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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies., Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes., Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020., Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years., Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed., Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%)., Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival., Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.

Background: Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer., Methods: A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided., Results: Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P  <   .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps  >   .11)., Conclusions: Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo., Methods: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models., Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone., Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples., Methods: VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables., Results: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L., Conclusions: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Background: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples., Methods: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided., Results: Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin., Conclusions: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened. We review the rationale for a modified approach to evaluation and outline the key steps that will optimize development of this agent in breast cancer, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.

Background: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo.Methods: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone.Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers. [ABSTRACT FROM AUTHOR]

Background: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. Methods: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. Results: Mean age was 52.1 ±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. Conclusions: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin. [ABSTRACT FROM AUTHOR]