Time-restricted eating and metformin (TEAM) in invasive breast cancer or DCIS: A randomized, phase IIb, window-of-opportunity presurgical trial.

Abstract

10524 Background: Preclinical studies indicate that metformin administered during fasting synergizes with feeding–fasting cycles to suppress tumor growth through activation of the PP2A–GSK3β–MCL1 pathway. The TEAM trial evaluated the feasibility, safety, biological, metabolic, and clinical effects of a short-term metabolic intervention combining prolonged nightly fasting and metformin in operable hormone receptor–positive breast cancer. Methods: TEAM is a randomized, phase IIb, presurgical window-of-opportunity trial. Women with hormone receptor-positive operable invasive breast cancer or DCIS were randomized 1:1 to either ≥16-hour nightly fasting plus metformin 750 mg bid and nutritional counseling (experimental [exp] arm) or to healthy WCRF lifestyle recommendations (control arm). Both groups wore a Continuous Glucose Monitor (CGM) per protocol data downloads. Treatment duration was 4–6 weeks before surgery. The primary endpoint is the absolute change in centrally assessed Ki67 between biopsy and surgery in invasive disease or DCIS. A co-primary endpoint was the difference in post-treatment Ki67 in cancer-adjacent DCIS. Analyses were intention-to-treat. Results: A total of 120 patients were randomized and completed the study (mean±SD, 32±8.6 days). As of December 31, 2025, 105 were evaluable for paired Ki67 analysis due to tissue availability. Since the complete results will be presented at the meeting, current data are descriptive with no inferential statistics and p-values, as per DSMB recommendation. Median baseline Ki67 was 15% in both arms. Median absolute Ki67 change was −3 percentage points (IQR −7 to 1) in the exp arm versus −2 (IQR −4 to 4) in the control arm. The median absolute change in invasive disease was -3 (-7 to 2) versus -1 (-3 to 4), and Ki67 reduction ≥3% occurred in 53% versus 32%, in the exp and control arm, respectively. Post-treatment Ki67 in cancer-adjacent DCIS was 3.5 (2-8.5) vs 4 (2-7). There were 3 pathological CR in the exp arm and 0 in the control arm during the presurgical window. Median weight decreased by 1.75 kg in the exp arm relative to the control arm. Mean tumor 18F-FDG PET SUV decreased by 22% versus 4% in a subgroup of 25 patients with tumors ≥ 15 mm. Reductions were observed in glucose, HOMA-IR, leptin, C-peptide, insulin and IGF-I. Changes in CIP2A and MCL1 were observed in patients with Ki67 reduction. Median adherence to ≥16-hour fasting was 100% (97.4-100); overall metformin adherence was 95% (85%-99%). No dose-limiting toxicities or grade ≥3 hypoglycemia occurred. Conclusions: These preliminary results show that short-term metabolic intervention was feasible, safe, highly compliant, and very inexpensive, and was associated with favorable antiproliferative and metabolic changes that warrant further investigation in breast cancer prevention and treatment. Full results will be presented at the meeting. Clinical trial information: NCT05023967 .