Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo

Abstract

Background Circulating levels of CA 15–3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a non-randomized neoadjuvant study. We examine effects of metformin (vs placebo) on CA 15–3 in participants of MA.32, a Phase 3 randomized trial in early-stage breast cancer. Methods 3649 subjects with T1-3, N0-3, M0 breast cancer were randomized; pretreatment and 6 month on-treatment fasting plasma was centrally assayed for CA 15–3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism (SNP). Absolute and relative change of CA 15–3 (metformin versus 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 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 SNP status (all P ≥0.11). 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.

Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer

“…The findings reported herein are consistent with randomized trials that failed to identify a beneficial effect of metformin (in addition to standard chemotherapy or hormone therapy) on outcomes in patients with metastatic breast cancer without diabetes . These findings suggest the metabolic changes previously reported in this trial population and any potential direct antitumor effects of metformin were not sufficient to affect breast cancer outcomes . They underscore the need for well-conducted randomized trials prior to the clinical adoption of interventions that appear to benefit cancer when they are investigated in observational studies.…”

“…Prior to randomization, clinical and radiological assessments were required at diagnosis or later to rule out metastases; blood samples were collected to verify adequate kidney and liver function and to ensure that the fasting glucose value was 126 mg/dL or less. Patients provided consent for collection of tumor and normal breast tissue and fasting blood samples for analyses of metabolic and related factors as previously reported …”

The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta‐analysis of randomized controlled trials

“…A total of 41 RCTs (45 publications) evaluated the effect of MTF versus placebo/control on anthropometric variables; 16,17,46–88 23 RCTs included LSM as a co‐intervention in both arms and its definition was variable across RCTs. Five RCTs recommended a hypocaloric diet, defined as allowing 1300 to 1500 kcal/day or 25 kcal/kg ideal body weight.…”

Clinical and Translational Applications of Serological and Histopathological Biomarkers in Metastatic Breast Cancer: A Comprehensive Review

“…Overexpression of CA 27-29 has been observed in breast cancer cells, particularly in advanced stages of the disease. Elevated serum levels of CA 27-29 have been associated with tumor burden and metastatic spread in breast cancer patients [34]. Several studies have shown that CA 27-29 levels may be useful for monitoring disease progression in patients with MBC and have shown that an increase in CA 27-29 levels may precede radiological evidence of disease progression, suggesting that it may serve as an early indicator of treatment failure or tumor recurrence.…”