Miracle Drugs?

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From Paths of Progress 2016

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Our Medicine Cabinet May Already Hold Keys to Fighting Some Cancers

by Rob Levy

To view the latest drugs being tested to prevent cancer, you could visit any of hundreds of academic and pharmaceutical laboratories around the world. There, you'd see scientists poring over images of chemical structure and computer data, attempting to identify the most promising drug candidates.

Or, you could visit your medicine cabinet.

The notion that existing drugs – not just compounds created at a cost of millions of dollars and consuming decades of research work – could help prevent cancer might sound like a disreputable Internet rumor. But research findings stretching over more than a decade argue in favor of it.

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The names of these potentially cancer-preventing drugs and compounds read like the inventory of any self-respecting local pharmacy: aspirin, vitamin D, and metformin (widely used for diabetes). And, if one of the healthiest activities known to humankind counts as preventive medicine, exercise should be included as well.

"There's a great deal of interesting science being done to understand the fundamental biologic pathways involved in cancer. We're discovering that a number of compounds used routinely to treat other conditions or maintain health may actually target some of these pathways," says Charles Fuchs, MD, MPH, chief of the Division of Gastrointestinal Oncology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC).

Fuchs has led numerous studies of aspirin and other common medicines' ability to prevent colorectal cancer, or prevent it from recurring in people who have had the disease. The advantage of such known compounds is not only economic but logistical: As they're already known to be safe, they can pass through clinical testing more speedily.

Early Clues

The first sign that aspirin might have a future in colorectal cancer prevention came in the 1980s, in laboratory studies that suggested that aspirin-like compounds can reduce the proliferation of colon cancer cells. It was postulated that aspirin interfered with a growth-related enzyme called COX-2 in the tumor cells.

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Paired with healthy habits like exercise, common medicine cabinet items such as aspirin, vitamin D, and metformin show potential in preventing some cancers.

To pursue the matter further, Fuchs and his colleagues analyzed data from a long-term epidemiological study in which a connection between aspirin and cancer prevention wasn't even on the radar. The Nurses' Health Study, which began tracking the health of 122,000 nurses in 1976, had been collecting data on participants' aspirin use since its inception. Study leaders were hoping to determine if regular use reduced the risk of heart disease. Fuchs put the data through a different kind of filter: "We asked whether women who took aspirin had a lower risk of colon cancer," he says.

The result, published in 2005, was unequivocal: Regular aspirin-takers had a significantly lower risk of developing colorectal cancer, and the benefit was directly related to how much aspirin they took. Those who took higher amounts received, on average, more of a gain than those who took lower amounts. This kind of accordance, known as a "dose-response" relationship, is powerful information in science. "When we see that kind of relationship, it gives us a better sense that associations are real," Fuchs says.

Investigators now had two types of evidence that aspirin and related compounds could lessen the risk of colorectal cancer occurrence or recurrence – results from laboratory experiments and from a large "observational" study that followed people's health over a period of many years. The strongest evidence would need to come from an interventional clinical trial, a carefully controlled study in which the effect of aspirin would be compared to that of a placebo, or inactive pill, in people at risk for colorectal cancer.

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The results of that trial showed that participants who took aspirin or celecoxib, a pain-reliever that hits the same molecular target as aspirin, had a smaller chance of developing adenomatous colon polyps – noncancerous growths in the lining of the colon that can be a forerunner of cancer – than those who took a placebo. "The findings of this study provided Level I evidence, the strongest type, that aspirin can be a form of chemo-prevention for colon cancer," Fuchs remarks.

Fuchs and his team next set out to determine whether aspirin could help people already diagnosed with colorectal cancer. As before, they hopped aboard a study that was already underway. "The National Institutes of Health had launched a clinical trial of a potential new therapy for patients with stage III colon cancer," he relates. "We 'nested' a study inside it, distributing questionnaires about aspirin use to the study participants." The compliance rate – the proportion of participants who completed and turned in the questionnaire – was an astounding 98 percent. Aspirin and related medications again came out as winners: Patients who took aspirin or celecoxib along with chemotherapy following surgery survived longer than those who took a placebo.

On the basis of these findings, DF/BWCC's Jeffrey Meyerhardt, MD, MPH, and Fuchs launched a nationwide clinical trial in which patients newly diagnosed with colon cancer were randomly assigned to receive either celecoxib or a placebo to determine if adding celecoxib to standard therapy could improve patient results.

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Kimmie Ng, MD, MPH, and her colleagues study whether vitamin D has a protective effect again colon cancer.

Researchers then circled back to the place where hints of an anti-cancer role for aspirin first surfaced – the laboratory. By studying the molecular machinery within colorectal tumors, they're hoping to identify which patients have the most to gain from aspirin therapy. One study, led by Fuchs, found that patients with colorectal tumors high in COX-2 had a sharply lower chance of dying of colorectal cancer if they took aspirin following treatment. Another study, led by Dana-Farber's Shuji Ogino, MD, PhD, found a similar survival boost for patients whose colorectal tumor cells carried a mutation in the gene PIK3CA. (Both sets of findings will need further confirmation before they affect patient treatment.)

With the case for aspirin as a colorectal cancer preventer seemingly sealed, one might expect public health authorities to recommend it for people at risk for the disease. In 2007, however, the U.S. Preventive Services Task Force announced that while there's sufficient evidence of aspirin's effectiveness, the potential risks of regular aspirin consumption (mainly gastrointestinal bleeding) outweigh its benefits. Some in the research community have argued vigorously against this ruling, and in late 2015 the task force announced it is reconsidering its decision.

Familiar Names

Meanwhile, evidence is mounting that vitamin D can also help protect against colorectal cancer. A study presented last year by Dana-Farber's Kimmie Ng, MD, MPH, found that patients with metastatic colorectal cancer who had high levels of the vitamin in their bloodstream prior to chemotherapy treatment survived longer, on average, than patients with lower levels. The study didn't examine whether there is a biological cause-and-effect relationship between higher vitamin D levels and extended survival, so it's premature to recommend the vitamin as a treatment for colorectal cancer, researchers say.

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Another agent gaining attention in colorectal cancer prevention is metformin, a standard drug for type 2 diabetes. Able to reduce glucose (sugar) production by the liver, metformin also has a way of easing cancer cells' frenzied use of energy – possibly mimicking the benefits of healthy diet and exercise. Meyerhardt is leading a clinical trial of metformin for patients with colorectal cancer.

The most readily available, least expensive of all health interventions – exercise – is also getting a look as a potential colorectal cancer deterrent. "We've led three observational studies on exercise, and they consistently show that patients who are more physically active have a lower risk of recurrence and of dying from the disease," Meyerhardt says. The optimal amount of exercise necessary to attain maximum benefit seems to be about 150 minutes a week of moderate activity such as brisk walking, although lower levels of exercise probably are beneficial as well. Meyerhardt is now leading a study involving survivors of colorectal or breast cancer to see whether exercise affects participants' blood levels of insulin and inflammation-causing compounds, high amounts of which can spur cancer growth.

Because so much evidence points to, but doesn't conclusively show, an anti-colorectal cancer role for aspirin, vitamin D, metformin, and exercise, Meyerhardt walks a fine line when discussing them with patients. "I tell them we have observational studies of the benefits of these approaches, but no definitive data from randomized clinical trials yet," he remarks. "I say that the data for the benefits of exercise are strong and consistent. For exercise and vitamin D, in particular, I talk about the general health benefits they can provide."

Up Next: Breast Cancer

The encouraging news about aspirin and colorectal cancer has sparked interest in studying it in other forms of cancer as well. Ironically, however, the very ordinariness of aspirin has militated against such research.

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Wendy Chen, MD, MPH, helped lead a study that found aspirin can be beneficial for women with breast cancer.

"Clinical trials on drugs are typically funded by the companies that develop and produce them. In the case of aspirin – a generic drug that costs less than $6 for a year's supply – there's no financial incentive for manufacturers to understand how it might be helpful in cancer," says Wendy Chen, MD, MPH, a breast cancer physician-researcher in the Susan F. Smith Center for Women's Cancers at Dana-Farber.

The obstacles don't end there; some exist within academic research centers themselves. Internal review panels – which examine proposed studies to ensure they protect patients and are scientifically sound – are often more interested in research into cutting-edge, targeted therapies than in old standby drugs, however compelling the science in their favor may be, Chen remarks.

Such impediments didn't dissuade Chen. In 2010 she and Michelle Holmes, MD, PhD, of the Harvard T.H. Chan School of Public Health published an observational study that showed that women with breast cancer who took aspirin at least once a week were 50 percent less likely to die of breast cancer. A British study two years later produced similar findings.

Chen, Holmes, and Eric Winer, MD, director of Breast Oncology at the Susan F. Smith Center, procured a $10 million Breakthrough Grant from a U.S. Department of Defense Office research program to organize a clinical trial that will test whether aspirin helps women (and men) with breast cancer avoid a recurrence of the disease and live longer. The trial will enroll 3,000 patients in the first clinical test in the U.S. of aspirin in the disease.

While such studies may lack the cachet of trials involving the latest laboratory creations, they deserve to be carried out with equal scientific rigor and care, Fuchs says. "Our goal is to test these familiar drugs with the same scrupulousness as we would use in a test of chemotherapy agents. If we're going to recommend them for use in patients, we want to be sure the science supports us."

Learn more about exercise and cancer prevention.

Paths of Progress 2016 Table of Contents

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