Triple Negative Breast Cancer: Worse or Just Different?

The term “triple negative breast cancer” (TNBC) is applied to a subtype of breast cancers that do not express the estrogen or progesterone receptors. Nor do they overexpress the HER2 gene. This disease constitutes 15 – 20 percent of all breast cancers and has a predisposition for younger women, particularly those of black and Hispanic origin. This disease may becoming more common; although, this could reflect the greater awareness and recognition of this disease as a distinct biological entity.

On molecular profiling, TNBC has distinct features on heat maps. The usual hormone response elements are deficient, while a number of proliferation markers are upregulated.  Not surprisingly, this disease does not respond to the usual forms of therapy like Tamoxifen and the other selective estrogen response modifiers known as SERMs. Nonetheless, TNBC can be quite sensitive to cytotoxic chemotherapy. Indeed, the responsiveness to chemotherapy can provide these patients with complete remissions. Unfortunately, the disease can recur. Complete remission maintained over the first three to five years is associated with a favorable prognosis, with recurrence rates diminishing over time and late recurrences more often seen in estrogen receptor-positive cancers.

Triple negative breast cancer is not one, but many diseases.

MTOR-pathway-ger Among the subtypes are those that respond to metabolic inhibitors such as the PI3K and mTOR directed drugs. Another subset may respond to drugs that target epidermal growth factor. There are basal-types that may be somewhat more refractory to therapy, while a subset may have biology related to the BRCA mutants, characterized by DNA repair deficiencies and exquisite sensitivity to Cisplatin-based therapies. Finally, a last group is associated with androgen signaling and may respond to drugs that target the androgen receptor.

Some years ago, we used the EVA-PCD platform to study refractory patients with breast cancer and identified exquisite sensitivity to the combination of Cisplatin plus Gemcitabine in this patient group. We published our observations in the Journal of Clinical Oncology and the combination of Cisplatin or Carboplatin plus Gemcitabine has become an established part of the armamentarium in these patients.

The I-SPY-2 trial has now used genomic analyses confirming our observations for the role of platins in TNBC. This iSignal_transduction_pathways.svgn part reflects the DNA repair deficiency subtype associated with the BRCA-like biology. More recently, we have examined TNBC patients for their sensitivity to novel therapeutic interventions. Among them, the PI3K and mTOR inhibitors, as well as the glucose metabolism pathway inhibitors like Metformin. Additional classes of drugs that are revealing activity are the cyclin-dependent kinase inhibitors, some of which are moving forward through clinical trials.

One feature of triple negative breast cancer is avid uptake on PET scan. This reflects, in part, the proliferation rate of these tumors, but may also reflect metabolic changes associated with altered glucose metabolism. In this regard, the use of drugs that change mitochondrial function may be particularly active. Metformin, a member of the biguanide family influences mitochondrial metabolism at the level of AMP kinase. The activity of Metformin and related classes of drugs in triple negative breast cancer is a fertile area of investigation that we and others are pursuing.

When we examine the good response of many triple negative breast cancers to appropriately selected therapies, the potential for durable complete remissions and the distinctly different biology that TNBC represents, the question arises whether TNBC is actually a worse diagnosis, or simply a different entity that requires different thinking. We have been very impressed by the good outcome of some of our triple negative breast cancer patients and believe this a very fertile area for additional investigation

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), a plant used in folk medicine for several centuries.  (Wikipedia)

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.