Reference
El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clin Exp Metastasis. 2016;33(4):339-357.
Objective
To investigate the impact of adding metformin to breast cancer adjuvant therapy in nondiabetic women
Study Design and Participants
Participants included women aged 40 to 65 from Damanhour Oncology Center (Damanhour, Egypt) with newly diagnosed breast cancer. After applying exclusion criteria, a total of 129 nondiabetic women were randomized into 2 main groups—a control group (n=61) who followed adjuvant therapy alone (chemotherapy treatment [CT] and hormonal therapy [HT]) and a metformin group (n=68) who followed adjuvant therapy plus metformin therapy. Following the initial CT, women in the control group with estrogen receptor (ER)-positive breast cancer received tamoxifen, while women in the metformin group with ER-positive breast cancer received both tamoxifen and metformin. Women with ER-negative breast cancer in both control and metformin groups were only treated with CT. A total of 102 women completed the 12-month treatment regimen, with an equal number (n=51) in each group. In the control group, 43 ER-positive women received tamoxifen, and 8 (ER-negative) received only CT; in the metformin group, 42 ER-positive women received tamoxifen plus metformin and 9 (ER- negative) received only metformin in addition to the first round of CT.
Study Medication and Dosage
The women in the metformin group received 850 mg of metformin twice daily. All women were treated with adjuvant therapy, according to the protocols of Ministry of Health and Population and National Cancer Institute, Egypt. Women received either 5-fluorouracil, Adriamycin, and cyclophosphamide (FAC regimen) or Adriamycin, cyclophosphamide, and Taxol (AC-T regimen). The majority of the women received FAC (51 in the control group and 58 in the metformin group). Both the metformin group and the control group received intramuscular vitamin B12 every 3 days to avoid incidence of vitamin B12 deficiency, which could occur with long-term use of metformin.
Outcome Measures
Blood samples were collected at baseline, after chemotherapy (CT), after 6 months of hormonal therapy (6-HT), and after 12 months of hormonal therapy (12-HT) for analysis of insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), insulin, fasting blood glucose (FBG), the molar ratio of IGF-1 to IGFBP-3, homeostatic model assessment of insulin resistance (HOMA-IR), and cancer antigen (CA) 15-3 (marker of metastasis). Evaluation of metastasis was documented clinically and radiologically.
Key Findings
Metformin resulted in a significant reduction of IGF-1, IGF-1: IGFBP-3 molar ratio, insulin, FBG, and HOMA-IR and a significant increase of IGFBP-3, the main IGF transport protein in the blood. (High levels of IGFBP-3 within tumors are associated with increased cancer severity [or worse outcome] for some cancers, but decreased severity or better outcome for others.)
This current study is notable because the patients did not have diabetes, which suggests that diabetes and elevated blood sugar are not prerequisites for metformin to be an effective cancer treatment.
Metformin use was significantly associated with a decrease of metastatic events in ER-positive women after 6 months of tamoxifen compared to the control group.
The ER-positive women who received metformin showed a significant decrease (P=0.042) in metastatic events at 6 months compared to ER-positive controls (no metastatic events in the metformin group vs 9.3% in the control group). At 12 months, metformin showed a nonsignificant reduction (P=0.144) of metastatic events in ER-positive women compared to ER-positive controls (9.5% metastatic events in the metformin group vs 20.9% in the control group).
For ER-negative women, metformin gave a nonsignificant reduction (P=0.453) of metastatic events at 6 months compared to the ER-negative controls (11.1% metastatic events in the metformin group vs 25% in the control group). Metformin also showed a nonsignificant reduction (P=0.232) of metastatic events at 12 months in ER-negative women compared to ER-negative controls (22.5% metastatic events in the metformin group vs 50% in the control group).
Practice Implications
The study sought to assess the potential chemopreventive effects of adding metformin to adjuvant breast cancer therapy in nondiabetic women. The results suggest that the addition of metformin to adjuvant therapy has antitumor and antimetastatic effects, which was demonstrated either in decreasing the incidence of metastatic events or increasing the duration until metastasis. The antitumor and antimetastatic effects of metformin may be due to other effects of metformin itself or to its probable effect on the reduction of the insulin resistance mitogenic biomarkers, IGF-1, IGF1:IGFBP-3, insulin, FBG, HOMA-IR index and/or the elevation of the apoptotic inducer marker, IGFBP-3.
Considering what is now known about the anticancer benefits of metformin,1 these results are hardly a surprise. This study illustrates a basic principle in naturopathic oncology, to which little attention is paid by standard oncology. That is, instead of waiting to see if recurrence develops after chemotherapy, we employ relatively nontoxic agents with the goal of prolonging a remission.
There have been other publications showing increased benefit when metformin is added to chemotherapy. One of the first to record an increased benefit of metformin with chemotherapy was a retrospective study in 2009 of diabetic breast cancer patients. The rate of complete response was 24% in the metformin-added group compared to 8.0% in the non-metformin group (P=0.02).2 This current study is notable because the patients did not have diabetes, which suggests that diabetes and elevated blood sugar are not prerequisites for metformin to be an effective cancer treatment.
Limitations
While all trends in this study suggested benefit in the use of metformin, only the ER-positive group at 6 months reached statistical significance. The small number of participants is cited as a possible reason for not finding a significant difference between the number of metastatic events in the metformin group and the control at 12 months.
Editor’s note
Is metformin natural medicine?
Our practice at the Natural Medicine Journal is to highlight the use of natural and complementary medicines so that our primary readership, naturopathic physicians, may stay informed of current research as it impacts their clinical practices. Featuring information on the prescription drug metformin may appear as a departure from that practice. After careful consideration we have made the decision to review a pair of research papers on metformin because the information is of clinical relevance to many of our patients. Some would argue that as a prescription drug, metformin is not a natural medicine. Others would argue that as a synthetic mimic of a chemical derived from Galega officinalis, it falls in a less defined category. Prescribing metformin now falls within the scope of many of our colleagues so this distinction may be fading in relevance. Even for those of us who cannot prescribe metformin, its new potential utility in prevention and treatment of cancer is still relevant, because many natural substances and lifestyle practices we routinely prescribe patients may have similar impacts on physiology.
As of June 2016 there were nearly 2000 papers referenced on PubMed (by MeSH terms) related to metformin and cancer. Two publications published in 2016 will be discussed in this issue. The mechanisms of metformin action result in a list of anticancer benefits, including blocking the mTOR pathway, stimulating apoptosis of cancer stem cells, inhibiting angiogenesis, suppressing HER2 (human epidermal growth factor receptor 2, a protein sometimes associated with breast cancer), increasing the benefit of several chemotherapies, and enhancing radiation cell kill. There is evidence that berberine may produce some of these same effects, and while this idea generates great enthusiasm among our colleagues in regard to employing berberine for similar situations, there is far more published evidence concerning metformin. There is no discernable structural similarity between metformin and berberine molecules and the 2 substances do not always produce the same actions. So though some may speak of berberine as a botanical substitute for metformin, care should be taken with such assumptions, especially if metformin has been shown to accomplish something not yet shown for berberine.
Jacob Schor
Editor, Abstracts & Commentary
Natural Medicine Journal
