NBCC asked a group of gifted and seasoned advocates who attended the San Antonio Breast Cancer Symposium to develop critical pieces on sessions that related to the two areas of focus for Breast Cancer Deadline 2020®. The areas are primary prevention of breast cancer and understanding metastasis and preventing deaths from the disease. Watch for a series of these excellent articles which include assessments of the relevance of the research to Breast Cancer Deadline 2020® goals, on the NBCC blog in the coming weeks. NBCC advocate, Nancy Ryan, starts off the series with a review of a poster presentation on Metformin and Statins.
Advocate Report: Nancy Ryan
Annual San Antonio Breast Cancer Symposium (SABCS)
December 6, 2012
Poster Discussion 3: Metformin/Statins
Adrian Lee, Ph.D., Chair
University of Pittsburgh Cancer Institute, Pittsburgh, PA
Michael Pollak, MD, Discussant
McGill University, Montreal, Canada
Vered Stearns, MD, Discussant
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Poster Discussion 3 focused on two agents: the drug metformin, an insulin lowering agent used in the treatment of diabetes, and statins, a class of drugs used primarily to treat lipid disorders, commonly used to lower cholesterol.
Based on observational studies suggesting metformin use in diabetic patients reduces the risk of certain cancers, several clinical trials presented in this session explored possible mechanisms for a metformin effect in patients with breast cancer.
Italian researchers measured cancer cell apoptosis (cell death) in 897 patients who were randomized to take metformin or a placebo for four weeks before surgery. (This kind of study is called a “window of opportunity trial”—a very short course of targeted therapy, placebo or no drug is given prior to surgery.) Apoptosis was measured in biopsy samples before starting metformin or placebo and again prior to surgery. The levels of apoptosis as measured by an assay called TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling) were higher in the surgical specimens than in the baseline biopsies, but the difference between the two arms was not significant. However, there was a borderline significant trend to a different metformin effect according to whether women were or were not insulin resistant. Insulin resistance is the body’s decreased ability to respond to the hormone insulin, which helps the body manage sugar. Patients who were not insulin resistant had a higher TUNEL level (higher apoptosis) with metformin than women with insulin resistance with metformin.
Following a different track, Canadian researchers further analyzed cancer tissues from a pre-operative window of opportunity trial to evaluate Adenosine Monophosphate Protein Kinase (AMPK). Protein kinases help regulate cell function. AMPK helps to maintain cellular energy homeostatsis. In this study, 47 non-diabetic patients were randomized to receive metformin or no drug before surgery. All had core biopsies at diagnosis and before surgery. Significant up-regulation, or increase in expression, of pAMPK and a fall in a protein associated with cell proliferation (Ki67) were demonstrated in treated patients compared to the control group. The investigators concluded, “Since down-regulation of pAMPK is a feature of breast cancer, this suggests mechanistic evidence for the therapeutic effects of metformin.”
Another small pre-surgical study enrolled 35 overweight and obese women. They started metformin two to four weeks before surgery. The primary endpoint was to analyze the change in Ki67 activities from baseline to surgery. Researchers “Did not identify a significant difference in tumor proliferation as measured by In (ki-67) tumor levels, before and after metformin use.”
Yet another group, looking at 39 non-diabetic patients given metformin from core biopsy to surgery reported, “Ki67 staining in tumor tissue decreased significantly and TUNEL increased significantly.” In other words, the measure of tumor cell proliferation decreased and the measure of apoptosis (cell death) increased.
Several posters dealt with the relationship between statins and breast cancer. Previous studies of the role of statins in breast cancer offer conflicting results. Some show no effect on cancer incidence, others show a small decrease in risk. Researchers are interested in the anti-tumor and anti-inflammatory properties of statins. Hence, some work has focused on Inflammatory Breast Cancer (IBC), a rare and aggressive form of breast cancer.
One team reviewed outcomes in 724 patients being treated for primary IBC over a 16-year period (a retrospective cohort study). They compared patients who were taking statins at the time of their IBC diagnosis and those who were not. Median PFS (progression free survival) was 1.76 years in patients with no record of statin use compared to 2.47 years in patients who reported using lipophilic (fat-soluble) statins, and 4.88 years in patients with a history of hydrophilic (water soluble) statin use. Researchers were surprised that the type of statin made a difference. The overall survival endpoint did not reach significance. The team concluded, “A prospective randomized study to evaluate the potential survival benefits of statins in the IBC population is warranted.” In other words, more work needs to be done.
In a Swedish window of opportunity trial researchers investigated the “anti-proliferative impact of a two-week, high-dose lipophilic statin therapy in patients with primary invasive breast cancer, while addressing the potential of HMGCR as a prognostic and potential predictive marker.” HMGCR (3-hydroxy-3-methylglutaryl-Coenzyme A reductase) is an enzyme involved in cholesterol synthesis. Previous studies have shown an HMCGR variation protein expression in human breast cancer. Atorvastin-induced tumor response was measured by Ki67. Atorvastin is commonly known as Lipitor. According to the analysis, “Among all tumors, Ki67-index in core biopsies showed an average of 24.0% compared to surgical samples with an average index of 21.9%, providing an average absolute reduction of 2.1% and an average relative reduction of 7.6%. The study also showed upregulation (increase in expression) of HMGCR in samples following two weeks of atorvastatin treatment and indicated that HMGCR is targeted by statins and could serve as a predictive marker for selecting who would benefit from treatment.
In updated findings from the Women’s Health Initiative (WHI), another team concluded, “There was no association between prior use of statins and risk of invasive breast cancer in the WHI.” The population studied included over 150,000 women enrolled in three clinical trials and one observational study. This result was a disappointing follow-up to a previous WHI analysis of 4,383 cases that showed an 18% reduction in breast cancer risk for users of lipophilic (fat soluble) statins (although no overall reduction in breast cancer risk).
The panel discussion following poster viewing raised numerous questions. Dr. Michael Pollak noted that most lab models use much higher doses of metformin than conventional human doses. Window of opportunity studies, he said, can be difficult to interpret because of small sample size, confounding factors and shortness of duration. He argued that these studies have not strengthened the evidence for metformin use in breast cancer. Other issues of concern involve potential flaws in tissue sampling when comparing core biopsy material to surgical samples, and whether metformin would be more useful as prevention or treatment. Also, current anti-diabetic doses of metformin are relatively safe, but are they large enough to affect breast cancer? A current Canadian NCIC Clinical Trials Group Phase III clinical trial (MA32) is underway to compare invasive disease-free survival of patients with early-stage breast cancer treated with metformin vs. placebo in addition to standard adjuvant therapy. Results are not expected for three years.
Dr. Vered Stearns noted that a meta-analysis of statin use and breast cancer showed no benefit in reducing risk. He cited several limitations of the posters presented. For example, statin users may also take other types of drugs not accounted for, there are many different types of statins in use, and we do not have the necessary biomarkers to measure the effects of statins.
The “take home message” from the panelists was clear — further research is warranted. We still need large, collaborative, well-run prospective studies on the role of both metformin and statins in reducing risk for and treating breast cancer.
It would be great if there was a drug that prevented breast cancer, recurrence or breast cancer metastasis — one that is well tolerated, already in wide use, easy to administer and relatively inexpensive. With a drug like metformin or statins — drugs that could be “repurposed” from treating one disease to treating another — we’d be closer to reaching our Breast Cancer Deadline 2020® January 1, 2020 goal.
Unfortunately, based on this poster discussion, we are still a long way away from that goal with metformin or statins. The relationship between insulin, obesity, diabetes, inflammation, metformin and statins is complex and not clear. It is similar to a 1,000 tiny-piece jig-saw puzzle in the toy store window. Researchers have only just completed the border. The complicated internal connections have yet to be deciphered.
It was not clear to what extent advocates were involved in any of the posters presented in this session. The women who consented to participating in the window of opportunity clinical trials are to be commended. The multi-centered MA32 clinical trial is currently enrolling patients and has trial sites in many US states, Canada, Switzerland, and the UK. Advocates can help by getting the word out about this trial.
In summary, I found the poster study questions intriguing because I felt like I was watching the science train switching tracks from basic observational studies to lab and clinical work designed to ferret out the “why” and “how” of the observations. I am excited about the idea of using an existing drug to end breast cancer, but if metformin or statins are going to help us reach our Breast Cancer Deadline 2020® goal, the train needs to get up a real head of steam, and soon. You might say we need a Shinkansen (Japan’s high-speed “Bullet Train”) for this task. The MA32 clinical trial may answer some of the questions raised during this session and help accelerate the train. Whether the train arrives at the station by January 1, 2020, remains to be seen.
For a listing of the abstracts on the posters presented, visit:
Nancy Ryan, (Project LEAD®, 2004; Project LEAD® Institute mentor, 2011)
New Hampshire Breast Cancer Coalition