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story.lead_photo.caption Beginning in the early 2000s, studies of diabetics showed that those who had taken metformin had unusually low rates of certain cancers -- in some analyses, the risk was halved -- and lower rates of cancer death. (Dreamstime/TNS)

Being too fat raises the risk of Type 2 diabetes. That's common knowledge.

What is less well-known is that scientists have linked cancer to the same obesity-related metabolic abnormalities that drive diabetes—especially resistance to insulin, the hormone that enables cells to absorb blood sugar and turn it into energy.

Indeed, an American Cancer Society report published this week shows that while overall cancer rates have been falling for 25 years, partly because of less smoking, obesity-related cancer deaths are rising.

The biologic connections are complex and still unclear, but they fit with a hallmark of cancer that was recognized a century ago: Malignant cells thrive on sugar, or glucose. They take up much more glucose than healthy tissue.

Obese patients' high blood sugar "may impact tumor growth by providing cancer cells with an abundance of fuel," explains a review article co-authored by Ryan Dowling, a biochemist at Princess Margaret Cancer Center in Toronto.

Although the worldwide obesity epidemic makes this cancer link ominous, the evolving understanding of it suggests that targeting insulin resistance could have anticancer effects. That's why metformin, the mainstay diabetes drug that reduces the liver's release of glucose, is being investigated to help treat and even prevent cancer. Scores of clinical trials around the world are testing it in breast, bladder, lung, colon, gynecological and other malignancies.

"I don't think anybody expects that metformin will have a drastic or long-term effect on cancer by itself," said Fox Chase Cancer Center oncologist Daniel Geynisman, who is conducting a trial of metformin in prostate cancer that has come back after conventional treatment. "The question is, can it augment our standards of care—not to mention helping with" insulin resistance.

Metformin also has the plus of being a well-tolerated, inexpensive, generic drug.

"It costs pennies a day," said Dowling in Toronto. "If it were to work, it would be a massive bonus."

Starting 50 years ago, population-based studies found that diabetes increased the risk of numerous types of cancer, and worsened the outlook. But an "association," as scientists call it, just raises a red flag.

"A critical question is whether the associations between diabetes and the risk of certain cancers is largely due to shared risk factors (obesity, poor diet, physical inactivity and aging), or whether the metabolic derangements typical of diabetes increase the risk for some types of cancer," the American Cancer Society and American Diabetes Association wrote in a 2010 joint report on diabetes and cancer.

Researchers are still deciphering the answer. Studies in cells and animals show that signaling proteins secreted by fat, called adipokines, are altered in obesity and sometimes overstimulate cancer cells. Chronic inflammation and sex hormones also seem to contribute to the interplay of obesity and cancer. But insulin, produced by the pancreas to regulate blood sugar, is most consistently implicated as a culprit in cancer development and outcomes.

Many types of cancer cells grown in lab dishes, particularly breast cancer cells, produce an abundance of protein "receptors" that receive signals from insulin and a closely related hormone called insulinlike growth factor. This signaling network helps malignant cells get and use glucose, and may activate pathways that drive cancer cell growth, proliferation, survival, and metastasis, the deadly spread to distant tissues.

"It also appears that insulin (signaling) may stimulate normal cells that are involved in cancer progression," such as smooth muscle cells that form new blood vessels needed by tumors, said the ADA/ACA joint report.

If malfunctioning insulin promotes cancer, could improving the hormone's function inhibit cancer? And could normalizing insulin help cancer patients even if they don't have diabetes?

Those logical questions led scientists to look at metformin, clinically developed in the 1950s and now the most-prescribed diabetes therapy in the world. Taken as a pill, it lowers blood sugar by preventing the liver from producing too much glucose, as well as by making muscle and fat cells more sensitive to circulating insulin.

Beginning in the early 2000s, studies of diabetics showed that those who had taken metformin had unusually low rates of certain cancers—in some analyses, the risk was halved—and lower rates of cancer death.

Cell and animal studies bolstered these observations, suggesting that metformin did indeed have antitumor effects and was worth testing in cancer patients.

The high hopes were tempered in 2015. One of the first rigorous clinical trials to compare metformin to placebo found it had no impact on survival. However, the trial was conducted in patients with advanced pancreatic cancer, a notoriously aggressive, hard-to-treat disease.

Ongoing trials in less formidable cancers are expected to reveal whether metformin has benefits—and survival is not the only measure. Some studies are also looking at weight loss, metabolic factors, cardiovascular disease, and quality of life.

Preliminary results from a large Canadian-led trial of early-stage breast cancer patients are encouraging. Ultimately, the study aims to see whether five years of metformin—given after standard breast cancer surgery and chemotherapy, if warranted—can keep cancer from recurring and improve survival over a decade. The women are not diabetic, although most are overweight or obese.

After the first six months, women on metformin had significantly greater decreases in weight, blood glucose, insulin and leptin (a hormone involved in fat storage) than women on a placebo.

The results "provide clear evidence that metformin improves the metabolic profile of nondiabetic breast cancer patients, regardless of initial weight or degree of insulin resistance," the researchers wrote in the Journal of the National Cancer Institute.

Study leader Pamela J. Goodwin, a breast oncologist at Mount Sinai Hospital and a professor at the University of Toronto, has spent decades researching the role of body size, nutrition, exercise, and factors such as insulin on breast cancer prognosis. Still, she said, it's too soon to draw conclusions about metformin's ability to reduce the chance of poor outcomes.

"It's possible that some of the impact of obesity and altered metabolism may be 'baked in' at the time of cancer diagnosis," Goodwin
said. "While the cancer was developing, it made an aggressive cancer that won't be changed by metformin."


Despite the unknowns, James Smith, 76, a retired electrical engineer in Blue Bell, thought that he had nothing to lose by joining the clinical trial that Geynisman is leading at Fox Chase Cancer Center for prostate cancer patients who are overweight or obese.

The trial is built on the observation that prostate cancer survivors who suffer a "biochemical" recurrence—meaning the only sign that cancer is back is a rising PSA blood test—may have a worse prognosis if they have elevated insulin levels. Such men are often put on a testosterone-suppressing drug, even though that has no clearly proven survival benefit, and its unpleasant side effects include sexual dysfunction.

When Smith's PSA began rising in 2015, five years after his prostate was removed, Geynisman recommended a course of radiation—and joining the trial. Participants get six months of a mild testosterone-inhibiting drug called bicalutamide, with or without metformin.

Smith, who was randomly assigned to the metformin group, saw his PSA level quickly fall and remain very low for two years. That can sometimes happen with bicalutamide alone, so the effect of adding metformin won't be clear until the trial ends two years from now. But Smith is hopeful.

"The trial (treatment) ended after six months, but since metformin seemed to be working so well, I continued on it for two years," he said. "From what they explained, cancer likes the sugar. But apparently, the cancer can become resistant."

"For the effort it took and the lack of side effects, metformin was a no-brainer," added Smith, who is now on a powerful testosterone-suppressing drug. "The only thing was, every time I went for a physical, the first question was, 'Do you have diabetes?' I said, 'No, I'm taking it for cancer.'"

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