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A randomized controlled study of neoadjuvant metformin with chemotherapy in nondiabetic breast cancer women: The
Manar A Serageldin1, Noha A El-Bassiouny2, Yasser El-Kerm3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
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/m2 and cyclophosphamide 600 mg/m2, followed by 12 cycles of weekly paclitaxel 80 mg/m2) 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).
Insights
Metformin improved breast cancer patient outcomes by increasing death receptors (DRs) and decreasing cancer stem cells (CD133+). This enhances response to neoadjuvant chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Metformin demonstrates antiproliferative, proapoptotic, and antimetastatic effects in cancer.
- Transmembrane tumor necrosis factor-related apoptosis-inducing ligand death receptors (DRs) and CD133, a breast cancer stem cell biomarker, are implicated in cancer progression.
Purpose of the Study:
- To investigate the roles of DRs and CD133 in metformin's beneficial effects on breast cancer (BC) patients undergoing neoadjuvant chemotherapy.
- To correlate molecular changes with pathological and clinical outcomes.
Main Methods:
- A randomized trial assigned 70 non-diabetic BC patients to neoadjuvant AC-T chemotherapy with or without metformin.
- Expressions of DR4, DR5, and CD133 were quantified in residual tumor tissues post-chemotherapy.
Main Results:
- Metformin significantly improved overall clinical response, breast-conserving surgery rates, and pathological complete response.
- Metformin upregulated DR4 and DR5 mRNA expression and significantly reduced CD133+ breast cancer stem cells.
- Enhanced DR expression negatively correlated with CD133+ stem cell levels.
Conclusions:
- Metformin enhances clinical and pathological responses to neoadjuvant AC-T chemotherapy in breast cancer.
- These improvements are mediated by increased DR expression and decreased CD133+ stem cells.
