Of Prostate Cancer, Glucose, Metabolism and Metformin

A study conducted by Canadian investigators and reported in the September 1, 2013 issue of the Journal of Clinical Oncology examined the impact of Metformin use on mortality in men with diabetes and prostate cancer (Margel D. Urbach DR., Lipscombe LL, Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes, Journal of Clinical Oncology, volume 31, #25, pgs 3069-3075, 2013). The investigators examined 3837 patient with a median age of 75 years. They conducted a retrospective analysis examining the Ontario Province heath care records. The intent was to examine duration of exposure to Metformin as a diabetes management in patients with prostate cancer to assess the impact on all-cause and prostate cancer-specific mortality.

The results are impressive and instructive. There was a significant decrease in the risk of prostate cancer-specific and all-cause mortality, which related to the dose and duration of exposure to Metformin. The adjusted hazard ratio for the study of 0.76 indicates that there is a 24% reduction in mortality for prostate cancer-specific events with the use of Metformin. This study was not perfect, as it was retrospective, there was no randomization and it was impossible to control for all other variables such as exercise, smoking history and clinical parameters of prostate cancer. Nonetheless, there is a clear and important trend toward reduced prostate cancer and even overall mortality. This is but one of a series of clinical studies that have examined the impact of Metformin upon not only prostate cancer but also breast cancer. Much of this work was originally pioneered by Dr. Michael Pollack from McGill University in Montreal.

The biguanide class of antidiabetic drugs, originates from the French lilac or goat’s rue (Galega officinalis). (Wikipedia)

Metformin and the closely related Phenformin are members of the class of drugs known as biguanides. While the exact mode of action of the biguanides is not fully understood, they are known to disrupt mitochondrial respiration at complex I. This upregulates an enzyme known as adenosine monophosphate kinase (AMPK) thereby altering energy metabolism within the cell and down regulating mTOR. In diabetics, this drives down blood glucose to control the disease. However, in cancer patients, a profound effect is observed that suppresses synthetic pathways necessary for energy metabolism, cellular survival and cellular proliferation. These effects appear responsible for the impact upon prostate cancer. Interestingly, these drugs are more effective in controlling already transformed cells and less effective in the prevention of cancer. This is consistent with the observation that malignantly transformed cells change their state of metabolism.

This article is interesting on many levels. The first and most obvious is that this relatively inexpensive and well-tolerated drug can have an impact on prostate cancer.

Secondly, these effects appear to cross the lines of different cancer types, such that breast cancer and other forms of cancer might also be successfully treated.

The third note of interest shows that even patients without diabetes can tolerate Metformin, suggesting this as an adjunct to many different treatments. Finally and most importantly this represents the new and important recognition that cancer is not a genomic disorder, but a metabolic disorder. Cancer may utilize normal genetic elements to its own advantage. AMP kinase, LKB1 and mTOR are not unique to cancer, but instead, are found in every cell. These normal proteins are simply altered in their function in malignantly transformed cells. Metformin is one of what will soon be a large number of metabolomic agents entering the clinical arena as cancer research moves from the nucleus to the mitochondrion.

A “Clinical Trial” Too Far

An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone-refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

Abiraterone works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone-refractory prostate cancer and we applaud their success.

The question remains: Did we really need to conduct this study?

On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone-refractory patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone-refractory disease develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.