Breast cancer and glucose: metformin

Metformin, an inexpensive drug that has been prescribed for diabetes for decades, may lower breast cancer risk in patients with type 2 diabetes. For diabetic patients, metformin provides about a 30% reduction in the lifetime risk of all cancers.

Epidemiological data link metformin use in diabetic patients to reduced cancer incidence; researchers are conducting clinical trials to assess its effect on breast cancer.

Metformin inhibits glucose production in the liver; it also acts as a weak “mitochondrial poison” while targeting cancer stem cells. Mitochondria provide each cell with energy by converting nutrients into molecules that the cell can use.

Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. Researchers are examining its possible role in the prevention of breast cancerMetformim activates AMPK.

However, researchers do not understand the precise molecular mechanisms of action of metformin.

The research

A 2009 study examined 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. The pathologic complete response (pCR) rate was 24% in the metformin group of diabetic patients; 8.0% in the nonmetformin group of diabetic patients; and 16% in the nondiabetic group.

Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.

In 2012, researchers identified aspirin, statins and metformin as commonly used drugs that “may reduce breast cancer mortality among those with the disease by an amount that rivals the mortality reduction gained by currently used therapies.”

… the evidence is strongest for aspirin (approximately 50% reduction), statins (approximately 25% reduction), and metformin (approximately 50% reduction). As these drugs are generic and inexpensive, there is little incentive for the pharmaceutical industry to fund the randomized trials that would show their effectiveness definitively. We advocate that confirmation of these findings in randomized trials be considered a high research priority, as the potential impact on human lives saved could be immense (emphasis added).

In 2014, researchers found that metformin combined with tamoxifen “additively inhibited the growth” of ER+ breast cancer cells. This was a laboratory test of human breast cancer cell lines MCF-7 and ZR-75-1. This is only one in vitro experiment that supports using metformin to treat breast cancer.

From a report of a 2014 meeting in Milan:

Metformin is being extensively tested in cancer trials, including in one preoperative trial by their group. Various recent findings indicate that metformin could replace fasting which has been shown to possibly increase the efficacy of chemotherapy, could be beneficial in combination with radiotherapy and would able to increase the lifespan of mice. This confirms the biological potential of metformin and its interest as a drug reposition to treat some cancers.

A 2015 study examined more than 100,000 electronic medical records from Vanderbilt University Medical Center and Mayo Clinic by Xu. Researchers showed that metformin use significantly reduced the risk of cancer mortality compared to patients who were not using metformin; this included breast cancer.

UK research from 2015 also provided “evidence that breast cancer-specific mortality decreased with each year of metformin use.” For patients who developed diabetes after their breast cancer diagnosis, taking sulphonylurea derivatives “was strongly associated with cancer-specific mortality.”

Data from Egypt, reported in 2016, showed that metformin significantly decreased the number of metastatic cases of breast cancer after six months of hormone therapy. Women in the metformin group received 850 mg twice a day.

Analysis of 14,766 women from the Surveillance, Epidemiology and End-Results (SEER)-Medicare database data, published in 2017, showed that metformin (n=2,558) lower risks of a second breast cancer event by 28%; breast cancer recurrence by 31%; and breast cancer death by 49%.

Diabetic patients with cancer who take other drugs, such as sulfonylureas or insulin, have been shown to have an increase in mortality relative to those taking metformin.

Which breast cancer types?

Breast cancer has been categorized into five major molecular subtypes:

  • luminal A
  • luminal B
  • HER2+
  • breast-like
  • basal-like/triple negative

The question remains: does metformin act equally on all subtypes?

…in vitro studies strongly support a role for metformin, which is one of the most commonly used diabetic medications, as a generic therapy for most, if not all, breast cancer subtypes.

A meta-analysis published in 2015 showed the metformin improved overall survival for breast cancer patients by 65% after adjusting for hormone receptor expression. In vitro studies also suggest aspirin adds to metformin’s ability to control breast cancer.

A 2017 report suggests that “metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control.”

The Care Oncology Clinic in London is prescribing “approved drugs with known anticancer activity,” according to Travis Christofferson in  Tripping Over the Truth: How the Metabolic Theory of Cancer is Overdue. The four repurposed drugs: metformin, a statin, doxycycline (an antibiotic), and mebendazole (anti-fungal).

Currently there more than 40 recruiting and completed clinical trials in the cliental trials database that are focused on the use of metformin with combinational cancer therapies.
 
 

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