically, ten studies[22, 24, 39, 44, 45, 52–55, 58] employed chemotherapy, four[21, 46, 47, 57] used hormone therapy, and two[40, 43] utilized both chemotherapy and hormone therapy. Among the studies examining chemotherapy, eight[22, 24, 39, 44, 45, 52, 55, 58] combined metformin with various chemotherapy regimens and compared them to chemotherapy alone. Two studies[53, 54] administered metformin in conjunction with chemotherapy and compared it with the same chemotherapy plus a placebo. Among the studies evaluating hormone therapy, two[21, 47] combined metformin with hormone therapy and compared it with hormone therapy without metformin. For Semiglazova's three-arm trial comparing metformin plus toremifene vs. toremifene alone and toremifene plus melatonin, we considered only the arms with metformin and its control for our review. Two studies[46, 57] combined metformin with hormone therapy, specifically an aromatase inhibitor, and compared it with the same hormone therapy plus a placebo. Finally, among two studies[40, 43] that tested both chemotherapy and hormone therapy in conjunction with metformin, the control groups underwent the same interventions without metformin. In El-Haggar's study[40], metformin was tested in combination with chemotherapy and hormone therapy as adjuvant systemic therapy. In Liubota's study[43], both systemic therapies were applied as neoadjuvant treatments, with some patients receiving four cycles of anthracycline-based chemotherapy on three-week schedules and postmenopausal patients with luminal breast cancer receiving hormone therapy (letrozole 2.5 mg per day) for 16 weeks. 3.8.1 Treatment Modalities Metformin was examined in various treatment modalities across the studies included in this review (Figure 2). Of the 25 studies with published results, twelve[24, 35, 39, 43, 45, 47, 49, 54–58] included metformin as a neoadjuvant treatment for breast cancer, while nine[21, 28, 40-42, 48, 50-52] incorporated it as an adjuvant treatment. Additionally, three studies[22, 46, 53] utilized metformin for palliative care. Finally, In one specific study[44], the treatment modality for investigating metformin in combination with standard chemotherapy was unclear. 3.8.1.1 Use of metformin in the context of palliative treatment Of the three studies that incorporated metformin into palliative breast cancer treatment, only the MYME Trial[22] and its substudy, TransMYME[23], explicitly stated the use of 100% first-line chemotherapy. In the other two studies involving participants with stage IV breast cancer receiving palliative oncological treatment, one[46] combined metformin with first-, second-, and third-line or subsequent treatments in 22 (36.7%), 35 (58.3%), and 3 (5.0%) of their patients, respectively. Another study[53] combined metformin with first-, second-, and third-line or subsequent treatments in 27 (67.5%), 7 (17.5%), and 6 (15%) of the participants, respectively. 3.9 Outcome Measures and Main findings Overall, among the 25 included studies with published results, the most frequently reported outcomes were toxicity, pathological complete response (pCR), objective response rate (ORR), clinical benefit rate (CBR), and insulin levels. Table 2 provides a list of clinical, nonclinical, and miscellaneous outcome measures evaluated by all 40 studies included in this review. Similarly, Supplement 5 includes three spreadsheets where readers may find a list of the outcome measures examined by each study according to the breast cancer phenotype, stage, and treatment modality of their samples. The first tab compiles the clinical outcomes mapped in the trials included in the scoping review, with survival outcomes presented initially, as they hold the utmost significance for patients with breast cancer. The second tab organizes nonclinical outcomes assessed in the trials by categories. The final tab consolidates other nonclinical outcomes that do not fit into any specific category. Clinical outcomes, including survival, quality of life, and cancer response rates, deserve special attention because they are considered the most important from the patients’ perspective. Therefore, we emphasize the presentation of results related to those outcomes in our narrative synthesis and figures. 3.9.1 Overall Survival (OS) OS, defined as the time from randomization to death, is considered the ‘gold standard’ primary clinical endpoint in oncology[74]. Figure 4A depicts the mapping of the nine studies[22, 28, 43, 44, 46, 53, 68, 71, 75] that evaluated OS according to the phenotype, stage and treatment modality of breast cancer, as well as the publication status of their results concerning that outcome. Six[22, 28, 43, 44, 46, 53] of those nine studies had published results. Only one of those studies [28] showed improved survival among participants treated with metformin. Importantly, that effect was observed only among HER2+ participants (Hazard Ratio [HR] = 0.54; 95% CI: 0.30-0.98; P = 0.04) and not among participants with luminal breast cancer or the overall group of participants with mixed phenotypes. 3.9.2 Disease-free survival (DFS) Seven studies[24, 28, 39, 40, 43, 62, 75] included DFS, defined as the time from randomization to disease recurrence[74], among their outcome measures. As shown in Figure 4B, four[28, 39, 40, 43] of those seven studies had published results, and all of them included participants with mixed phenotypes. In two[28, 40] of them, there was some evidence of improvement in DFS among participants treated with metformin. Goodwin’s study[28] revealed improved DFS among HER2+ participants (HR = 0.64; 95% CI: 0.43-0.95; P = 0.03) but not among participants with other phenotypes or the overall group of participants. In the study by El-Haggar[40], which did not present DFS results for specific phenotypes, metformin treatment was associated with an average increase in DFS of approximately two months (log rank test, p = 0.044) and a hazard ratio of 0.31 (95% CI: 0.11-0.86, P = 0.023), favoring the metformin group for that same outcome in a statistical model adjusted for age, tumor stage, adjuvant chemotherapy, and estrogen and HER2 receptor status. 3.9.3 Progression-free survival (PFS) PFS is defined as the time from randomization to disease progression or death[74]. Seven studies[22, 44, 46, 52, 53, 62, 71] reported PFS (Figure 4C). Four studies[22, 44, 46, 53] out of those seven had some published results, all of which were negative. One of those studies[46] included only participants with luminal breast cancer, whereas the other three [26,48,57] included people with mixed phenotypes. Although PFS is an outcome used to assess therapies targeting advanced or metastatic malignancies[74], we noticed that one[44] of those four studies included participants with earlier stages of breast cancer in addition to metastatic disease. The same issue occurred with a study with unpublished results[62]. Notably, Saif’s study[52], which included participants with 16 different cancers, did not provide results specific to patients with breast cancer in its published article. Furthermore, although that study claimed to have evaluated PFS using the Kaplan‒Meier method, such results were not presented in the publication. 3.9.4 Objective response rate (ORR) ORR is an outcome primarily used to assess neoadjuvant therapies and is defined as the proportion of patients who achieve a partial or complete response to therapy[74]. Fifteen studies[22, 39, 43–47, 54, 57, 58, 68–71, 75] evaluated ORR among their outcome measures (Figure 4D). Eight[22, 39, 43, 45–47, 57, 58] of those 15 studies had published results, and only one[43] of them was positive. In that study, which included patients with mixed phenotypes and stages II-A to III-C breast cancer treated with neoadjuvant chemotherapy, the authors found that 28 (77.5%) out of 36 participants in the metformin arm achieved either a complete or partial response, in contrast to 9 (25%) out of 36 participants in the control arm (p<0.05). Notably, of the eight studies with published results, five[22, 39, 43, 45, 58] included participants with mixed phenotypes, and three[46, 47, 57] included participants with the luminal phenotype; the latter of which were all negative. 3.9.5 Clinical benefit rate (CBR) CBR is defined as the proportion of patients who achieve a complete response, partial response, or stable disease for at least six months[74]. Nine studies[39, 43, 44, 46, 53, 54, 68–70] included the CBR in their outcomes (Figure 5A), and five[39, 43, 44, 46, 53] of them had published results. Only two[43, 44] of those studies reported positive results for that outcome. Both included participants with mixed phenotypes. Liubota’s study[43] included women with stages II to III disease who were receiving neoadjuvant chemotherapy and revealed a statistically significant increase in the proportion of patients with stable disease and complete or partial response (34 [94.5%] out of 36 in the metformin arm vs. 28 [78%] out of 36 in the control group, p<0.05). The study by Salah et al.[44] included 50 participants with stage II to IV breast cancer. Unfortunately, the numbers of participants who experienced partial response or stable disease were reported on a three-dimensional figure, which does not allow the accurate extraction of data. Zhao’s trial[46] was the only study with published results restricted to participants with luminal breast cancer (N = 60). In that study, metformin was added to palliative chemotherapy for women with stage IV breast cancer and was not associated with a significantly different CBR compared with that of the control group. 3.9.6 Pathological Complete Response (pCR) pCR is defined as the lack of residual invasive cancer in resected breast tissue or regional lymph nodes[74]. This outcome is commonly used for the accelerated approval of neoadjuvant therapies targeting breast cancer. Eight[24, 39, 43, 45, 47, 54, 55, 58] out of 14 studies[24, 39, 43, 45, 47, 54, 55, 57, 58, 63, 66–68, 70] had some published results on this outcome, and only one[43] of them, which included patients with mixed phenotypes and stage II to III breast cancer, was positive (Figure 5B). In that study, 9 (26.5%) out of 36 patients in the metformin arm achieved pCR, while 2 (6%) out of 36 patients in the control group achieved pCR (p<0.05). Of the remaining negative studies, four[39, 45, 55, 58] involved participants with mixed breast cancer, one[24] was restricted to participants with the HER2+ phenotype, and two[47, 54] focused on patients with luminal breast cancer. 3.9.7 Breast Conservation Rate (BCR) Neoadjuvant systemic therapy for operable breast cancer can increase the options for conservative surgery in patients with breast cancer rather than mastectomy[76]. Six studies[24, 39, 43, 45, 57, 70] included BCR in their outcomes (Figure 5C), and five[24, 39, 43, 45, 57] of them had published results. The only positive result came from Liubota’s study[43], which was already mentioned as the single study with positive ORR and pCR results. In that study, among the 35 participants with surgical indications, breast-conserving surgery was performed on 9 (50%) of the 18 patients in the metformin group and 4 (23.5%) of the 17 patients in the control group (p<0.05). 3.9.8 Quality of Life (QoL) Eight studies[28, 45, 47, 53, 58, 59, 72, 75] included QoL among their outcome measures (Figure 5D). Three[45, 47, 53] of those eight studies had published results, and all of them used the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Only Pimentel’s study[53], which included 40 women with metastatic breast cancer with mixed phenotypes, identified a statistically significant difference regarding one of the domains of quality of life evaluated by that instrument. Remarkably, participants in the metformin arm experienced a large worsening of their Global Health Status in comparison with those in the control arm (standardized difference of 0.8, p=0.006). Neither the other domains of quality of life nor the frequency of fatigue, diarrhea, nausea and vomiting, appetite loss, abdominal pain, or other symptoms measured by the EORT-QLC-C30 were significantly different between the two groups in that study. 3.9.9 Adverse Events Among the 25 studies with published results, 22[21, 22, 24, 28, 35, 39–42, 44–46, 48–57] provided data on adverse events related to metformin compared to control groups, while three[43, 47, 58] did not report adverse events in their trial results. The SNCIC CTG MA.32[28] was the only study in which participants in the metformin arm experienced a greater rate of severe adverse events. In that study, 391 (21.5%) patients in the metformin group and 328 (17.5%) in the placebo group experienced grade 3 or higher adverse events (P=0.003); the most common adverse events of grade 3 or higher included hypertension (2.4% metformin vs 1.9% placebo), irregular menses (1.5% metformin vs 1.4% placebo), and diarrhea (1.9% metformin vs 0.8% placebo). In contrast, in the MYME trial[22] , the metformin group experienced a lower frequency of grade 3 or 4 adverse events than did the control group, with 54% vs 72% of patients developing neutropenia, respectively (P=0.019). For the other 20 studies[21, 24, 35, 39–42, 44–46, 48–57] with published results, metformin was generally well tolerated and the incidence of severe adverse events was not greater in the metformin group than in the control group. However, as expected due to the well-known side effect profile of metformin, several studies have reported a greater rate of less severe (grades 1 and 2) gastrointestinal adverse events, such as diarrhea, associated with this medication. 3.10 Funding Thirty-four studies[21, 24, 28, 35, 41, 42, 45–52, 54–60, 62–73, 75] were conducted with not-for-profit funding, such as research foundations, governments, and universities. Only two [22, 53] studies had mixed funding sources, including for-profit and not-for-profit funders. The MYME Trial[22] was funded by the Italian Association for Cancer Research (AIRC) and TEVA Pharmaceuticals. In addition, Pimentel’s study[53] was funded by the Breast Cancer Research Foundation, Hold'em for Life Charity, and the contract research organization Ozmosis Research Inc. Three studies[39, 40, 43] did not provide information regarding their sources of funding. Finally, Salah’s trial[44] , which also included published results, was the only study in which its authors explicitly stated that it was conducted without sponsorship. 4. Discussion This is the most extensive and comprehensive review of RCTs that evaluated the use of metformin in the treatment of breast cancer. Our results provide insight into the growing body of literature that assesses the impact of metformin on the effectiveness of breast cancer treatment. We categorized existing studies based on breast cancer tumor phenotypes, stages, and possible treatment modalities. To the best of our knowledge, this comprehensive mapping and organization has not been previously undertaken by other studies of a similar nature. This charting effort is essential because it highlights knowledge gaps in the literature, identifying opportunities for new clinical trials and demonstrating the value and scope of further systematic reviews. Based on the findings of this review, we identified the need for the development of methodological guidelines that ensure the clear presentation of breast cancer phenotype-specific data in any new oncological clinical trial in this field. We believe that obtaining trial results from the perspective of cancer phenotypes will make the evidence more relevant to clinical oncology practice, which frequently addresses a variety of breast tumor types. Until the development and implementation of such guidelines becomes a reality, we suggest that researchers explore the possibility of retrospectively ascertaining the phenotypes of participants from previous primary studies. If feasible, this approach has the strategic potential to rapidly generate new phenotype-specific data without incurring the substantial cost of recruiting new patients for novel trials. Furthermore, the accumulation of new phenotype-specific evidence from such retrospective analyses of previously completed clinical trials may be compiled in future systematic reviews. This compilation may provide strong enough evidence to support not only clinical decisions but also regulatory decisions. Despite the variety of phenotypes, outcomes, disease states, treatment modalities, comparators, and publication status, our mapping of the field allows the envisioning of future phenotype- and outcome-specific meta-analyses. For example, there are six studies with published results, five of which involved mixed phenotypes and one focused on the luminal population (Figure 4A), which can be used to conduct a meta-analysis on OS. Additionally, an opportunity exists to evaluate DFS using the METTEN trial[24] results for the HER2+ population and the four studies already published, which involve mixed phenotypes (Figure 4B). Moreover, as previously highlighted, if future systematic reviewers are able to gain access to retrospectively ascertained phenotypes of breast cancer patients enrolled in previous RCTs, better and more meta-analyses would be possible, including performing individual patient data (IPD) meta-analyses taking that kind of information into account through a collaborative effort among researchers in this field. With regard to opportunities for new clinical trials in this field, our review also allows the identification of relevant knowledge gaps to be addressed. For example, although there are already studies involving neoadjuvant treatment modalities for all breast cancer phenotypes, the landscape is not the same for adjuvant, or palliative studies, as depicted in Figure 2. For example, innovative trials could be proposed to investigate the effectiveness of metformin within adjuvant and palliative treatment modalities in patients with HER2+ and triple-negative breast cancer. There is also a lack of evidence of adjuvant treatment with metformin specifically for the luminal phenotype. We believe it is essential to propose new RCTs that combine phenotypes that have been poorly explored with the most important outcomes for breast cancer patients. Currently, the METTEN Trial[24] is the only completed trial with published results that investigated neoadjuvant treatment with metformin in patients with the HER2+ phenotype. Additionally, the only other trial involving the same phenotype and treatment modality remains unpublished[66]. Both trials had pCR as the primary outcome. Therefore, we believe there is an opportunity for more neoadjuvant trials that aim to evaluate HER2+ breast tumors, focusing on strategic clinical outcomes such as DFS and BCR. Further evaluation of metformin in patients with HER2+ breast cancer is especially relevant due to the limited evidence from a subgroup analysis of a single large RCT suggesting that it could improve OS and DFS[28]. In a similar vein, the BREAKFAST Trial[68] is the only interventional study proposed to investigate the effect of metformin on triple-negative breast cancer treated with a neoadjuvant modality. At the time of our last literature search, its results had not been published yet. As a result, further investigations into this specific phenotype are needed, with a focus on outcomes such as OS, ORR, pCR, BCR, and relapse-free survival. Other relevant gaps in the literature that deserve mention include how treatment with metformin interacts with certain comorbidities and characteristics of participants such as overweight, obesity, metabolic syndrome, menopause status, and their physical activity levels. Such gaps may be addressed by new studies collecting that kind of data, reanalysis of existing data from specific studies, or even by IPD meta-analyses. This is particularly relevant because metformin may be effective among certain groups of people but not others. Importantly, our review offers a map of the landscape of RCT data on metformin for the treatment of breast cancer. It is beyond the scope of our discussion section to outline every possible knowledge gap and research opportunity available in terms of new RCTs or systematic reviews. Experts in this field will be able to use our charting effort to recognize further research gaps and opportunities just as expert travelers are able to devise new paths from triangulating information from maps and their own knowledge of a specific region. For example, the examination of figures 4 and 5 easily reveals a lack of published results on the most important clinical outcomes for people with triple-negative breast cancer throughout all stages of the disease. There are several major differences between our scoping review and previous reviews published on metformin and cancer. For instance, a systematic review[10] focused on in vitro and/or in vivo studies exploring the potential antiproliferative mechanisms of metformin. This review provided evidence of the effectiveness of metformin in cancer cell lines and/or animal models, confirming its antiangiogenic properties, as well as its ability to inhibit cellular metastasis and induce apoptosis. Another prior systematic review of 11 observational studies[9] analyzed the association between metformin use by diabetic women and the prognosis of breast cancer patients and revealed that the use of the drug is associated with better survival of breast cancer patients with diabetes (HR: 0.53; 95% CI: 0.39-0.71; p < 0.001). However, meta-analyses of observational studies are subject to bias due to residual confounding within the primary studies included. A single systematic review and meta-analysis attempted to assess the evidence from RCTs on the effectiveness of metformin in the treatment of breast cancer[11]. However, that review had several methodological limitations, including the absence of a registration of the review protocol, poor details of the search strategy for any database, and the exclusion of important databases and gray literature. Furthermore, there was insufficient description of the eligibility criteria, no flow diagram of the study selection process, no assessment of the certainty of evidence, and a limited range of evaluated outcomes. Importantly, that systematic review did not consider the different phenotypes, the staging of breast cancer, or the treatment modalities under which metformin was used in the primary studies. These aspects are crucial for interpreting the effectiveness of not only metformin but also any breast cancer treatment. Hence, it is likely that their meta-analyses were biased by too much clinical heterogeneity that compromised the quality of their pooled results. These limitations of the single systematic review of RCTs of metformin for the treatment of breast cancer corroborate the relevance of our scoping review in paving the way for future systematic reviews and clinical trials in this field. Our review has some limitations. First, the absence of risk of bias evaluation of included studies, the appraisal of overall certainty of evidence across studies, or even the performance of a meta-analysis as a form of quantitative synthesis. All three aspects are possible but lie beyond the scope of a scoping review, which aims to provide a broad overview and description of the general landscape of a field. Second, we did not contact any author from the original studies to request unpublished data because our aim was to chart the literature, including its areas of uncertainties. Requesting unpublished data such as study results stratified by phenotype will be better suited to the future systematic reviews that we envision our scoping review will foster. Third, primary prevention of breast cancer also fell outside the scope of our review. The primary prevention and treatment of breast cancer are complex and involve different populations, risk factors, and biological determinants. The present study also has relevant strengths. We established broad eligibility criteria not restricting the context, language, or publication date of the study reports because the best practice for a scoping review is to attempt to be as comprehensive as possible. We also searched gray literature and registers such as ICTRP, as well as using other methods such as Google Scholar, checking reference lists of relevant publications, reviewing conference abstract books, and seeking specialist referrals. These searches were crucial for identifying a large number of relevant study reports for this review. Additionally, two independent reviewers conducted the selection of studies and data extraction, while a third reviewer was available to resolve any disagreements that arose between the reviewers during that process. 5. Conclusion In summary, the proposed scoping review revealed a growing body of evidence from RCTs about the use of metformin for the treatment of breast cancer. We mapped the landscape of existing studies according to phenotypes, staging, treatment modality, types of interventions, comparators, outcomes, and their main findings. Given the clinical heterogeneity underlying breast cancer itself and the current existence of 40 different primary studies in this field, by charting that literature, we were able to identify new opportunities for clinical trials and systematic reviews. Specifically, we emphasize the necessity for standardizing the presentation of results from breast cancer clinical trials by phenotype and envision the potential for collaboration among researchers to retrospectively ascertain the phenotypes of breast cancer participants in previous studies. This could substantially enhance the possibility of conducting better and more cost-effective meta-analyses in this field, including IPD meta-analyses. Declarations Ethics approval and consent to participate: Not Applicable. Consent for publication: Not Applicable. Availability of data and materials: Not Applicable. Competing interests: The authors declare no competing interests. Funding: This research was supported by CAPES (Coordination for the Improvement of Higher Education Personnel—Ministry of Education, Brazil) through a grant to CFMA (Process number: 88882.432879/2019-01). The funder did not play any role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript EIOV was partially supported by a grant from the Brazilian National Council for Scientific and Technological Development (CNPq) (312499/2022-1). Authors' contributions: CFMA and EIOV designed the study. CFMA performed the literature searches. CFMA and LCN screened references and extracted data from primary reports included in the review. EIOV supervised the review process. CFMA and EIOV analyzed the data. CFMA, LCN, CRMA, CPS, ACB, FBF, and EIOV were involved in the interpretation of results. CFMA and EIOV drafted the first version of the manuscript. LCN, CRMA, CPS, ACB, and FBF revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgements: The authors wish to express their gratitude to Maximiliano Ribeiro Guerra, Mario Cirio Nogueira, Carlos Eduardo Paiva, and Leonardo Roberto da Silva for their comments on previous versions of our manuscript. References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. https://doi.org/10.3322/caac.21834. Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. The Breast. 2022;66:15–23. Health and Economic Benefits of Breast Cancer Interventions | Power of Prevention. 2023. https://www.cdc.gov/chronicdisease/programs-impact/pop/breast-cancer.htm. Accessed 17 Jun 2023. Prieto-Callejero B, Rivera F, Fagundo-Rivera J, Romero A, Romero-Martín M, Gómez-Salgado J, et al. Relationship between chemotherapy-induced adverse reactions and health-related quality of life in patients with breast cancer. Medicine (Baltimore). 2020;99:e21695. Schernthaner G. The right place for metformin today. Diabetes Res Clin Pract. 2020;159:107946. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014; Query date: 2021-09-30 09:48:10. Sachs RE, Ginsburg PB, Goldman DP. Encouraging New Uses for Old Drugs. JAMA. 2017;318:2421–2. Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2:56. Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. The …. 2015; Query date: 2021-09-30 09:48:10. Aljofan M, Riethmacher D. Anticancer activity of metformin: a systematic review of the literature. Future Sci OA. 5:FSO410. Zhang Z-J, Yuan J, Bi Y, Wang C, Liu Y. The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials. Pharmacol Res. 2019;141:551–5. Testa U, Castelli G, Pelosi E. Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments. Med Sci Basel Switz. 2020;8. Peters MDJ, Godfrey CM, Khalil H, McInerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015;13:141–6. Araujo CFM, Nunes LC, Murta-Nascimento C, Bragagnoli AC, Souza CP de, Fukushima FB, et al. Metformin for the Treatment of Breast Cancer: Protocol for a Scoping Review of Randomised Clinical Trials. 2021. Araujo C, Nunes L, Murta-Nascimento C, ... Metformin for the treatment of breast cancer: protocol for a scoping review of randomised clinical trials. BMJ Open. 2021; Query date: 2021-09-30 09:48:10. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5:210. Harzing AW. Publish or Perish. Harzing.com. 2016. https://harzing.com/resources/publish-or-perish. Accessed 11 Apr 2024. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169:467–73. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Hadad SM, Coates P, Jordan LB, Dowling RJO, Chang MC, Done SJ, et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat. 2015;150:149–55. EUCTR2014-004430-26-GB. Feasibility of the International Breast Intervention Study 3 (IBIS 3). Prevention of late recurrence in hormone receptor positive breast cancer survivors following 5 years of treatment. HttpwwwwhointtrialsearchTrial2aspxTrialIDEUCTR2014-004430-26-GB. 2015. Nanni O, Amadori D, De Censi A, Rocca A, Freschi A, Bologna A, et al. Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial. Breast Cancer Res Treat. 2019;174:433–42. Gennari A, Foca F, Zamarchi R, Rocca A, Amadori D, De Censi A, et al. Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial. Breast Cancer Res Treat. 2020;181:61–8. Martin-Castillo B, Pernas S, Dorca J, lvarez I, Martnez S, Prez-Garcia JM, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget. 2018;9:35687–704. Lopez-Bonet E, Bux M, Cuys E, Pernas S, Dorca J, lvarez I, et al. Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer. J Clin Med. 2019;8. Cuyàs E, Buxó M, Ferri Iglesias MJ, Verdura S, Pernas S, Dorca J, et al. The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin. Front Oncol. 2019;9:193. Cuyàs E, Fernández-Arroyo S, Buxó M, Pernas S, Dorca J, Álvarez I, et al. Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients. Aging. 2019;11:2874–88. Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022;327:1963–73. Goodwin P, Dowling R, Ennis M, Chen B, ... Effect of metformin versus placebo on metabolic factors in the MA. 32 randomized breast cancer trial. … Breast Cancer. 2021; Query date: 2021-09-30 09:48:10. Lohmann AE, Liebman MF, Brien W, Parulekar WR, Gelmon KA, Shepherd LE, et al. Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32. Breast Cancer Res Treat. 2017;164:371–8. Goodwin P, Dowling R, Ennis M, ... Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA. 32: A Breast Cancer Randomized Trial of Metformin vs Placebo. JNCI Cancer …. 2021; Query date: 2021-09-30 09:48:10. Pimentel I, Chen BE, Lohmann AE, Ennis M, Ligibel J, Shepherd L, et al. The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32. J Natl Cancer Inst. 2021;113:192–8. NCT01286233. Study of Biomarkers Associated With Fatigue in Patients With Early-Stage Breast Cancer Treated With Metformin or Placebo on NCIC-CTG-MA.32. https://clinicaltrials.gov/show/NCT01286233. 2011. Wood ME, Qin R, Le-Petross HT, Hwang ES, Ligibel JA, Mayer IA, et al. Change in mammographic density with metformin use: A companion study to NCIC study MA.32. J Clin Oncol. 2013;31. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:2593–600. Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, ... The effect of metformin on apoptosis in a breast cancer presurgical trial. … J Cancer. 2013; Query date: 2021-09-30 09:48:10. DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat. 2014;148:81–90. DeCensi A, Puntoni M, Guerrieri-Gonzaga A, ... Effect of metformin on breast ductal carcinoma in situ proliferation in a randomized presurgical trial. … Prev Res. 2015; Query date: 2021-09-30 09:48:10. Ahmed S, Ahmed MS, Morsi D, ... Added Metformin to Systematic Neoadjuvant Chemotherapy in Breast Cancer Patients: Randomized Study from Egypt. Med J …. 2021; Query date: 2021-09-30 09:48:10. El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clinical & Experimental Metastasis. 2016;33:339–57. Ko K, Ma S, Yang J, Hwang Y, Ahn C, Cho Y, et al. Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2015;153:361‐370. Davis S, Robinson P, Jane F, White S, ... The benefits of adding metformin to tamoxifen to protect the endometrium—A randomized placebo‐controlled trial. Clin …. 2018; Query date: 2021-09-30 09:48:10. https://doi.org/10.1111/cen.13830?casa_token=miQTssmCbfQAAAAA:snkCWNVwpJIgYT92JW9O0gHU1aZG9wL4MRIZ-qqSoQO1kBvQWf_uljBs-pyHtsCE1cx__8Rlavu192mbjA. Liubota R, Cheshuk V, Zotov O, ... Metformin in neoadjuvant systemic therapy of breast cancer patients with metabolic syndrome. Arch …. 2018; Query date: 2021-09-30 09:48:10. Salah H, Rabea H, Hassan A, Elberry A. Metformin as an Adjuvant Treatment in Non-Diabetic Metastatic Breast Cancer. Bahrain Med …. 2021; Query date: 2021-09-30 09:48:10. Barakat HE, Hussein RRS, Elberry AA, Zaki MA, Ramadan ME. The impact of metformin use on the outcomes of locally advanced breast cancer patients receiving neoadjuvant chemotherapy: an open-labelled randomized controlled trial. Sci Rep. 2022;12:7656. Zhao Y, Gong C, Wang Z, Zhang J, Wang L, Zhang S, et al. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget. 2017;8:84224–36. Semiglazova TYu, Osipov MA, Krivorotko PV, Klimenko VV, Dashyan GA, Paltuev RM, et al. Melatonin and metformin in neoadjuvant hormonotherapy in locally advanced breast cancer. Vopr Onkol. 2018;64:612–9. Patterson RE, Marinac CR, Sears DD, Kerr J, Hartman SJ, Cadmus-Bertram L, et al. The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes. J Natl Cancer Inst. 2018;110:1239–47. Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, ... Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res …. 2011; Query date: 2021-09-30 09:48:10. https://doi.org/10.1007/s10549-011-1612-1. Meyerhardt J.A., Irwin M.L., Jones L.W., Zhang S., Campbell N., Brown J.C., et al. Randomized phase II trial of exercise, metformin, or both on metabolic biomarkers in colorectal and breast cancer survivors. JNCI Cancer Spectr. 2020;4. Yeh H-C, Maruthur NM, Wang N-Y, Jerome GJ, Dalcin AT, Tseng E, et al. Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial. J Clin Endocrinol Metab. 2021;106:e4179–91. Saif MW, Rajagopal S, Caplain J, Grimm E, Serebrennikova O, Das M, et al. A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors. Cancer Chemother Pharmacol. 2019;84:1323–31. Pimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon D, Elser C, et al. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019;48:17–23. Arce-Salinas C, Alamilla G, Flores-Diaz D, Deneken CZ, Mendoza-Galindo L, Ramirez-Morales R, et al. Randomized, double blind trial to evaluate the safety and efficacy of metformin vs placebo plus neoadjuvant chemotherapy in locally advanced breast cancer. J Clin Oncol. 2016;34. Azazy HA, Gado NM, Salem DA, El-Ghamry WR. Metformin with neoadjuvant chemotherapy in stage II-III breast cancer: A phase II clinical trial. Ann Oncol. 2020;31 (Azazy H.A.; Gado N.M.; Salem D.A.; El-Ghamry W.R.) Clinical Oncology Department (ASCOD), Ain Shams University Hospital-Faculty of Medicine, Cairo, Egypt:S323–4. Sadighi S, Saberian M, Nagafi M, Jahanzad I, Omranipoor R, Behrouzi B. Metformin anti-proliferative effect on a cohort of non-diabetic breast cancer patients. Ann Oncol. 2016;27 (Sadighi S.; Saberian M.) Medical Oncology-Hematology, Cancer Institute of Iran, Tehran, Iran. Kim J, Lim W, Kim E-K, Kim M-K, Paik N-S, Jeong S-S, et al. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR). BMC Cancer. 2014;14. Semiglazova TY, Osipov M, Krivorotko P, Semiglazov V, Protsenko S, Berstein L, et al. Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer. Ann Oncol. 2019;30 (Semiglazova T.Y.; Protsenko S.; Klimenko V.) Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation:v100. Vernieri C, Nichetti F, Ligorio F, Zattarin E, Beninato T, Lobefaro R, et al. Efficacy of metfOrmin in PrevenTIngglucocorticoid-induced diabetes in Melanoma, breAst orLung Cancer patients with brain metastases: The phase IIOPTIMAL study. Cancer Res. 2020;80 16 SUPPL. TCTR20200116007. Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer patient, a randomized controlled trial. https://www.thaiclinicaltrials.org/show/TCTR20200116007. Accessed 2 Jul 2022. ChiCTR1900023487. The Clinical Study of Metformin in Ovarian Reserve and Function Protection for Breast Cancer Survivors Treated with Chemotherapy. https://www.chictr.org.cn/showproj.aspx?proj=39171. 2019. https://www.chictr.org.cn/showproj.aspx?proj=39171. Accessed 2 Jul 2022. ChiCTR1900027489. A randomized, double-blind, placebo-controlled clinical study of metformin in protecting reproductive system development and fertility in women with malignant tumors of chemotherapy-induced ovarian injury. https://www.chictr.org.cn/showproj.aspx?proj=45172. 2019. https://www.chictr.org.cn/showproj.aspx?proj=45172. Accessed 2 Jul 2022. ChiCTR-IPR-16008553. Clinical study on the anti-cancer effect of metformin in the breast cancer patients with prediabetes during neoadjuvant chemotherapy. https://www.chictr.org.cn/showproj.aspx?proj=14483. https://www.chictr.org.cn/showproj.aspx?proj=14483. Accessed 3 Jul 2022. ACTRN12612000416897. Sequential evaluation of tumours undergoing pre-operative therapy with aromatase inhibitors and metformin (setup-aim) a neo-adjuvant pilot study in operable hormone sensitive breast cancer in post menopausal women. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000416897. 2012. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000416897. Accessed 3 Jul 2022. EUCTR2015-001001-14-IT. Effect of metformin in overweight breast cancer survivors at increased risk of recurrence. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001001-14/IT. 2021. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001001-14/IT. Accessed 4 Jul 2022. NCT03238495. Randomized Trial of Neo-adjuvant Chemotherapy With or Without Metformin for HER2 Positive Operable Breast Cancer. 2017. NCT04170465. Role of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (METNEO). https://clinicaltrials.gov/show/NCT04170465. 2019. NCT04248998. Calorie Restriction With or Without Metformin in Triple Negative Breast Cancer. https://clinicaltrials.gov/show/NCT04248998. 2020. NCT04387630 M. Neoadjuvant Chemotherapy With or Without Metformin in Early Breast Cancer. 2020. NCT01929811. NeoMET Study in Neoadjuvant Treatment of Breast Cancer. https://clinicaltrials.gov/show/NCT01929811. 2013. NCT01477060. Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer. https://clinicaltrials.gov/show/NCT01477060. 2011. NCT02472353. Use of Metformin to Reduce Cardiac Toxicity in Breast Cancer. https://clinicaltrials.gov/show/NCT02472353. 2015. NCT02360059. Metformin for Reduction of Paclitaxel-Related Neuropathy in Patients With Breast Cancer. https://clinicaltrials.gov/show/NCT02360059. 2015. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11:1121–31. Zhang J, Ma X, Li Y, Liu R, Li Y, Zhang P, et al. Metformin intervention against ovarian toxicity during chemotherapy for early breast cancer: Study protocol for a randomized double-blind placebo-controlled trial. Maturitas. 2020;137:1–6. James T, McCahill L, Ratliff J, Ashikaga T, Single R, Sheehey-Jones J, et al. Quality assessment of neoadjuvant therapy use in breast conservation: barriers to implementation. Breast J. 2009;15:524–6. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Supplement1SearchStrategy.docx Supplement2PRISMAScRChecklist.docx Supplement3ExcludedReports.docx Supplement4StudiesWITHOUTRESULTS14out23.docx Supplment5.xlsx Cite Share Download PDF Status: Published Journal Publication published 21 Aug, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Accepted 09 Jun, 2025 Reviews received at journal 15 Oct, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers agreed at journal 13 Oct, 2024 Reviewers invited by journal 08 Oct, 2024 Submission checks completed at journal 07 Oct, 2024 First submitted to journal 07 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4593019","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":452128483,"identity":"682d8b2f-29b9-11f0-91e4-06cc9d20a69f","order_by":0,"name":"Carolina Fumico Massuda Araujo","email":"","orcid":"","institution":"São Paulo State University (UNESP)","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"Fumico Massuda","lastName":"Araujo","suffix":""},{"id":452128649,"identity":"6fbd90cf-29b9-11f0-91e4-06cc9d20a69f","order_by":1,"name":"Lélia Cápua Nunes","email":"","orcid":"","institution":"São Paulo State University (UNESP)","correspondingAuthor":false,"prefix":"","firstName":"Lélia","middleName":"Cápua","lastName":"Nunes","suffix":""},{"id":452128741,"identity":"76a7ae0a-29b9-11f0-91e4-06cc9d20a69f","order_by":2,"name":"Cristiane Murta Ramalho Nascimento","email":"","orcid":"","institution":"São Paulo State University (UNESP)","correspondingAuthor":false,"prefix":"","firstName":"Cristiane","middleName":"Murta Ramalho","lastName":"Nascimento","suffix":""},{"id":452128815,"identity":"7e5bc3bc-29b9-11f0-91e4-06cc9d20a69f","order_by":3,"name":"Arinilda Campos Bragagnoli","email":"","orcid":"","institution":"Barretos Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Arinilda","middleName":"Campos","lastName":"Bragagnoli","suffix":""},{"id":452128880,"identity":"85bc515c-29b9-11f0-91e4-06cc9d20a69f","order_by":4,"name":"Fernanda Bono Fukushima","email":"","orcid":"","institution":"São Paulo State University (UNESP)","correspondingAuthor":false,"prefix":"","firstName":"Fernanda","middleName":"Bono","lastName":"Fukushima","suffix":""},{"id":452128963,"identity":"8ec4daff-29b9-11f0-91e4-06cc9d20a69f","order_by":5,"name":"Cristiano de Pádua Souza","email":"","orcid":"","institution":"Barretos Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cristiano","middleName":"de Pádua","lastName":"Souza","suffix":""},{"id":452129018,"identity":"98c00783-29b9-11f0-91e4-06cc9d20a69f","order_by":6,"name":"Edison Iglesias de Oliveira Vidal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYFCCxAYwxcaQwHjgAwOUTawWhoMziNOSgGAc5iFGCz97cvOHjzsYEvvYkx8ctm27Iyc/u4HtcQUeLZI9D9skZ55hSGzjeWZwOLftmbHBnQPshmfwaDG4kdjGzNvGYMwmkQDScjhxg0QCm2QDHi32NxKbP0O0pH84bNl2uH7+DAJaDCQSG6SBWuTYJHIMDjO2HU5guEFAi8QZkF/aJOTYeN4UHOw5d9hww52D7Yb4tPC3pz/+8LHNhke+PX3jgx9lh+XlZzcfe4hPC8wyZDYjERpwax8Fo2AUjIJRAAQAjbFP1z+EGjAAAAAASUVORK5CYII=","orcid":"","institution":"São Paulo State University (UNESP)","correspondingAuthor":true,"prefix":"","firstName":"Edison","middleName":"Iglesias de Oliveira","lastName":"Vidal","suffix":""}],"badges":[],"createdAt":"2024-06-17 09:07:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4593019/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4593019/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-14468-3","type":"published","date":"2025-08-21T16:29:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82144870,"identity":"93a483c4-db6a-4a50-84df-167f8e5bf568","added_by":"auto","created_at":"2025-05-07 06:48:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1725235,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of included studies in the scoping review\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/e87aadfa130c162c6806a040.jpg"},{"id":82144871,"identity":"5e33ca49-aa5d-4132-8e26-63f821188ad0","added_by":"auto","created_at":"2025-05-07 06:48:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1750004,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of the Studies Included in the Scoping Review According to Phenotypes, Stages of Breast Cancer, Treatment Modalities, and Status of Publication Results\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/dc294b34ba4ec558656425ba.jpg"},{"id":82143152,"identity":"290e80b2-6c67-4c5d-b496-1d601e961ec1","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1964511,"visible":true,"origin":"","legend":"\u003cp\u003eClinical and Nonclinical Outcomes in Studies Involving Mixed Breast Cancer Phenotypes\u003c/p\u003e\n\u003cp\u003eBCR = breast conservation rate; CBR = clinical benefit rate; cCr = clinical complete response; CRP = C-reactive protein; DFS = disease free survival; DRFS = distant recurrence–free survival; DIN= ductal intraepithelial neoplasia; ER = estrogen receptor; FBG = fasting blood glucose; HbA1c = glycated hemoglobin; HER2 = human epidermal growth factor receptor 2; HOMA-IR = homeostatic model assessment for insulin resistance; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; IDFS = invasive desease-free survival; LIN = lobular intraepithelial neoplasia; ORR = objective response rate; pPR = partial pathological response; pCR = pathological complete response; PgR = progesterone receptor; RRR = radiological response rate; RR = response rates; SHBG = sex hormone-binding globulin.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/b30a0e1dee44cf9c55a370e9.jpg"},{"id":82143154,"identity":"71a704f4-8f60-4087-97b7-c1ddacd0a2c0","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1976440,"visible":true,"origin":"","legend":"\u003cp\u003eResults for overall survival, disease-free survival, progression-free survival, and objective response rate according to phenotype, breast cancer stage, and treatment modality adopted from primary studies.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e# \u003c/sup\u003ePositive for HER2+ phenotype only.\u003c/p\u003e\n\u003cp\u003e* Included other types of cancer in addition to breast cancer.\u003c/p\u003e\n\u003cp\u003e** In the published article, the authors presented data on the frequency of partial response, stable disease and disease progression. However, they did not present complete response or partial response analyses of the overall response rate (ORR)\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/f414dd102a4ea636151b8b74.jpg"},{"id":82144873,"identity":"9fa68207-4228-488e-a3f7-519f9aa49819","added_by":"auto","created_at":"2025-05-07 06:48:30","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1874985,"visible":true,"origin":"","legend":"\u003cp\u003eResults for the Clinical Benefit Rate, Pathological Complete Response, Breast Conservation Rate, and Quality of Life Outcomes According to Phenotype, Breast Cancer Stage, and Treatment Modality Adopted by Primary Studies\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/55334dac474b341280abd46d.jpg"},{"id":89847827,"identity":"5017fa43-5624-435c-a22f-e737ad332fa0","added_by":"auto","created_at":"2025-08-25 16:44:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10536359,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/0bfe8e46-a992-48df-9ba3-3c634638a789.pdf"},{"id":82146572,"identity":"7ec92c9e-ff82-4b14-be96-af16b6ccfb32","added_by":"auto","created_at":"2025-05-07 06:56:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":123825,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/cac8dc4ff4c9f3d21f59c77e.docx"},{"id":82144869,"identity":"92c9006c-3580-45bc-8074-891c62c20f0f","added_by":"auto","created_at":"2025-05-07 06:48:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":31371,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/9e585774eeb25929f7886df1.docx"},{"id":82143148,"identity":"c71633cb-842f-4b3a-9724-f59a35cd599e","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":26278,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement1SearchStrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/24054262ec05ddcdee6517ea.docx"},{"id":82143150,"identity":"7ac41056-6419-4b82-b85a-c08c366db893","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":26992,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement2PRISMAScRChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/b8b4bf27992098d91a607e78.docx"},{"id":82143155,"identity":"29e5701b-7afa-46b0-99e7-06f7dc884e90","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":33106,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement3ExcludedReports.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/798e8ad6943f3e7933bc63bf.docx"},{"id":82143157,"identity":"529a9958-56a9-425b-a258-41b7a4cdc460","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":42411,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement4StudiesWITHOUTRESULTS14out23.docx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/fc9eedd7bb688f07d78bfe1d.docx"},{"id":82143158,"identity":"3cb7e969-4820-43f1-8923-5016d81a13b6","added_by":"auto","created_at":"2025-05-07 06:40:30","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":70647,"visible":true,"origin":"","legend":"","description":"","filename":"Supplment5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4593019/v1/c9e35d8c62272a7144a48245.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAccording to the most recent Global Cancer Statistics report, female breast cancer was the second leading cancer worldwide in 2022, accounting for 11.6% of all cancer cases, an estimated 2.3 million new cases, and 666,000 deaths[1]. Breast cancer accounts for approximately one in four cancer cases and one in six cancer deaths among women in the world. In addition, there are predictions for the year 2040 that the burden of breast cancer will increase to more than 3 million new cases and 1 million deaths every year due to population growth and aging alone[2].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBreast cancer treatments are expensive, and chemotherapy treatments are associated with major toxicity. In the USA, breast cancer has the highest treatment cost of any cancer, accounting for 14% of all cancer treatment costs[3]. In 2020, the cost of medical services for breast cancer patients was $26.2 billion, with an additional $3.5 billion spent on prescription drugs. Furthermore, chemotherapy is a common treatment for breast cancer and has been shown to improve survival. However, it often leads to adverse effects, including nausea, dysgeusia, peripheral neuropathy, loss of appetite, myalgia, and peripheral edema, which can significantly impact various aspects of quality of life[4].\u0026nbsp;Due to the high cost and toxicity associated with various treatments, less aggressive and more affordable breast cancer treatments are desirable.\u003c/p\u003e\n\u003cp\u003eMetformin is one of the most common medications used worldwide and has been used for more than 60 years because of its efficacy and safety[5]. It is a synthetic biguanide often prescribed as the first-line drug to treat type 2 diabetes mellitus (T2DM). In addition, it is an extremely inexpensive medication, costing approximately 15 cents per tablet[5]. Currently, it is used daily by more than 200 million diabetic patients around the world as monotherapy or in combination with other medications. Nevertheless, the precise mechanisms responsible for its therapeutic benefits are still not fully understood[6].\u003c/p\u003e\n\u003cp\u003eThere are several public health interests in the repurposing of generic drugs for new therapeutic targets, as it represents a unique and cheaper strategy of innovation with several advantages compared with the long and costly process of developing new drugs from scratch[7]. With their initial indication, generic drugs have already passed all the phases required by regulatory agencies to be approved for commercialization. They have well-established pharmacodynamic and pharmacokinetic profiles with well-mapped adverse effects.\u003c/p\u003e\n\u003cp\u003eOver the past decades, besides treating T2DM, several other beneficial effects of metformin have been identified, such as preventing diabetes, and treating polycystic ovarian syndrome[8]. Importantly, metformin has shown promising effects against certain types of cancers and is being investigated in several studies, including observational studies[9], \u003cem\u003ein vitro\u003c/em\u003e and/or \u003cem\u003ein vivo\u0026nbsp;\u003c/em\u003eexperimental studies[10], and clinical trials[11].\u003c/p\u003e\n\u003cp\u003eThe number of Randomized Clinical Trials (RCTs) of metformin for the treatment of breast cancer has been growing, but the landscape of this field remains unclear[12]. Moreover, breast cancer is a heterogeneous disease with great variation in its morphological and molecular characteristics, as well as in its clinical response. Furthermore, different stages of breast cancer are associated with distinct treatment modalities, which are associated with a variety of specific outcomes.\u003c/p\u003e\n\u003cp\u003eImportantly, a recent systematic review attempted to assess the evidence from RCTs on the effectiveness of metformin in the treatment of breast cancer[11]. However, that study was restricted to a limited range of outcomes and did not consider the different phenotypes, stages of breast cancer, or treatment modalities examined in the original studies. These factors are central to the appropriate interpretation of the effectiveness of any breast cancer treatment.\u003c/p\u003e\n\u003cp\u003eTo date, metformin does not have an established role in breast cancer therapy. Given the sources of clinical heterogeneity underlying breast cancer and the many clinical trials conducted or planned to be initiated in this field, a scoping review is needed to show the extent of the landscape of existing studies and inform future directions and opportunities for research. Therefore, our goal with this scoping review was to map the literature on RCTs of metformin for the treatment of breast cancer.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch2\u003e2.1\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Registration of the scoping review protocol\u003c/h2\u003e\n\u003cp\u003eThis scoping review was conducted according to the recommendations of the Joanna Briggs Institute guidance for systematic scoping reviews[13]. We registered the protocol with the Open Science Framework[14] (osf.io/yquba), and we published it elsewhere[15].\u003c/p\u003e\n\u003ch2 id=\"_Toc149558019\"\u003e2.2\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Scoping review questions\u003c/h2\u003e\n\u003cp\u003eWe pursued answers to the following research questions:\u003c/p\u003e\n\u003cp\u003e1. What is the extent of the randomized clinical trials literature on the use of metformin in the treatment of breast cancer?\u003c/p\u003e\n\u003cp\u003e2. What phenotypes and stages of breast cancer were examined in those studies?\u003c/p\u003e\n\u003cp\u003e3. What treatment modalities, regimens, and comparators were used in those studies?\u003c/p\u003e\n\u003cp\u003e4. What outcomes were evaluated in those studies and what were their main findings?\u003c/p\u003e\n\u003ch2 id=\"_Toc149558020\"\u003e2.3\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Eligibility criteria\u003c/h2\u003e\n\u003cp\u003eWe delineated the eligibility criteria following the ‘population, concept, and context’ (PCC) framework.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558021\"\u003e2.3.1\u0026nbsp; \u0026nbsp;Population\u003c/h3\u003e\n\u003cp\u003eWe included 18-year-old adult patients of both sexes with any phenotype and stage of breast cancer. We considered the reports to belong to the same study when the investigated population was the same. We considered those studies that used a subset of the population of a larger study as substudies.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558022\"\u003e2.3.2\u0026nbsp; \u0026nbsp;Concept\u003c/h3\u003e\n\u003cp\u003eWe accepted RCTs that included any intervention for treating breast cancer using metformin. Regarding the unit of randomization of the trials, we included both individuals and clusters of individuals in the population. We included trials in which patients were treated with metformin either alone or in combination with other systemic pharmacological treatments (e.g., hormone therapy or chemotherapy), local radiological treatments, surgical procedures, or behavioral interventions such as weight loss, exercise training, or nutritional interventions.\u003c/p\u003e\n\u003cp\u003eWe included studies that used a placebo, standard treatment, or other behavioral interventions as long as they did not include metformin as a comparator/control. Those studies involving the use of metformin combined with other treatments must include a comparator using the same treatments without metformin so that the drug effect could be identified. For those studies that investigated metformin alone, we also included control groups with no treatment. We did not limit the outcomes evaluated in the selected studies. Specifically, we intended to map the outcomes of the clinical trials that proposed the use of metformin for breast cancer treatment.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558023\"\u003e2.3.3\u0026nbsp; \u0026nbsp;Context\u003c/h3\u003e\n\u003cp\u003eThere were no restrictions related to the context, language, or date of publication of the studies identified to be included in the scoping review.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558024\"\u003e2.4\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Literature Search\u003c/h2\u003e\n\u003cp\u003eOn April 2021, we searched the following databases for potential studies: MEDLINE through PubMed, EMBASE, LILACS, Web of Science, and CENTRAL. The electronic search strategies are shown in \u003cstrong\u003eSupplement 1\u003c/strong\u003e. Additionally, we conducted a gray literature search in two databases: the System for Information on Grey Literature in Europe (OpenGrey) and the National Library of Medicine Bookshelf.\u003c/p\u003e\n\u003cp\u003eIn addition to looking for relevant studies in databases, we also searched some registers. We screened ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP).\u003c/p\u003e\n\u003cp\u003eWe further extended our search efforts through other methods. We searched websites via Google Scholar, and we also hand-searched reference lists of relevant publications, conference abstract books, and specialist referrals.\u003c/p\u003e\n\u003cp\u003eFinally, during the analysis of the data in this review, we updated our search for references in September 2023 and verified whether the results of ongoing studies included in this review had already been published.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558025\"\u003e2.5\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Selection of studies\u003c/h2\u003e\n\u003cp\u003eThe study selection process followed careful identification steps. First, two researchers (CFMA and LCN) independently screened and reviewed the titles and abstracts of all records indexed in the databases using Rayyan software[16]. Second, they separately examined the full versions of the selected records from the first step. Third, the reviewers independently selected the first 200 results found via Google Scholar through Publish or Perish software[17] and screened them using the Rayyan software again. Finally, the investigators hand-searched the included reports as they extracted data for the review. A third reviewer (EIOV) resolved any disagreements that arose between the first two reviewers during the process.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558026\"\u003e2.6\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Data charting process\u003c/h2\u003e\n\u003cp\u003eWe developed a data extraction form to collect information from the included studies. We subsequently refined the standardized form according to the progress of the data charting process. All the extractions were performed independently and in duplicate by the two reviewers. Disagreements about the extracted data were resolved by discussion and consensus, and an independent third reviewer (EIOV) was consulted when conflicts and doubts persisted. We did not appraise the methodological quality of the included articles in alignment with the methodological expectations for scoping reviews.\u003c/p\u003e\n\u003cp\u003eExtracted data included: first author; study title; reports used for the data extraction; complete reference; is this a secondary report from a larger study? ; the time period when the study was conducted; the geographical location where the study took place; study design; is the study protocol available? ; type and frequency of breast cancer phenotypes, type and frequency of histological subtypes, type and frequency of other genetic characteristics (e.g. single nucleotide polymorphisms [SNP]); type and frequency of breast cancer stage under investigation; were other types of cancer included?; inclusion/exclusion criteria; sample size; characteristics of the population (e.g., mean age, mean Body Mass Index (BMI), frequency of obesity/overweight, menopause, physical activity, presence of comorbidities such as diabetes, hypertension, hyperlipidemia, and metabolic syndrome, frequency of treatment line chemotherapy provided in palliative care); details of the interventions, including treatment modality (i.e., neoadjuvant or adjuvant; palliative, or unclear), metformin dose, frequency and duration of metformin treatment, cointerventions; details of comparators, including type, dose, frequency, and duration; follow-up; outcome measures with the definitions used by the study authors; statistical analyses; results; adverse events; conclusions reported by the study authors; research limitations; funding sources; and references cited in studies’ reports to be evaluated for possible inclusion in our review. In addition, there was a field for free registration of other information deemed relevant by the reviewers.\u003c/p\u003e\n\u003cp\u003ePublished articles with results were chosen to guide the full filling of extraction forms because they show the most recent and complete data related to the study. Reports such as study protocols and conference abstracts supported the charting of the data. Commonly, researchers make the results of their studies available in more than one article. To better organize one study’s data that are spread across multiple published articles, we filled out one form per article with results. When no published articles reported the results of included studies, we used data from study protocols and/or abstracts presented in conference proceedings to complete the extraction forms.\u003c/p\u003e\n\u003cp\u003eWe stored the data extracted from each study in digital word-processing documents. At the same time, we organized the same data in digital spreadsheets in a summarized format while filling out the standardized forms. This approach facilitated a comprehensive overview of all studies and allowed for effective data synthesis.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558027\"\u003e2.7\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Collating, summarizing, and reporting the results\u003c/h2\u003e\n\u003cp\u003eWe structured the presentation of our results around the different phenotypes of breast cancer, their stages, treatment modalities, types of interventions with metformin, comparators, outcomes evaluated in the primary studies, and their main findings. Because none of the studies whose population was restricted to participants with estrogen and/or progestogen receptor positive breast cancer presented their results separated by Luminal A and B phenotypes, we presented those studies under a single Luminal phenotype category. We constructed figures to present the results of the most relevant clinical outcomes evaluated by more than one included study. For these figures, we adopted the criterion of signaling statistically significant results favoring either the metformin group or the control group if at least one aspect of the outcome assessed by the study was positive. For example, if a significantly better overall survival (OS) was observed for patients with the HER2+ phenotype of breast cancer taking metformin in comparison to placebo, but no difference was observed for patients with other phenotype subgroups, the OS outcome was marked as favoring the metformin group for that study in the figure dedicated to that specific outcome.\u003c/p\u003e\n\u003cp\u003eThe reporting of results was guided by the PRISMA-ScR statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews)[18]. Our PRISMA-ScR checklist comprising our review is available in \u003cstrong\u003eSupplement 2\u003c/strong\u003e.\u003c/p\u003e"},{"header":"3. Results","content":"\u003ch2\u003e3.1\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Selection of studies and reports\u003c/h2\u003e\n\u003cp\u003eWe identified 40 studies based on eligibility criteria outlined by our PCC framework. Our searches identified 122 reports related to the 40 studies that were included in the scoping review after screening titles and abstracts and examining full versions of potentially relevant studies. Figure 1 outlines the flowchart for inclusion of reports in this review[19]. \u003cstrong\u003eSupplement 3\u0026nbsp;\u003c/strong\u003elists the reports that were evaluated in full and excluded from databases, the ICTRP, and Google Scholar, along with the reasons for their exclusion. The reasons for exclusion were based on incompatibilities with our previously mentioned eligibility criteria. These included duplicate studies, incorrect study designs, mismatched populations, and incorrect comparators.\u003c/p\u003e\n\u003ch2\u003e3.2\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Nature of reports\u003c/h2\u003e\n\u003cp\u003eOf the 122 reports, 39 were full articles, 42 were protocols, 37 were conference abstracts, two were statistical analysis plans (SAP), only one was a thesis related to the study with the protocol number EudraCT 2007-000306-70[20], and only one was a feasibility study whose results were available in the European Union Clinical Trials Registry (EUCTR)\u0026nbsp;[21]. In addition, our review encompassed four large studies, each of which included several substudies: the\u0026nbsp;MYME Trial[22, 23], the METTEN Trial[24–27], the NCIC CTG MA.32 (National Cancer Institute of Canada - Clinical Trials Group MA.32)[28–34], and a trial with the protocol number EudraCT number 2008-004912-10[35–38].\u003c/p\u003e\n\u003ch2\u003e3.3\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Availability of studies’ results\u003c/h2\u003e\n\u003cp\u003eThe dissemination of results from the included studies exhibited a heterogeneous and often incomplete pattern. Out of the 40 identified studies, 25 had some form of published results, with 19\u003csup\u003e[26,28,32,39, 43–57]\u003c/sup\u003e of them appearing as full articles and six[21, 54–58]\u0026nbsp;having results published solely in the form of conference abstracts. In contrast, 15 of the included studies did not have published results; for 11 of them, only their protocols were available[59–69],\u0026nbsp;and four were terminated prematurely without their results being published[70–73].\u003c/p\u003e\n\u003cp\u003eIn addition, the characteristics of the included studies with published results are available in \u003cstrong\u003eTable 1\u003c/strong\u003e. Similarly, the characteristics of the included studies without published results are available in \u003cstrong\u003eSupplement 4\u003c/strong\u003e.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558032\"\u003e3.4\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Breast cancer and other tumors\u003c/h2\u003e\n\u003cp\u003eOf the 40 clinical trials included, 35 focused exclusively on patients with breast cancer, while five[50–52, 59, 62]\u0026nbsp;included participants with multiple types of cancer. Two of these trials[59, 62]\u0026nbsp;were available only in the form of a conference abstract and a trial registry without results or detailed research protocols. Although the other three studies[50–52]\u0026nbsp;published their results, they did not report them separately by type of cancer.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558033\"\u003e3.5\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;General characteristics of participants from the included studies\u003c/h2\u003e\n\u003cp\u003eIn total, the 25 studies with published results focused on individuals with breast cancer and included 5,623 participants. The participant counts ranged from 40 to 3,649 (median 73 and interquartile range [IQR] 51 to 121). While most studies involved female participants, four studies[28, 52, 59, 73]\u0026nbsp;included both men and women with breast cancer in their samples, with the majority comprised by women.\u003c/p\u003e\n\u003cp\u003eThe three studies[50–52], which included individuals with multiple types of cancer and had some form of published results, did not offer separate data for the 176 patients with breast cancer.\u003c/p\u003e\n\u003cp\u003eThe total population enrolled in the four studies[70–73] that were terminated without publishing their results was 244 patients. Finally, the total number of participants planned to enroll according to the research protocols of ongoing studies[59–69] was 2,090.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558034\"\u003e3.6\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The distribution of comorbidities among participants in the included studies\u003c/h2\u003e\n\u003cp\u003eThe level of reporting on participants’ comorbidities in the included studies was heterogeneous. The most frequently reported comorbidities included obesity, overweight status, hypercholesterolemia, hypertension, diabetes, prediabetes, and metabolic syndrome.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558035\"\u003e3.6.1\u0026nbsp; \u0026nbsp;Obesity/overweight\u003c/h3\u003e\n\u003cp\u003eLiubota’s trial[43]\u0026nbsp;was the only study in which all participants were obese (BMI \u0026gt; 30). In three other studies[41, 48, 51], participants were either overweight or obese (BMI \u0026gt; 25). In contrast, the METTEN Trial\u0026nbsp;[24]\u0026nbsp;was the only study that excluded any potential participants with a BMI above 30. For the remaining studies with published results\u0026nbsp;[22, 45, 47, 54, 58],\u0026nbsp;the prevalence of overweight and/or obesity among participants ranged from 13% to 43%. Fifteen studies[20, 21, 28, 39, 40, 42, 44, 46, 47, 50, 52, 55–58]\u0026nbsp;did not report any data on that characteristic of their samples.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558036\"\u003e3.6.2\u0026nbsp; \u0026nbsp;Diabetes and prediabetes\u003c/h3\u003e\n\u003cp\u003eOf the 25 studies with published results, 18[20–22, 24, 28, 35, 40, 42, 44, 45, 47, 50, 53–58]\u0026nbsp;exclusively recruited participants without diabetes. Five[39, 43, 46, 48, 52]\u0026nbsp;of these studies did not provide information about the diabetes status of their samples. Only two studies did not exclude participants with diabetes or prediabetes. In one study[41], 1% of participants had diabetes, while in the\u0026nbsp;other study[51], 17% of participants had prediabetes.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558037\"\u003e3.6.3\u0026nbsp; \u0026nbsp;Metabolic syndrome\u003c/h3\u003e\n\u003cp\u003eAmong the studies reviewed, only three[35, 43, 54]\u0026nbsp;provided data regarding the frequency of metabolic syndrome among their participants. Notably, one[43]\u0026nbsp;of these studies exclusively included participants with metabolic syndrome. In the remaining two[35, 54]\u0026nbsp;studies, the prevalence of metabolic syndrome among participants ranged from 26% to 58%. It is worth noting that 22[20–22, 24, 28, 39–42, 44–48, 50–53, 55–58]\u0026nbsp;of the studies did not include any data related to this particular characteristic of their samples.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558038\"\u003e3.6.4\u0026nbsp; \u0026nbsp;Menopause status\u003c/h3\u003e\n\u003cp\u003eAmong the 25 studies with published results, one study[47]\u0026nbsp;exclusively involved a postmenopausal population. Additionally, five studies[21, 42, 46, 48, 57]\u0026nbsp;specifically focused on postmenopausal women. Ten studies[22, 24, 28, 35, 39, 41, 43–45, 49]\u0026nbsp;examined a mixed population, encompassing pre, peri-, and postmenopausal women. Moreover, nine studies[40, 50–56, 58]\u0026nbsp;did not provide information about the menopausal status of the participants.\u003c/p\u003e\n\u003ch2\u003e3.7\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Characteristics of breast cancer\u003c/h2\u003e\n\u003ch3 id=\"_Toc149558040\"\u003e3.7.1\u0026nbsp; \u0026nbsp;Histological type\u003c/h3\u003e\n\u003cp\u003eOnly five studies[35, 39, 41, 43, 49]\u0026nbsp;provided information on the frequencies of histological types of breast cancer among their participants. In these studies, the frequencies of ductal, lobular, mixed, or other histological types ranged from 3% to 90%, 4% to 10%, 3% to 8%, and 3% to 3.5%, respectively.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558041\"\u003e3.7.2\u0026nbsp; \u0026nbsp;Breast cancer phenotype\u003c/h3\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e presents an overview of the studies included in the scoping review according to four aspects: phenotypes, stages of breast cancer, treatment modalities, and status of publication results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe reporting of breast cancer phenotypes varied considerably among the 25 studies with published results. Six studies[21, 42, 50–52, 56] did not mention the phenotypic classification of breast cancer. Five studies[20, 46, 47, 54, 57] explicitly included only participants with the luminal phenotype. A single study[24], consisting of three substudies[25–27], included only HER2+ breast cancer patients. Thirteen studies[22, 28, 35, 39–41, 43–45, 48, 53, 55, 58] included participants with mixed phenotypes. In this group, the frequencies of luminal, HER2+, and triple-negative phenotypes ranged from 62% to 84%, 6% to 40%, and 9% to 12%, respectively. Six mixed studies[22, 28, 35, 44, 53, 58] only provided information about the frequency of the hormonal and HER2 receptors of breast cancers in isolation, without explicitly determining the frequency of each phenotype.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3\u003c/strong\u003e illustrates the clinical and nonclinical outcomes of the 13 studies involving mixed breast cancer phenotypes. While all of these studies traditionally presented results according to intervention arms, six studies[28, 35, 39–41, 45] segmented some outcome results by subgroups based on phenotypes, receptors, or stages of breast cancer. Ahmed’s study[39] provided pathological complete response (pCR) results according to phenotypes, and Bonanni’s study[35] reported ki67 results for the luminal phenotype. Six studies [28, 38–41, 45] reported relevant clinical outcomes, such as pCR, objective response rate (ORR), invasive disease–free survival (IDFS), and overall survival (OS), according to hormone and HER2 receptor subgroups. Finally, two studies[40, 45] reported results for clinical and nonclinical outcomes based on subgroups of breast cancer stages.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558042\"\u003e3.7.3\u0026nbsp; \u0026nbsp;Stages of breast cancer\u003c/h3\u003e\n\u003cp\u003eThe stages of breast cancer investigated were also heterogeneous among the 25 studies with some published results (Figure 2). Two studies[20, 35]\u0026nbsp;included participants with stages I and II disease. Six studies[28, 40–42, 48, 50]\u0026nbsp;included participants with breast cancer stages ranging from I to III. Six other trials[24, 43, 45, 55, 57, 58]\u0026nbsp;included patients with stages II to III disease. Three studies[39, 47, 54]\u0026nbsp;included only stage III patients. One study[44]\u0026nbsp;involved a stage interval from IIa to IV. Three studies[22, 46, 53]\u0026nbsp;were restricted to participants with stage IV breast cancer. Finally, four studies[21, 51, 52, 56]\u0026nbsp;did not provide any information regarding the stage of breast cancer among their participants.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558043\"\u003e3.8\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Interventions and Comparators\u003c/h2\u003e\n\u003cp\u003eThe RCTs included in this review examined metformin as a standalone intervention or in combination with various oncological treatments, employing a variety of comparators.\u0026nbsp;The dosages of metformin investigated in these trials ranged from 850 mg to 2550 mg per day.\u003c/p\u003e\n\u003cp\u003eOf the 25 studies with published results, four trials[28, 35, 41, 42]\u0026nbsp;administered metformin as a single intervention and compared it with placebo. In Sadighi's study[56]\u0026nbsp;and the NeoMet Trial[49], metformin was given to participants in the experimental group, while the participants in the control group received no medication.\u003c/p\u003e\n\u003cp\u003eFurthermore, among the same set of studies, three trials[48, 50, 51]\u0026nbsp;combined metformin with behavioral interventions such as weight loss or exercise training, aiming to prevent recurrence after cancer treatment. The SPIRIT trial[51]\u0026nbsp;had three intervention arms: metformin alone, coach-directed weight loss, and self-directed weight loss. The Reach for Health trial[48], a 2 by 2 factorial randomized trial, included groups receiving metformin alone and weight loss with metformin interventions and compared them with placebo groups and weight loss with a placebo. Meyerhardt's study[50]\u0026nbsp;compared metformin with training exercises, exercise training alone, and metformin alone, and the results were compared with those of an educational information group without treatment.\u003c/p\u003e\n\u003cp\u003eOf the 25 studies with published results, 16 incorporated metformin in combination with standard care systemic therapy, which could involve chemotherapy, hormone therapy, or a combination of both. Specifically, ten studies[22, 24, 39, 44, 45, 52–55, 58]\u0026nbsp;employed chemotherapy, four[21, 46, 47, 57]\u0026nbsp;used hormone therapy, and two[40, 43]\u0026nbsp;utilized both chemotherapy and hormone therapy.\u003c/p\u003e\n\u003cp\u003eAmong the studies examining chemotherapy, eight[22, 24, 39, 44, 45, 52, 55, 58]\u0026nbsp;combined metformin with various chemotherapy regimens and compared them to chemotherapy alone. Two studies[53, 54]\u0026nbsp;administered metformin in conjunction with chemotherapy and compared it with the same chemotherapy plus a placebo.\u003c/p\u003e\n\u003cp\u003eAmong the studies evaluating hormone therapy, two[21, 47]\u0026nbsp;combined metformin with hormone therapy and compared it with hormone therapy without metformin. For Semiglazova's three-arm trial comparing metformin plus toremifene vs. toremifene alone and toremifene plus melatonin, we considered only the arms with metformin and its control for our review. Two studies[46, 57]\u0026nbsp;combined metformin with hormone therapy, specifically an aromatase inhibitor, and compared it with the same hormone therapy plus a placebo.\u003c/p\u003e\n\u003cp\u003eFinally, among two studies[40, 43]\u0026nbsp;that tested both chemotherapy and hormone therapy in conjunction with metformin, the control groups underwent the same interventions without metformin. In El-Haggar's study[40], metformin was tested in combination with chemotherapy and hormone therapy as adjuvant systemic therapy. In Liubota's study[43], both systemic therapies were applied as neoadjuvant treatments, with some patients receiving four cycles of anthracycline-based chemotherapy on three-week schedules and postmenopausal patients with luminal breast cancer receiving hormone therapy (letrozole 2.5 mg per day) for 16 weeks.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558044\"\u003e3.8.1 Treatment Modalities\u003c/h3\u003e\n\u003cp\u003eMetformin was examined in various treatment modalities across the studies included in this review (Figure 2). Of the 25 studies with published results, twelve[24, 35, 39, 43, 45, 47, 49, 54–58]\u0026nbsp;included metformin as a neoadjuvant treatment for breast cancer, while nine[21, 28, 40-42, 48, 50-52] incorporated it as an adjuvant treatment. Additionally, three studies[22, 46, 53]\u0026nbsp;utilized metformin for palliative care. Finally, In one specific study[44], the treatment modality for investigating metformin in combination with standard chemotherapy was unclear.\u0026nbsp;\u003c/p\u003e\n\u003ch3 id=\"_Toc149558045\"\u003e3.8.1.1\u0026nbsp; \u0026nbsp; \u0026nbsp;Use of metformin in the context of palliative treatment\u003c/h3\u003e\n\u003cp\u003eOf the three studies that incorporated metformin into palliative breast cancer treatment, only the MYME Trial[22]\u0026nbsp;and its substudy, TransMYME[23], explicitly stated the use of 100% first-line chemotherapy. In the other two studies involving participants with stage IV breast cancer receiving palliative oncological treatment, one[46]\u0026nbsp;combined metformin with first-, second-, and third-line or subsequent treatments in 22 (36.7%), 35 (58.3%), and 3 (5.0%) of their patients, respectively. Another study[53]\u0026nbsp;combined metformin with first-, second-, and third-line or subsequent treatments in 27 (67.5%), 7 (17.5%), and 6 (15%) of the participants, respectively.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558046\"\u003e3.9\u0026nbsp; \u0026nbsp; \u0026nbsp;Outcome Measures and Main findings\u003c/h2\u003e\n\u003cp\u003eOverall, among the 25 included studies with published results, the most frequently reported outcomes were toxicity, pathological complete response (pCR), objective response rate (ORR), clinical benefit rate (CBR), and insulin levels. \u003cstrong\u003eTable 2\u003c/strong\u003e provides a list of clinical, nonclinical, and miscellaneous outcome\u0026nbsp;measures evaluated by all 40 studies included in this review. Similarly, \u003cstrong\u003eSupplement 5\u003c/strong\u003e includes three spreadsheets where readers may find a list of the outcome measures examined by each study according to the breast cancer phenotype, stage, and treatment modality of their samples. The first tab compiles the clinical outcomes mapped in the trials included in the scoping review, with survival outcomes presented initially, as they hold the utmost significance for patients with breast cancer. The second tab organizes nonclinical outcomes assessed in the trials by categories. The final tab consolidates other nonclinical outcomes that do not fit into any specific category.\u003c/p\u003e\n\u003cp\u003eClinical outcomes, including survival, quality of life, and cancer response rates, deserve special attention because they are considered the most important from the patients’ perspective. Therefore, we emphasize the presentation of results related to those outcomes in our narrative synthesis and figures.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558047\"\u003e3.9.1 Overall Survival (OS)\u003c/h3\u003e\n\u003cp\u003eOS, defined as the time from randomization to death, is considered the ‘gold standard’ primary clinical endpoint in oncology[74].\u0026nbsp;\u003cstrong\u003eFigure 4A\u003c/strong\u003e depicts the mapping of the nine studies[22, 28, 43, 44, 46, 53, 68, 71, 75] that evaluated OS according to the phenotype, stage and treatment modality of breast cancer, as well as the publication status of their results concerning that outcome. Six[22, 28, 43, 44, 46, 53] of those nine studies had published results. Only one of those studies [28] showed improved survival among participants treated with metformin. Importantly, that effect was observed only among HER2+ participants (Hazard Ratio [HR] = 0.54; 95% CI: 0.30-0.98; P = 0.04) and not among participants with luminal breast cancer or the overall group of participants with mixed phenotypes.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.9.2 Disease-free survival (DFS)\u003c/h3\u003e\n\u003cp\u003eSeven studies[24, 28, 39, 40, 43, 62, 75]\u0026nbsp;included DFS, defined as the time from randomization to disease recurrence[74], among their outcome measures. As shown in\u0026nbsp;Figure 4B,\u0026nbsp;four[28, 39, 40, 43]\u0026nbsp;of those seven studies had published results, and all of them included participants with mixed phenotypes. In two[28, 40]\u0026nbsp;of them, there was some evidence of improvement in DFS among participants treated with metformin. Goodwin’s study[28]\u0026nbsp;revealed improved DFS among HER2+ participants (HR = 0.64; 95% CI: 0.43-0.95; P = 0.03) but not among participants with other phenotypes or the overall group of participants. In the study by El-Haggar[40], which did not present DFS results for specific phenotypes, metformin treatment was associated with an average increase in DFS of approximately two months (log rank test, p = 0.044) and a hazard ratio of 0.31 (95% CI: 0.11-0.86, P = 0.023), favoring the metformin group for that same outcome in a statistical model adjusted for age, tumor stage, adjuvant chemotherapy, and estrogen and HER2 receptor status.\u003c/p\u003e\n\u003ch3\u003e3.9.3 Progression-free survival (PFS)\u003c/h3\u003e\n\u003cp\u003ePFS is defined as the time from randomization to disease progression or death[74]. Seven studies[22, 44, 46, 52, 53, 62, 71]\u0026nbsp;reported PFS (Figure 4C). Four studies[22, 44, 46, 53]\u0026nbsp;out of those seven had some published results, all of which were negative. One of those studies[46]\u0026nbsp;included only participants with luminal breast cancer, whereas the other three\u003csup\u003e[26,48,57]\u003c/sup\u003e included people with mixed phenotypes. Although PFS is an outcome used to assess therapies targeting advanced or metastatic malignancies[74], we noticed that one[44]\u0026nbsp;of those four studies included participants with earlier stages of breast cancer in addition to metastatic disease. The same issue occurred with a study with unpublished results[62]. Notably, Saif’s study[52], which included participants with 16 different cancers, did not provide results specific to patients with breast cancer in its published article. Furthermore, although that study claimed to have evaluated PFS using the Kaplan‒Meier method, such results were not presented in the publication.\u003c/p\u003e\n\u003ch3\u003e3.9.4 Objective response rate (ORR)\u003c/h3\u003e\n\u003cp\u003eORR is an outcome primarily used to assess neoadjuvant therapies and is defined as the proportion of patients who achieve a partial or complete response to therapy[74]. Fifteen studies[22, 39, 43–47, 54, 57, 58, 68–71, 75]\u0026nbsp;evaluated ORR among their outcome measures (Figure 4D). Eight[22, 39, 43, 45–47, 57, 58]\u0026nbsp;of those 15 studies had published results, and only one[43]\u0026nbsp;of them was positive. In that study, which included patients with mixed phenotypes and stages II-A to III-C breast cancer treated with neoadjuvant chemotherapy, the authors found that 28 (77.5%) out of 36 participants in the metformin arm achieved either a complete or partial response, in contrast to 9 (25%) out of 36 participants in the control arm (p\u0026lt;0.05). Notably, of the eight studies with published results, five[22, 39, 43, 45, 58]\u0026nbsp;included participants with mixed phenotypes, and three[46, 47, 57]\u0026nbsp;included participants with the luminal phenotype; the latter of which were all negative.\u003c/p\u003e\n\u003ch3\u003e3.9.5 Clinical benefit rate (CBR)\u003c/h3\u003e\n\u003cp\u003eCBR is defined as the proportion of patients who achieve a complete response, partial response, or stable disease for at least\u0026nbsp;six months[74]. Nine studies[39, 43, 44, 46, 53, 54, 68–70] included the CBR in their outcomes (Figure 5A), and five[39, 43, 44, 46, 53] of them had published results. Only two[43, 44] of those studies reported positive results for that outcome. Both included participants with mixed phenotypes. Liubota’s study[43] included women with stages II to III disease who were receiving neoadjuvant chemotherapy and revealed a statistically significant increase in the proportion of patients with stable disease and complete or partial response (34 [94.5%] out of 36 in the metformin arm vs. 28 [78%] out of 36 in the control group, p\u0026lt;0.05). The study by Salah et al.[44] included 50 participants with stage II to IV breast cancer. Unfortunately, the numbers of participants who experienced partial response or stable disease were reported on a three-dimensional figure, which does not allow the accurate extraction of data. Zhao’s trial[46] was the only study with published results restricted to participants with luminal breast cancer (N = 60). In that study, metformin was added to palliative chemotherapy for women with stage IV breast cancer and was not associated with a significantly different CBR compared with that of the control group.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558052\"\u003e3.9.6 Pathological Complete Response (pCR)\u003c/h3\u003e\n\u003cp\u003epCR is defined as the lack of residual invasive cancer in resected breast tissue or regional lymph nodes[74]. This outcome is commonly used for the accelerated approval of neoadjuvant therapies targeting breast cancer. Eight[24, 39, 43, 45, 47, 54, 55, 58]\u0026nbsp;out of 14 studies[24, 39, 43, 45, 47, 54, 55, 57, 58, 63, 66–68, 70]\u0026nbsp;had some published results on this outcome, and only one[43]\u0026nbsp;of them, which included patients with mixed phenotypes and stage II to III breast cancer, was positive\u0026nbsp;(Figure 5B). In that study, 9 (26.5%) out of 36 patients in the metformin arm achieved pCR, while 2 (6%) out of 36 patients in the control group achieved pCR (p\u0026lt;0.05). Of the remaining negative studies, four[39, 45, 55, 58]\u0026nbsp;involved participants with mixed breast cancer, one[24]\u0026nbsp;was restricted to participants with the HER2+ phenotype, and two[47, 54]\u0026nbsp;focused on patients with luminal breast cancer.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558053\"\u003e3.9.7 Breast Conservation Rate (BCR)\u003c/h3\u003e\n\u003cp\u003eNeoadjuvant systemic therapy for operable breast cancer can increase the options for conservative surgery in patients with breast cancer rather than mastectomy[76]. Six studies[24, 39, 43, 45, 57, 70]\u0026nbsp;included BCR in their outcomes\u0026nbsp;(Figure 5C), and five[24, 39, 43, 45, 57]\u0026nbsp;of them had published results. The only positive result came from Liubota’s study[43], which was already mentioned as the single study with positive ORR and pCR results. In that study, among the 35 participants with surgical indications, breast-conserving surgery was performed on 9 (50%) of the 18 patients in the metformin group and 4 (23.5%) of the 17 patients in the control group (p\u0026lt;0.05).\u003c/p\u003e\n\u003ch3 id=\"_Toc149558054\"\u003e3.9.8 Quality of Life (QoL)\u003c/h3\u003e\n\u003cp\u003eEight studies[28, 45, 47, 53, 58, 59, 72, 75]\u0026nbsp;included QoL among their outcome measures\u0026nbsp;(Figure 5D). Three[45, 47, 53]\u0026nbsp;of those eight studies had published results, and all of them used the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Only Pimentel’s study[53], which included 40 women with metastatic breast cancer with mixed phenotypes, identified a statistically significant difference regarding one of the domains of quality of life evaluated by that instrument. Remarkably, participants in the metformin arm experienced a large worsening of their Global Health Status in comparison with those in the control arm (standardized difference of 0.8, p=0.006). Neither the other domains of quality of life nor the frequency of fatigue, diarrhea, nausea and vomiting, appetite loss, abdominal pain, or other symptoms measured by the EORT-QLC-C30 were significantly different between the two groups in that study.\u003c/p\u003e\n\u003ch3 id=\"_Toc149558055\"\u003e3.9.9 Adverse Events\u003c/h3\u003e\n\u003cp\u003eAmong the 25 studies with published results, 22[21, 22, 24, 28, 35, 39–42, 44–46, 48–57]\u0026nbsp;provided data on adverse events related to metformin compared to control groups, while three[43, 47, 58]\u0026nbsp;did not report adverse events in their trial results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe SNCIC CTG MA.32[28]\u0026nbsp;was the only study in which participants in the metformin arm experienced a greater rate of severe adverse events. In that study, 391 (21.5%) patients in the metformin group and 328 (17.5%) in the placebo group experienced grade 3 or higher adverse events (P=0.003); the most common adverse events of grade 3 or higher included hypertension (2.4% metformin vs 1.9% placebo), irregular menses (1.5% metformin vs 1.4% placebo), and diarrhea (1.9% metformin vs 0.8% placebo). In contrast, in the MYME trial[22]\u003csup\u003e,\u003c/sup\u003e the metformin group experienced a lower frequency of grade 3 or 4 adverse events than did the control group, with 54% vs 72% of patients developing neutropenia, respectively (P=0.019).\u003c/p\u003e\n\u003cp\u003eFor the other 20 studies[21, 24, 35, 39–42, 44–46, 48–57]\u0026nbsp;with published results, metformin was generally well tolerated and the incidence of severe adverse events was not greater in the metformin group than in the control group. However, as expected due to the well-known side effect profile of metformin, several studies have reported a greater rate of less severe (grades 1 and 2) gastrointestinal adverse events, such as diarrhea, associated with this medication.\u003c/p\u003e\n\u003ch2 id=\"_Toc149558056\"\u003e3.10\u0026nbsp; \u0026nbsp;\u0026nbsp;Funding\u003c/h2\u003e\n\u003cp\u003eThirty-four studies[21, 24, 28, 35, 41, 42, 45–52, 54–60, 62–73, 75] were conducted with not-for-profit funding, such as research foundations, governments, and universities. Only two [22, 53] studies had mixed funding sources, including for-profit and not-for-profit funders. The MYME Trial[22] was funded by the Italian Association for Cancer Research (AIRC) and TEVA Pharmaceuticals. In addition, Pimentel’s study[53] was funded by the Breast Cancer Research Foundation, Hold'em for Life Charity, and the contract research organization Ozmosis Research Inc. Three studies[39, 40, 43] did not provide information regarding their sources of funding. Finally, Salah’s trial[44]\u003csup\u003e,\u003c/sup\u003e which also included published results, was the only study in which its authors explicitly stated that it was conducted without sponsorship.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis is the most extensive and comprehensive review of RCTs that evaluated the use of metformin in the treatment of breast cancer. Our results provide insight into the growing body of literature that assesses the impact of metformin on the effectiveness of breast cancer treatment. We categorized existing studies based on breast cancer tumor phenotypes, stages, and possible treatment modalities. To the best of our knowledge, this comprehensive mapping and organization has not been previously undertaken by other studies of a similar nature. This charting effort is essential because it highlights knowledge gaps in the literature, identifying opportunities for new clinical trials and demonstrating the value and scope of further systematic reviews.\u003c/p\u003e\n\u003cp\u003eBased on the findings of this review, we identified the need for the development of methodological guidelines that ensure the clear presentation of breast cancer phenotype-specific data in any new oncological clinical trial in this field. We believe that obtaining trial results from the perspective of cancer phenotypes will make the evidence more relevant to clinical oncology practice, which frequently addresses a variety of breast tumor types. Until the development and implementation of such guidelines becomes a reality, we suggest that researchers explore the possibility of retrospectively ascertaining the phenotypes of participants from previous primary studies. If feasible, this approach has the strategic potential to rapidly generate new phenotype-specific data without incurring the substantial cost of recruiting new patients for novel trials. Furthermore, the accumulation of new phenotype-specific evidence from such retrospective analyses of previously completed clinical trials may be compiled in future systematic reviews. This compilation may provide strong enough evidence to support not only clinical decisions but also regulatory decisions.\u003c/p\u003e\n\u003cp\u003eDespite the variety of phenotypes, outcomes, disease states, treatment modalities, comparators, and publication status, our mapping of the field allows the envisioning of future phenotype- and outcome-specific meta-analyses. For example, there are six studies with published results, five of which involved mixed phenotypes and one focused on the luminal population (Figure 4A), which can be used to conduct a meta-analysis on OS. Additionally, an opportunity exists to evaluate DFS using the METTEN trial[24] results for the HER2+ population and the four studies already published, which involve mixed phenotypes (Figure 4B). Moreover, as previously highlighted, if future systematic reviewers are able to gain access to retrospectively ascertained phenotypes of breast cancer patients enrolled in previous RCTs, better and more meta-analyses would be possible, including performing individual patient data (IPD) meta-analyses taking that kind of information into account through a collaborative effort among researchers in this field.\u003c/p\u003e\n\u003cp\u003eWith regard to opportunities for new clinical trials in this field, our review also allows the identification of relevant knowledge gaps to be addressed. For example, although there are already studies involving neoadjuvant treatment modalities for all breast cancer phenotypes, the landscape is not the same for adjuvant, or palliative studies, as depicted in Figure 2. For example, innovative trials could be proposed to investigate the effectiveness of metformin within adjuvant and palliative treatment modalities in patients with HER2+ and triple-negative breast cancer. There is also a lack of evidence of adjuvant treatment with metformin specifically for the luminal phenotype.\u003c/p\u003e\n\u003cp\u003eWe believe it is essential to propose new RCTs that combine phenotypes that have been poorly explored with the most important outcomes for breast cancer patients. Currently, the METTEN Trial[24] is the only completed trial with published results that investigated neoadjuvant treatment with metformin in patients with the HER2+ phenotype. Additionally, the only other trial involving the same phenotype and treatment modality remains unpublished[66]. Both trials had pCR as the primary outcome. Therefore, we believe there is an opportunity for more neoadjuvant trials that aim to evaluate HER2+ breast tumors, focusing on strategic clinical outcomes such as DFS and BCR. Further evaluation of metformin in patients with HER2+ breast cancer is especially relevant due to the limited evidence from a subgroup analysis of a single large RCT suggesting that it could improve OS and DFS[28].\u0026nbsp;In a similar vein, the BREAKFAST Trial[68]\u0026nbsp;is the only interventional study proposed to investigate the effect of metformin on triple-negative breast cancer treated with a neoadjuvant modality. At the time of our last literature search, its results had not been published yet. As a result, further investigations into this specific phenotype are needed, with a focus on outcomes such as OS, ORR, pCR, BCR, and relapse-free survival.\u003c/p\u003e\n\u003cp\u003eOther relevant gaps in the literature that deserve mention include how treatment with metformin interacts with certain comorbidities and characteristics of participants such as overweight, obesity, metabolic syndrome, menopause status, and their physical activity levels. Such gaps may be addressed by new studies collecting that kind of data, reanalysis of existing data from specific studies, or even by IPD meta-analyses. This is particularly relevant because metformin may be effective among certain groups of people but not others.\u003c/p\u003e\n\u003cp\u003eImportantly, our review offers a map of the landscape of RCT data on metformin for the treatment of breast cancer. It is beyond the scope of our discussion section to outline every possible knowledge gap and research opportunity available in terms of new RCTs or systematic reviews. Experts in this field will be able to use our charting effort to recognize further research gaps and opportunities just as expert travelers are able to devise new paths from triangulating information from maps and their own knowledge of a specific region. For example, the examination of figures 4 and 5 easily reveals a lack of published results on the most important clinical outcomes for people with triple-negative breast cancer throughout all stages of the disease.\u003c/p\u003e\n\u003cp\u003eThere are several major differences between our scoping review and previous reviews published on metformin and cancer. For instance, a systematic review[10] focused on \u003cem\u003ein vitro\u003c/em\u003e and/or \u003cem\u003ein vivo\u003c/em\u003e studies exploring the potential antiproliferative mechanisms of metformin. This review provided evidence of the effectiveness of metformin in cancer cell lines and/or animal models, confirming its antiangiogenic properties, as well as its ability to inhibit cellular metastasis and induce apoptosis.\u003c/p\u003e\n\u003cp\u003eAnother prior systematic review of 11 observational studies[9] analyzed the association between metformin use by diabetic women and the prognosis of breast cancer patients and revealed that the use of the drug is associated with better survival of breast cancer patients with diabetes (HR: 0.53; 95% CI: 0.39-0.71; p \u0026lt; 0.001). However, meta-analyses of observational studies are subject to bias due to residual confounding within the primary studies included.\u003c/p\u003e\n\u003cp\u003eA single systematic review and meta-analysis attempted to assess the\u0026nbsp;evidence from RCTs on the effectiveness of metformin in the treatment of breast cancer[11]. However, that review had several methodological limitations, including the absence of a registration of the review protocol, poor details of the search strategy for any database, and the exclusion of important databases and gray literature. Furthermore, there was insufficient description of the eligibility criteria, no flow diagram of the study selection process, no assessment of the certainty of evidence, and a limited range of evaluated outcomes. Importantly, that systematic review did not consider the different phenotypes, the staging of breast cancer, or the treatment modalities under which metformin was used in the primary studies. These aspects are crucial for interpreting the effectiveness of not only metformin but also any breast cancer treatment. Hence, it is likely that their meta-analyses were biased by too much clinical heterogeneity that compromised the quality of their pooled results. These limitations of the single systematic review of RCTs of metformin for the treatment of breast cancer corroborate the relevance of our scoping review in paving the way for future systematic reviews and clinical trials in this field.\u003c/p\u003e\n\u003cp\u003eOur review has some limitations. First, the absence of risk of bias evaluation of included studies, the appraisal of overall certainty of evidence across studies, or even the performance of a meta-analysis as a form of quantitative synthesis. All three aspects are possible but lie beyond the scope of a scoping review, which aims to provide a broad overview and description of the general landscape of a field. Second, we did not contact any author from the original studies to request unpublished data because our aim was to chart the literature, including its areas of uncertainties. Requesting unpublished data such as study results stratified by phenotype will be better suited to the future systematic reviews that we envision our scoping review will foster. Third, primary prevention of breast cancer also fell outside the scope of our review. The primary prevention and treatment of breast cancer are complex and involve different populations, risk factors, and biological determinants.\u003c/p\u003e\n\u003cp\u003eThe present study also has relevant strengths. We established broad eligibility criteria not restricting the context, language, or publication date of the study reports because the best practice for a scoping review is to attempt to be as comprehensive as possible. We also searched gray literature and registers such as ICTRP, as well as using other methods such as Google Scholar, checking reference lists of relevant publications, reviewing conference abstract books, and seeking specialist referrals. These searches were crucial for identifying a large number of relevant study reports for this review. Additionally, two independent reviewers conducted the selection of studies and data extraction, while a third reviewer was available to resolve any disagreements that arose between the reviewers during that process.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, the proposed scoping review revealed a growing body of evidence from RCTs about the use of metformin for the treatment of breast cancer. We mapped the landscape of existing studies according to phenotypes, staging, treatment modality, types of interventions, comparators, outcomes, and their main findings. Given the clinical heterogeneity underlying breast cancer itself and the current existence of 40 different primary studies in this field, by charting that literature, we were able to identify new opportunities for clinical trials and systematic reviews. Specifically, we emphasize the necessity for standardizing the presentation of results from breast cancer clinical trials by phenotype and envision the potential for collaboration among researchers to retrospectively ascertain the phenotypes of breast cancer participants in previous studies. This could substantially enhance the possibility of conducting better and more cost-effective meta-analyses in this field, including IPD meta-analyses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was supported by CAPES (Coordination for the Improvement of Higher Education Personnel—Ministry of Education, Brazil) through a grant to CFMA (Process number: 88882.432879/2019-01). The funder did not play any role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript EIOV was partially supported by a grant from the Brazilian National Council for Scientific and Technological Development (CNPq) (312499/2022-1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e CFMA and EIOV designed the study. CFMA performed the literature searches. CFMA and LCN screened references and extracted data from primary reports included in the review. EIOV supervised the review process. CFMA and EIOV analyzed the data. CFMA, LCN, CRMA, CPS, ACB, FBF, and EIOV were involved in the interpretation of results. CFMA and EIOV drafted the first version of the manuscript. LCN, CRMA, CPS, ACB, and FBF revised the manuscript for important intellectual content. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors wish to express their gratitude to Maximiliano Ribeiro Guerra, Mario Cirio Nogueira, Carlos Eduardo Paiva, and Leonardo Roberto da Silva for their comments on previous versions of our manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. https://doi.org/10.3322/caac.21834.\u003c/li\u003e\n\u003cli\u003eArnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. The Breast. 2022;66:15\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eHealth and Economic Benefits of Breast Cancer Interventions | Power of Prevention. 2023. https://www.cdc.gov/chronicdisease/programs-impact/pop/breast-cancer.htm. Accessed 17 Jun 2023.\u003c/li\u003e\n\u003cli\u003ePrieto-Callejero B, Rivera F, Fagundo-Rivera J, Romero A, Romero-Mart\u0026iacute;n M, G\u0026oacute;mez-Salgado J, et al. Relationship between chemotherapy-induced adverse reactions and health-related quality of life in patients with breast cancer. Medicine (Baltimore). 2020;99:e21695.\u003c/li\u003e\n\u003cli\u003eSchernthaner G. The right place for metformin today. Diabetes Res Clin Pract. 2020;159:107946.\u003c/li\u003e\n\u003cli\u003eForetz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eSachs RE, Ginsburg PB, Goldman DP. Encouraging New Uses for Old Drugs. JAMA. 2017;318:2421\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eJohnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2:56.\u003c/li\u003e\n\u003cli\u003eXu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. The \u0026hellip;. 2015; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eAljofan M, Riethmacher D. Anticancer activity of metformin: a systematic review of the literature. Future Sci OA. 5:FSO410.\u003c/li\u003e\n\u003cli\u003eZhang Z-J, Yuan J, Bi Y, Wang C, Liu Y. The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials. Pharmacol Res. 2019;141:551\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eTesta U, Castelli G, Pelosi E. Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments. Med Sci Basel Switz. 2020;8.\u003c/li\u003e\n\u003cli\u003ePeters MDJ, Godfrey CM, Khalil H, McInerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015;13:141\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eAraujo CFM, Nunes LC, Murta-Nascimento C, Bragagnoli AC, Souza CP de, Fukushima FB, et al. Metformin for the Treatment of Breast Cancer: Protocol for a Scoping Review of Randomised Clinical Trials. 2021.\u003c/li\u003e\n\u003cli\u003eAraujo C, Nunes L, Murta-Nascimento C, ... Metformin for the treatment of breast cancer: protocol for a scoping review of randomised clinical trials. BMJ Open. 2021; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eOuzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan\u0026mdash;a web and mobile app for systematic reviews. Syst Rev. 2016;5:210.\u003c/li\u003e\n\u003cli\u003eHarzing AW. Publish or Perish. Harzing.com. 2016. https://harzing.com/resources/publish-or-perish. Accessed 11 Apr 2024.\u003c/li\u003e\n\u003cli\u003eTricco AC, Lillie E, Zarin W, O\u0026rsquo;Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169:467\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.\u003c/li\u003e\n\u003cli\u003eHadad SM, Coates P, Jordan LB, Dowling RJO, Chang MC, Done SJ, et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat. 2015;150:149\u0026ndash;55.\u003c/li\u003e\n\u003cli\u003eEUCTR2014-004430-26-GB. Feasibility of the International Breast Intervention Study 3 (IBIS 3). Prevention of late recurrence in hormone receptor positive breast cancer survivors following 5 years of treatment. HttpwwwwhointtrialsearchTrial2aspxTrialIDEUCTR2014-004430-26-GB. 2015.\u003c/li\u003e\n\u003cli\u003eNanni O, Amadori D, De Censi A, Rocca A, Freschi A, Bologna A, et al. Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial. Breast Cancer Res Treat. 2019;174:433\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eGennari A, Foca F, Zamarchi R, Rocca A, Amadori D, De Censi A, et al. Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial. Breast Cancer Res Treat. 2020;181:61\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMartin-Castillo B, Pernas S, Dorca J, lvarez I, Martnez S, Prez-Garcia JM, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget. 2018;9:35687\u0026ndash;704.\u003c/li\u003e\n\u003cli\u003eLopez-Bonet E, Bux M, Cuys E, Pernas S, Dorca J, lvarez I, et al. Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer. J Clin Med. 2019;8.\u003c/li\u003e\n\u003cli\u003eCuy\u0026agrave;s E, Bux\u0026oacute; M, Ferri Iglesias MJ, Verdura S, Pernas S, Dorca J, et al. The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin. Front Oncol. 2019;9:193.\u003c/li\u003e\n\u003cli\u003eCuy\u0026agrave;s E, Fern\u0026aacute;ndez-Arroyo S, Bux\u0026oacute; M, Pernas S, Dorca J, \u0026Aacute;lvarez I, et al. Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients. Aging. 2019;11:2874\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eGoodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, et al. Effect of Metformin vs Placebo on Invasive Disease\u0026ndash;Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022;327:1963\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003eGoodwin P, Dowling R, Ennis M, Chen B, ... Effect of metformin versus placebo on metabolic factors in the MA. 32 randomized breast cancer trial. \u0026hellip; Breast Cancer. 2021; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eLohmann AE, Liebman MF, Brien W, Parulekar WR, Gelmon KA, Shepherd LE, et al. Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32. Breast Cancer Res Treat. 2017;164:371\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eGoodwin P, Dowling R, Ennis M, ... Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA. 32: A Breast Cancer Randomized Trial of Metformin vs Placebo. JNCI Cancer \u0026hellip;. 2021; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003ePimentel I, Chen BE, Lohmann AE, Ennis M, Ligibel J, Shepherd L, et al. The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32. J Natl Cancer Inst. 2021;113:192\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eNCT01286233. Study of Biomarkers Associated With Fatigue in Patients With Early-Stage Breast Cancer Treated With Metformin or Placebo on NCIC-CTG-MA.32. https://clinicaltrials.gov/show/NCT01286233. 2011.\u003c/li\u003e\n\u003cli\u003eWood ME, Qin R, Le-Petross HT, Hwang ES, Ligibel JA, Mayer IA, et al. Change in mammographic density with metformin use: A companion study to NCIC study MA.32. J Clin Oncol. 2013;31.\u003c/li\u003e\n\u003cli\u003eBonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:2593\u0026ndash;600.\u003c/li\u003e\n\u003cli\u003eCazzaniga M, DeCensi A, Pruneri G, Puntoni M, ... The effect of metformin on apoptosis in a breast cancer presurgical trial. \u0026hellip; J Cancer. 2013; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eDeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat. 2014;148:81\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eDeCensi A, Puntoni M, Guerrieri-Gonzaga A, ... Effect of metformin on breast ductal carcinoma in situ proliferation in a randomized presurgical trial. \u0026hellip; Prev Res. 2015; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eAhmed S, Ahmed MS, Morsi D, ... Added Metformin to Systematic Neoadjuvant Chemotherapy in Breast Cancer Patients: Randomized Study from Egypt. Med J \u0026hellip;. 2021; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eEl-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clinical \u0026amp; Experimental Metastasis. 2016;33:339\u0026ndash;57.\u003c/li\u003e\n\u003cli\u003eKo K, Ma S, Yang J, Hwang Y, Ahn C, Cho Y, et al. Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2015;153:361‐370.\u003c/li\u003e\n\u003cli\u003eDavis S, Robinson P, Jane F, White S, ... The benefits of adding metformin to tamoxifen to protect the endometrium\u0026mdash;A randomized placebo‐controlled trial. Clin \u0026hellip;. 2018; Query date: 2021-09-30 09:48:10. https://doi.org/10.1111/cen.13830?casa_token=miQTssmCbfQAAAAA:snkCWNVwpJIgYT92JW9O0gHU1aZG9wL4MRIZ-qqSoQO1kBvQWf_uljBs-pyHtsCE1cx__8Rlavu192mbjA.\u003c/li\u003e\n\u003cli\u003eLiubota R, Cheshuk V, Zotov O, ... Metformin in neoadjuvant systemic therapy of breast cancer patients with metabolic syndrome. Arch \u0026hellip;. 2018; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eSalah H, Rabea H, Hassan A, Elberry A. Metformin as an Adjuvant Treatment in Non-Diabetic Metastatic Breast Cancer. Bahrain Med \u0026hellip;. 2021; Query date: 2021-09-30 09:48:10.\u003c/li\u003e\n\u003cli\u003eBarakat HE, Hussein RRS, Elberry AA, Zaki MA, Ramadan ME. The impact of metformin use on the outcomes of locally advanced breast cancer patients receiving neoadjuvant chemotherapy: an open-labelled randomized controlled trial. Sci Rep. 2022;12:7656.\u003c/li\u003e\n\u003cli\u003eZhao Y, Gong C, Wang Z, Zhang J, Wang L, Zhang S, et al. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget. 2017;8:84224\u0026ndash;36.\u003c/li\u003e\n\u003cli\u003eSemiglazova TYu, Osipov MA, Krivorotko PV, Klimenko VV, Dashyan GA, Paltuev RM, et al. Melatonin and metformin in neoadjuvant hormonotherapy in locally advanced breast cancer. Vopr Onkol. 2018;64:612\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003ePatterson RE, Marinac CR, Sears DD, Kerr J, Hartman SJ, Cadmus-Bertram L, et al. The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes. J Natl Cancer Inst. 2018;110:1239\u0026ndash;47.\u003c/li\u003e\n\u003cli\u003eHadad S, Iwamoto T, Jordan L, Purdie C, Bray S, ... Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res \u0026hellip;. 2011; Query date: 2021-09-30 09:48:10. https://doi.org/10.1007/s10549-011-1612-1.\u003c/li\u003e\n\u003cli\u003eMeyerhardt J.A., Irwin M.L., Jones L.W., Zhang S., Campbell N., Brown J.C., et al. Randomized phase II trial of exercise, metformin, or both on metabolic biomarkers in colorectal and breast cancer survivors. JNCI Cancer Spectr. 2020;4.\u003c/li\u003e\n\u003cli\u003eYeh H-C, Maruthur NM, Wang N-Y, Jerome GJ, Dalcin AT, Tseng E, et al. Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial. J Clin Endocrinol Metab. 2021;106:e4179\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eSaif MW, Rajagopal S, Caplain J, Grimm E, Serebrennikova O, Das M, et al. A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors. Cancer Chemother Pharmacol. 2019;84:1323\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003ePimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon D, Elser C, et al. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019;48:17\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eArce-Salinas C, Alamilla G, Flores-Diaz D, Deneken CZ, Mendoza-Galindo L, Ramirez-Morales R, et al. Randomized, double blind trial to evaluate the safety and efficacy of metformin vs placebo plus neoadjuvant chemotherapy in locally advanced breast cancer. J Clin Oncol. 2016;34.\u003c/li\u003e\n\u003cli\u003eAzazy HA, Gado NM, Salem DA, El-Ghamry WR. Metformin with neoadjuvant chemotherapy in stage II-III breast cancer: A phase II clinical trial. Ann Oncol. 2020;31 (Azazy H.A.; Gado N.M.; Salem D.A.; El-Ghamry W.R.) Clinical Oncology Department (ASCOD), Ain Shams University Hospital-Faculty of Medicine, Cairo, Egypt:S323\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eSadighi S, Saberian M, Nagafi M, Jahanzad I, Omranipoor R, Behrouzi B. Metformin anti-proliferative effect on a cohort of non-diabetic breast cancer patients. Ann Oncol. 2016;27 (Sadighi S.; Saberian M.) Medical Oncology-Hematology, Cancer Institute of Iran, Tehran, Iran.\u003c/li\u003e\n\u003cli\u003eKim J, Lim W, Kim E-K, Kim M-K, Paik N-S, Jeong S-S, et al. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR). BMC Cancer. 2014;14.\u003c/li\u003e\n\u003cli\u003eSemiglazova TY, Osipov M, Krivorotko P, Semiglazov V, Protsenko S, Berstein L, et al. Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer. Ann Oncol. 2019;30 (Semiglazova T.Y.; Protsenko S.; Klimenko V.) Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation:v100.\u003c/li\u003e\n\u003cli\u003eVernieri C, Nichetti F, Ligorio F, Zattarin E, Beninato T, Lobefaro R, et al. Efficacy of metfOrmin in PrevenTIngglucocorticoid-induced diabetes in Melanoma, breAst orLung Cancer patients with brain metastases: The phase IIOPTIMAL study. Cancer Res. 2020;80 16 SUPPL.\u003c/li\u003e\n\u003cli\u003eTCTR20200116007. Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer patient, a randomized controlled trial. https://www.thaiclinicaltrials.org/show/TCTR20200116007. Accessed 2 Jul 2022.\u003c/li\u003e\n\u003cli\u003eChiCTR1900023487. The Clinical Study of Metformin in Ovarian Reserve and Function Protection for Breast Cancer Survivors Treated with Chemotherapy. https://www.chictr.org.cn/showproj.aspx?proj=39171. 2019. https://www.chictr.org.cn/showproj.aspx?proj=39171. Accessed 2 Jul 2022.\u003c/li\u003e\n\u003cli\u003eChiCTR1900027489. A randomized, double-blind, placebo-controlled clinical study of metformin in protecting reproductive system development and fertility in women with malignant tumors of chemotherapy-induced ovarian injury. https://www.chictr.org.cn/showproj.aspx?proj=45172. 2019. https://www.chictr.org.cn/showproj.aspx?proj=45172. Accessed 2 Jul 2022.\u003c/li\u003e\n\u003cli\u003eChiCTR-IPR-16008553. Clinical study on the anti-cancer effect of metformin in the breast cancer patients with prediabetes during neoadjuvant chemotherapy. https://www.chictr.org.cn/showproj.aspx?proj=14483. https://www.chictr.org.cn/showproj.aspx?proj=14483. Accessed 3 Jul 2022.\u003c/li\u003e\n\u003cli\u003eACTRN12612000416897. Sequential evaluation of tumours undergoing pre-operative therapy with aromatase inhibitors and metformin (setup-aim) a neo-adjuvant pilot study in operable hormone sensitive breast cancer in post menopausal women. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000416897. 2012. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000416897. Accessed 3 Jul 2022.\u003c/li\u003e\n\u003cli\u003eEUCTR2015-001001-14-IT. Effect of metformin in overweight breast cancer survivors at increased risk of recurrence. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001001-14/IT. 2021. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001001-14/IT. Accessed 4 Jul 2022.\u003c/li\u003e\n\u003cli\u003eNCT03238495. Randomized Trial of Neo-adjuvant Chemotherapy With or Without Metformin for HER2 Positive Operable Breast Cancer. 2017.\u003c/li\u003e\n\u003cli\u003eNCT04170465. Role of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (METNEO). https://clinicaltrials.gov/show/NCT04170465. 2019.\u003c/li\u003e\n\u003cli\u003eNCT04248998. Calorie Restriction With or Without Metformin in Triple Negative Breast Cancer. https://clinicaltrials.gov/show/NCT04248998. 2020.\u003c/li\u003e\n\u003cli\u003eNCT04387630 M. Neoadjuvant Chemotherapy With or Without Metformin in Early Breast Cancer. 2020.\u003c/li\u003e\n\u003cli\u003eNCT01929811. NeoMET Study in Neoadjuvant Treatment of Breast Cancer. https://clinicaltrials.gov/show/NCT01929811. 2013.\u003c/li\u003e\n\u003cli\u003eNCT01477060. Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer. https://clinicaltrials.gov/show/NCT01477060. 2011.\u003c/li\u003e\n\u003cli\u003eNCT02472353. Use of Metformin to Reduce Cardiac Toxicity in Breast Cancer. https://clinicaltrials.gov/show/NCT02472353. 2015.\u003c/li\u003e\n\u003cli\u003eNCT02360059. Metformin for Reduction of Paclitaxel-Related Neuropathy in Patients With Breast Cancer. https://clinicaltrials.gov/show/NCT02360059. 2015.\u003c/li\u003e\n\u003cli\u003eDelgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11:1121\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eZhang J, Ma X, Li Y, Liu R, Li Y, Zhang P, et al. Metformin intervention against ovarian toxicity during chemotherapy for early breast cancer: Study protocol for a randomized double-blind placebo-controlled trial. Maturitas. 2020;137:1\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eJames T, McCahill L, Ratliff J, Ashikaga T, Single R, Sheehey-Jones J, et al. Quality assessment of neoadjuvant therapy use in breast conservation: barriers to implementation. Breast J. 2009;15:524\u0026ndash;6.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Metformin, Breast cancer, Review, Clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-4593019/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4593019/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Metformin has been the focus of substantial interest in the field of oncology. Although breast cancer is the type of cancer where metformin was most extensively-studied through randomized clinical trials (RCTs), none of the previous reviews in this field provided a comprehensive overview of the landscape of RCTs taking into account the phenotype of breast cancer, its staging, and treatment modalities. This scoping review sought to comprehensively map the literature of RCTs focusing on the use of metformin in the treatment of breast cancer and followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Extension for Scoping Reviews guidelines. The eligibility criteria encompassed all RCTs involving metformin for adult patients with breast cancer, with no constraints regarding context, language, publication date, or outcomes. We included 122 reports from 40 RCTs comprising a total of 5,623 participants and 107 distinct outcomes. The results showed that most studies did not present results by phenotype of breast cancer and highlighted critical gaps and opportunities in the literature. Notably, limited evidence from subgroup analyses within a large RCT suggested potential benefits of metformin in improving overall and disease-free survival among HER2+ participants but not among patients with other phenotypes. Our findings highlight the potential for considerably expanding the current knowledge base in this field through the retrospective determination of participant phenotypes, facilitating cost-effective and time-efficient individual participant data meta-analyses. Furthermore, we recommend that funding agencies and journals mandate the comprehensive presentation of results from RCTs on breast cancer based on phenotype.","manuscriptTitle":"Metformin for the treatment of breast cancer: a scoping review of randomized clinical trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:40:25","doi":"10.21203/rs.3.rs-4593019/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-06-09T10:18:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-15T06:47:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241096437497109454072101303227858096404","date":"2024-10-15T06:16:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224809331450680574453893829730344845369","date":"2024-10-13T11:39:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-08T11:27:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-08T01:48:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-10-07T09:00:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"278d6c33-82b7-451a-bfab-d4aa21071fea","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:40:52+00:00","versionOfRecord":{"articleIdentity":"rs-4593019","link":"https://doi.org/10.1186/s12885-025-14468-3","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-08-21 16:29:50","publishedOnDateReadable":"August 21st, 2025"},"versionCreatedAt":"2025-05-07 06:40:25","video":"","vorDoi":"10.1186/s12885-025-14468-3","vorDoiUrl":"https://doi.org/10.1186/s12885-025-14468-3","workflowStages":[]},"version":"v1","identity":"rs-4593019","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4593019","identity":"rs-4593019","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}