A randomized controlled study of neoadjuvant metformin with chemotherapy in nondiabetic breast cancer women: The METNEO study

Aims Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor‐related apoptosis‐inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy. Methods We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC‐T chemotherapy (4 cycles of adriamycin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 , followed by 12 cycles of weekly paclitaxel 80 mg/m 2 ) or AC‐T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells. Results The overall clinical response (odds ratio: 22.67 [2.77–185.18], P = .004), breast‐conserving surgery (odds ratio: 3.67 [1.303–10.321], P = .014) and pathological complete response (β = 2.49 ± 1.13 [0.274–4.712], P = .028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ± 0.25 vs . 4.87 ± 0.53, P = .0003) and DR5 (0.21 ± 0.25 vs . 4.29 ± 0.95, P = .0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs . 100.00%, P < .0001) and nuclear sites (4.35 vs . 95.00%, P < .0001). Conclusion Metformin improves clinical and pathological responses to neoadjuvant AC‐T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465 ).