加拿大多伦多大学Pamela J. Goodwin团队比较了二甲双胍与安慰剂对乳腺癌患者侵袭性无病生存率的影响。相关论文于2022年5月24日发表在《美国医学会杂志》上。

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，二甲双胍与乳腺癌亚型的潜在获益相关。

为了确定无糖尿病的乳腺癌患者辅助服用二甲双胍（与安慰剂相比）是否能改善预后，研究组在加拿大、瑞士、美国和英国进行了一项临床3期、随机、安慰剂对照、双盲试验，纳入2010年8月至2013年3月接受标准治疗的3649名高危非转移性乳腺癌患者，并随访至2020年10月。

将患者随机分组，其中1824例每日两次口服850mg二甲双胍，1825例每日两次口服安慰剂，持续5年。按激素受体（雌激素受体和/或孕激素受体[ER/PgR]）阳性与阴性、体重指数≤30或>30、人表皮生长因子受体2（ERBB2，以前为HER2或HER2/neu）阳性或阴性，以及接受任何化疗与无化疗进行分层。主要结局是激素受体阳性乳腺癌的侵袭性无病生存率。8项次要结局分析了总生存率、无远端复发生存率和无乳腺癌间隔时间。

3649名随机患者的平均年龄为52.4岁，3643名为女性（99.8%），所有患者（100%）均被纳入分析。在第二次中期分析后，ER/PgR阴性患者被宣布无效，因此，对2533例ER/PgR阳性患者进行了初步分析。ER/PgR阳性组的中位随访时间为96.2个月。

465名ER/PgR阳性患者发生侵袭性无病生存事件。二甲双胍组侵袭性无病生存事件的发生率为2.78/100患者-年，而安慰剂组为2.74/100患者-年，危险比（HR）为1.01；二甲双胍组的死亡率为1.46/100患者-年，安慰剂组为1.32/100患者-年，HR为1.10。

在ER/PgR阴性患者中，平均随访94.1个月后，侵袭性无病生存事件的发生率分别为3.58和3.60/100患者-年，HR为1.01。ER/PgR阳性组中分析的3个次要结局均无统计学显著差异。

二甲双胍组3级非血液学毒性事件的发生率为21.5%，显著高于安慰剂组的17.5%。二甲双胍组和安慰剂组中最常见的3级及以上不良事件为高血压（分别为2.4%与1.9%）、月经不调（1.5%与1.4%）和腹泻（1.9%与7.0%）。

研究结果表明，在无糖尿病的高危可手术乳腺癌患者中，在标准乳腺癌治疗中添加二甲双胍与安慰剂相比并没有显著提高侵袭性无病生存率。

附：英文原文

Title: Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial

Author: Pamela J. Goodwin, Bingshu E. Chen, Karen A. Gelmon, Timothy J. Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A. Ligibel, Dawn L. Hershman, Ingrid A. Mayer, Timothy J. Hobday, Judith M. Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, John R. Mackey, Vandana G. Abramson, Conrad Oja, Robert Wesolowski, Alastair M. Thompson, Daniel W. Rea, Paul M. Stos, Lois E. Shepherd, Vuk Stambolic, Wendy R. Parulekar

Issue&Volume: 2022/05/24

Abstract:

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.

DOI: 10.1001/jama.2022.6147

Source: https://jamanetwork.com/journals/jama/fullarticle/2792615