Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medicine, University of Toronto, Toronto, ON, Canada.
Hoffman-La Roche Limited, Mississauga, ON, Canada.
JNCI Cancer Spectr. 2021 Jul 28;5(5). doi: 10.1093/jncics/pkab066. eCollection 2021 Oct.
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.
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 tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided.
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%, <.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 >.11).
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.
在一项非随机新辅助研究中，二甲双胍降低了肿瘤标志物和细胞代谢调节剂循环水平的癌症抗原（CA）15-3。我们检查了二甲双胍（与安慰剂相比）对 MA.32 中早期乳腺癌的 III 期随机试验中参与者的 CA 15-3 的影响。
共有 3649 名 T1-3、N0-3、M0 乳腺癌患者被随机分配；空腹血浆进行预处理和 6 个月的治疗，并进行中央检测 CA 15-3。分析了 rs11212617 单核苷酸多态性的基因组 DNA。使用 Wilcoxon 秩和检验比较 CA 15-3 的绝对和相对变化（二甲双胍与安慰剂）。调整基线差异的回归模型并评估关键相互作用。所有统计检验均为双侧。
平均（标准差）年龄为 52.4（10.0）岁。大多数患者患有 T2/3、淋巴结阳性、激素受体阳性、HER2 阴性的乳腺癌，接受了（新）辅助化疗和激素治疗。平均（标准差）基线 CA 15-3 为 17.7（7.6）和 18.0（8.1）U/mL。在 6 个月时，与安慰剂相比，二甲双胍组的 CA 15-3 统计学显著降低（CA 15-3 的绝对几何平均降低率为 7.7%对 2.0%，<.001；调整年龄、基线体重指数和基线 CA 15-3 后，二甲双胍与安慰剂的 CA 15-3 水平[比值比]为 0.94，95%置信区间为 0.92 至 0.96）。这种降低独立于肿瘤特征、围手术期全身治疗、基线体重指数、胰岛素和单核苷酸多态性状态（均>.11）。
我们的观察结果表明，二甲双胍可将 CA 15-3 降低约 6%，这在一项大型安慰剂对照随机试验中得到了证实。在 MA.32 的乳腺癌结局的后续疗效分析中，将探讨 CA 15-3 降低的临床意义。
