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    Research Grants Awarded

    Clinical And Biologic Effects Of Metformin In Early Stage Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Clinical and Biological Effects of Metformin in Early Stage Breast Cancer Scientific Rationale: There is strong clinical evidence that high fasting insulin levels are associated with poor BC outcomes. These high insulin levels can be reduced by metformin (a biguanide derivative used for over 50 years to treat type 2 diabetes), leading to the hypothesis that metformin will reduce BC proliferation (as measured by Ki67). Growing molecular evidence that metformin may also exert a direct (insulin independent) anti-tumour effect via activation of AMPK-dependent energy stress response and/or inhibition of PI3K/Akt/mTOR signaling strengthens the rationale for studying metformin. Identification of IRS related genes that predict BC outcome suggests it may be possible to identify a gene signature that predicts Ki67 response to metformin. Based on this body of evidence we plan to study BC patients in preoperative setting to examine effects of metformin on cell proliferation (Ki67 ? our primary outcome) and a group of clinical factors including circulating insulin and insulin sensitivity. We will explore biologic effects of metformin, examining signaling via mTOR and PKB/Akt pathways, the impact of TNF alpha (and its primary protease TACE and associated inhibitor TIMP3) on Ki67 response, and the ability of gene expression to predict metformin effects on Ki67 (focusing on insulin resistance genes). This biologic work will enhance understanding of mechanisms of action of metformin in BC. Identification of antiproliferative effects resulting from metformin administration will strengthen the justification for future adjuvant studies. Hypotheses and Expected Results: Our primary hypothesis is that metformin will reduce cell proliferation rates (measured using Ki67). In exploratory work we will examine mechanisms of metformin action, hypothesizing that both direct (insulin independent) and indirect (insulin dependent) effects will be seen. We also hypothesize we will identify a specific gene signature that predicts Ki67 response to metformin. Research Aims and Study Design: We will examine the effect of metformin on (i) Ki67 (our primary outcome), (ii) molecular markers of mTOR and insulin signaling (e. P-4E-BP1, P-PKB/Akt, P-AMPK), (ii) host and tumour related factors that may mediate or modify metformin effects (e.g. insulin and its receptor, IGF-1R, p53 and its transcriptional target p21, ER, TACE and TIMP3), and (iv) gene expression profiles, focusing on genes associated with insulin resistance. In exploratory analyses, we plan to develop a ?core molecular profile? of response to metformin. Our design involves a single arm, before-after study of 40 women with newly diagnosed locoregional BC who are awaiting definitive breast surgery. Women will receive metformin 500 mg. po t.i.d. for up to 3 weeks prior to surgery. Serial core biopsies, FNAs and fasting blood specimens will be obtained at study entry and at surgery. Forty subjects will provide 80-90% power to identify a Ki67 reduction of 4.7-5.5 percentage points (similar to changes of 6.3 percentage points seen with anti-estrogens in other BC studies) and a two point change in immunohistochemical assays (using the Allred scoring system). Impact: Despite growing evidence that insulin may play a clinically important role in BC growth and progression, no studies have targeted insulin reduction as a therapeutic modality. This rationale alone would justify evaluation of metformin. The recent observation that metformin may exert additional insulin-independent anti-proliferative effects strengthens this justification. Based on the observed strength of the association between insulin levels and risk of breast cancer recurrence, we estimate that metformin has the potential to improve 5 year disease free survival by as much as 5-6% (absolute). This effect would be considered highly clinically significant and is comparable to effects of other recently adopted adjuvant therapies, such as AIs and taxanes. Because metformin is an available agent with known pharmacology, its development can proceed rapidly. Results of the proposed study will be available in 2-3 years, and a subsequent adjuvant study could be completed 5-6 years later. Thus, if our hypotheses prove to be correct, metformin could be used in the standard treatment of breast cancer within the next decade. Our research exploits the link between host factors (obesity, hyperinsulinemia) and BC outcomes ? in doing this it challenges existing treatment paradigms that focus primarily on tumor related factors and opens the door to a new class of safe, inexpensive and non-toxic treatment.

    Lay Abstract:
    Clinical and Biological Effects of Metformin in Early Stage Breast Cancer Our team is studying the clinical and biological effects of metformin (an inexpensive drug that is commonly used to treat diabetes) on cell proliferation (growth) in women with breast cancer. We hypothesize the drug will reduce cell proliferation in 2 ways: (1) indirectly by lowering circulating levels of insulin (a growth factor in breast cancer) and (2) directly by inhibiting key growth pathways within breast cancer cells. If we find the metformin slows breast cancer cell growth the likelihood that it will improve breast cancer outcomes will be increased. Obesity is an accepted marker of recurrence in early stage breast cancer; we and others have shown that this effect is likely due to the presence of high insulin levels in overweight women. These high levels of insulin react with insulin receptors that are present on almost all breast cancer cells to stimulate growth. Therefore, by lowering insulin levels, metformin may inhibit breast cancer growth. Recent research has shown that metformin may also slow the growth of breast cancer cells through other mechanisms (independent of changes in insulin) by interfering with important growth pathways. Thus, if our hypotheses prove to be correct, metformin may be a useful, non-toxic and inexpensive drug to prevent recurrences in women with early stage breast cancer. We will study 40 women with newly diagnosed breast cancer during the 2-3 weeks they are waiting for surgery (this is the usual time taken to schedule surgery in Canada)? women will take metformin during this time and we will obtain tumour and blood specimens before they start metformin and at the time of their breast cancer surgery. Specimens will be analyzed for insulin and related factors, and for selected molecular markers within the tumors. The results will allow us to determine the impact of metformin on growth of breast cancer cells, and to understand how metformin impacts breast cancer cell growth. One of the unique aspects of this study is that we will focus on insulin reduction as a therapeutic target in breast cancer. The evidence that insulin plays a clinically important role in breast cancer by itself justifies our decision to study metformin. The recent discovery that metformin may also impact breast cancer growth through other mechanisms strengthens the justification for its evaluation. We estimate metformin may improve 5 year recurrence rates by 5-6% (absolute), comparable to effects seen with other newly adopted therapies such as aromatase inhibitors or taxanes ? these are very important clinical effects. Because metformin has been used for over 50 years its pharmacology is well known, and its evaluation as an anti-cancer agent can proceed in an accelerated fashion. This study (which will take between 2 and 3 years) is one step in that process ? if metformin slows breast cancer cell growth we will then conduct an adjuvant study (involving 4000-5000 women) to see if it reduces the risk of recurrence and death. That study would take 5 to 6 years ? thus, it is possible metformin could be used in the standard treatment of breast cancer within the next decade. If our research is successful, women with newly diagnosed breast cancer will be able to take metformin (a pill costing less that a dollar a day that is very well tolerated and is one of the most commonly used drugs to treat diabetes) to lower her risk of breast cancer recurring. Because the drug targets a novel patient related factor (insulin) we believe it is likely that is will provide added benefit to existing therapies.