Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada.
JAMA. 2022 May 24;327(20):1963-1973. doi: 10.1001/jama.2022.6147.
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.
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.
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.
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.
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%).
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.
ClinicalTrials.gov Identifier: NCT01101438.
二甲双胍是一种常用于治疗 2 型糖尿病的双胍类药物，在观察性和临床前研究中，它与乳腺癌各亚型的潜在有益作用相关。
确定辅助治疗乳腺癌的二甲双胍（与安慰剂相比）是否能改善无糖尿病的乳腺癌患者的结局。
设计、地点和参与者：MA.32 是一项 3 期随机、安慰剂对照、双盲试验，在加拿大、瑞士、美国和英国进行，纳入了 3649 例接受标准治疗的高危非转移性乳腺癌患者，入组时间为 2010 年 8 月至 2013 年 3 月，随访至 2020 年 10 月。
患者被随机（按激素受体[雌激素受体和/或孕激素受体{ER/PgR}]状态、阳性与阴性；体重指数，≤30 与>30；人表皮生长因子受体 2[ERBB2，以前称为 HER2 或 HER2/neu]，阳性与阴性；以及任何与无化疗）分为每天口服 850 mg 二甲双胍两次（n = 1824）或每天口服安慰剂两次（n = 1825），疗程为 5 年。
主要结局是激素受体阳性乳腺癌的无侵袭性疾病生存。在 8 个次要结局中，分析了总生存、远处无复发生存和乳腺癌无间隔。
在 3649 例随机患者中（平均年龄 52.4 岁；3643 例女性[99.8%]），所有患者（100%）均纳入分析。在第二次中期分析后，宣布 ER/PgR-患者无效，因此对 2533 例 ER/PgR+患者进行了主要分析。ER/PgR+组的中位随访时间为 96.2 个月（范围，0.2-121 个月）。在 ER/PgR+患者中发生了 465 例侵袭性疾病无事件。二甲双胍组的无侵袭性疾病无事件发生率为每 100 患者年 2.78 例，安慰剂组为每 100 患者年 2.74 例（危险比[HR]，1.01；95%置信区间[CI]，0.84-1.21；P = 0.93），死亡率分别为每 100 患者年 1.46 例和每 100 患者年 1.32 例（HR，1.10；95%CI，0.86-1.41；P = 0.47）。在 ER/PgR-患者中，中位随访 94.1 个月，无侵袭性疾病无事件发生率分别为每 100 患者年 3.58 例和 3.60 例（HR，1.01；95%CI，0.79-1.30；P = 0.92）。在 ER/PgR+组中分析的 3 个次要结局均无统计学差异。服用二甲双胍的患者比服用安慰剂的患者更常发生 3 级非血液学毒性事件（分别为 21.5%与 17.5%，P = 0.003）。二甲双胍组比安慰剂组更常见的 3 级或更高级别的不良事件为高血压（2.4%比 1.9%）、不规则月经（1.5%比 1.4%）和腹泻（1.9%比 7.0%）。
在无糖尿病的高危可手术乳腺癌患者中，与标准乳腺癌治疗相比，添加二甲双胍并不能显著改善无侵袭性疾病生存。
ClinicalTrials.gov 标识符：NCT01101438。
