Spring 2013

The study that saved tens of thousands of lives
By Rachel Tompa




When Ruth Ross signed up for a women’s health study at Fred Hutchinson Cancer Research Center more than 15 years ago, she wasn’t looking to make history. She just wanted to help future generations of women live healthier lives.

Ruth Ross
Ruth Ross
Ross didn’t know then that she had become part of an unprecedented research effort that would impact her own immediate health and the health of millions of other women of her generation—and those to come.

The 72-year-old Woodinville, Wash., resident is part of a legion of more than 160,000 postmenopausal women who volunteered for the Women’s Health Initiative, one of the largest women’s health studies ever conducted in the U.S.

Since Ross joined the WHI, many important discoveries have been announced, but none more important than the breast cancer risk finding in 2002. That breakthrough discovery alone shocked the medical community and the public, and it helped save the lives of tens of thousands of women each year in the U.S. and throughout the world.

“It feels very good that there was something I was able to contribute that could help save lives—and now, rather than later,” Ross said.

Headquartered at Fred Hutch, the WHI reaches a major milestone this year—its 20th anniversary.

As WHI researchers at Fred Hutch and throughout the country—and the thousands of women like Ross who continue to participate in WHI studies—pause to celebrate their contributions, one thing remains clear in their minds: WHI’s discoveries over the past 20 years have reduced the risk of breast cancer, heart disease and stroke for women.

Today, the WHI remains a crucial contributor to the understanding of women’s health issues and shows no signs of slowing down. 

A pivotal finding in cancer risk

As WHI researchers uncovered 10 years ago, Ross and millions of other U.S. women were swallowing pills every day which, unbeknownst to them, were increasing their risk for disease.

In July 2002, the WHI released its findings that combination hormone replacement therapy—at the time prescribed to 15 million post-menopausal women in the U.S. to alleviate symptoms of menopause— dramatically increased the risk of heart disease, stroke and breast cancer. This type of therapy was also common in many other countries.

Ross’ doctor had prescribed hormone replacement therapy for its purported health benefits before she ever joined the WHI, and she paid close attention to the study’s findings.

“The next time I saw my primary care physician, I talked with her about it and we literally started taking me off of it. I did stop, right there and then,” Ross said. “The hormone replacement therapy results caused such a sea change.”

Within a year of the study’s finding, 5 million women had dropped the therapy, reversing a long-held trend of taking hormones to relieve menopausal

Dr,. Ross Prentice
Dr. Ross Prentice
symptoms. Also, there was a widespread belief that hormones would reduce women’s risk of heart disease and keep them youthful and healthy.

The WHI study singularly changed the face of women’s health around the world: Because of the decrease in hormone therapy use following the finding’s release, an estimated 20,000 U.S. women per year since 2002 have been spared from developing breast cancer, with likely tens of thousands more around the world. Researchers also determined that decreases in heart attack and stroke in postmenopausal women were likely due to the drop in hormone use.

“There’s no doubt that this is the signature finding of the WHI. It gave rise to a major change in clinical practice in this country,” said Fred Hutch’s Dr. Ross Prentice, a chronic disease prevention scientist and one of WHI’s founders.

As part of the WHI’s initial set of clinical trials, the hormone therapy studies began in 1993 to test, as previous small studies had suggested, whether long-term use of these drugs could prevent heart disease, hip fractures and other diseases. They didn’t.

“The release of these findings was really a watershed moment after which many things changed with respect to hormone therapy and disease,” said Fred Hutch’s Dr. Andrea LaCroix, a WHI investigator and public health expert. LaCroix is currently conducting another WHI study that has enlisted 8,000 participants over 62 to determine activity levels needed to maintain heart health and prevent injury from falls.

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Stopping cancer before it starts

According to the American Association for Cancer Research, two-thirds of the estimated 575,000 cancer deaths in the U.S. in 2012 were caused by preventable risk factors such as smoking, poor diet and lack of exercise. These facts underscore the continued importance of the WHI, which seeks to prevent women from getting cancer and other diseases.

"Many cancer prevention efforts also prevent other diseases, like heart disease, stroke and diabetes," said Dr. Garnet Anderson, a lead WHI investigator and director of Fred Hutch’s Public Health Sciences Division. "So it just makes sense that we should be promoting health."

Dr. Garnet Anderson
Dr. Garnet Anderson 

Researchers like Anderson recognize that stopping cancer before it ever starts is a lofty goal and one that typically requires large and lengthy studies to determine which lifestyle factors or treatments can prevent cancer years down the road. But considering how much WHI has contributed to women’s health already, it’s imperative to stay on track.

"These findings had an immediate public health impact, because women could make the decision to change their lifestyle on their own," Anderson said about the 2002 study. "They could just decide, ‘I’m not going to take these risks, I’m going to stop taking these pills today.’ It was also a dramatic research finding because it contradicted a lot of the preliminary work that motivated that trial."

The Fred Hutch/WHI connection

Fred Hutch houses the WHI’s Clinical Coordinating Center and, jointly with the University of Washington, one of its 40 clinical sites. Fred Hutch researchers have led many of the WHI findings in the last two decades including some of the groundbreaking hormone therapy findings.

WHI owes its beginnings to two pioneering researchers at Fred Hutch: Prentice and the late Dr. Maureen Henderson. The two had been trying to study the effects of a low-fat diet on breast cancer risk since the early 1980s, but met with little success raising the kind of funds needed for such ambitious work.

Prevention studies by their nature often require thousands of healthy volunteers and many years to follow their health. In 1991, in what Prentice calls the WHI’s "pivotal event," the late Dr. Bernadine Healy became the first female director of the National Institutes of Health and set about rectifying the disparities in research fields that had largely focused on men’s health in previous decades.

Under her direction, Prentice, Henderson and WHI colleagues around the country got what they had been wishing for: $625 million to start and coordinate the WHI, the largest study of women’s health ever undertaken in the U.S. The initial study was funded to run for 15 years, and portions of the WHI have since been extended to 2015, bringing the total amount of funding to approximately $800 million.

Hundreds of millions of dollars and decades of studies is a substantial investment. But these large, careful trials are extremely important for women’s health and for general disease prevention, Prentice said. In fact, the hormone therapy arm of the WHI, which yielded such a clear improvement in women’s health, met with the most criticism during planning phases.

Prentice and his colleagues had to fight to keep these trials in place during early reviews of the WHI, as many researchers were convinced that the drugs would only benefit women based on results from earlier studies.

"It’s astonishing that hormone therapy use had gone on for so many years, had been used by millions and millions of women, without an adequate study examining its effects," Anderson said.

As for the studies’ price tag, the savings from prescription costs of hormone therapy that U.S. women are no longer using more than cover the entire $800 million cost of the WHI, and the savings in health care costs from the number of women who have been spared from breast cancer, heart disease and stroke add up to many times that amount, Anderson said.

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Devoted WHI participants

Over the years, the many studies conducted by the WHI have unveiled another surprise: the diligent dedication of study participants who came to understand they were taking part in something larger than themselves.

The WHI conducted trials to ask three different questions about the health of postmenopausal women: Does hormone therapy protect women against heart disease, breast cancer and hip fractures? Does a diet low in fat and high in fruits, vegetables and grains reduce the risk of breast cancer, colon cancer and heart disease? Can calcium and vitamin D protect women from hip fractures and colon cancer?

Together, answering these questions required the volunteer commitment of more than 68,000 women between the ages of 50 and 79. The WHI also included an observational study that followed an additional nearly 94,000 women and tracked their lifestyle, general health and disease outcomes.

The 161,808 women who volunteered for these four segments of the WHI were seen at 40 different clinical centers around the country, including more than 3,400 who participated through the Seattle clinic.

WHI organizers expected challenges in attracting and retaining so many study volunteers for such an ambitious trial. But the devotion of these women, who gave their time and effort freely to the cause of preventing cancer and heart disease, has never ceased to amaze researchers.

Even now, nearly 20 years after they originally joined, about 93 percent of WHI volunteers who agreed to extended participation still answer study questions every year.

“These women are amazing troopers to stay in a study for 20 years,” Anderson said. “They are very dedicated, wonderful participants.”

Ross is among that group of women who still answers research questions, and she has since signed up to volunteer for another WHI offshoot study on diet.

“Being in the WHI made me aware that there are other studies out there that I could help with,” she said.

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 The study that keeps on giving

While the hormone therapy findings had the most obvious impact on women’s health, the WHI’s two other original trials have made their mark on prevention research as well.

The calcium/vitamin D trial showed that these supplements provide a modest reduction in risk of hip fracture in older women and also increase bone density. The nutrition studies found a possible but modest reduction in breast cancer risk for women who ate a low-fat diet.

“These two trials are building blocks for future research areas that are really quite important,” Prentice said. “The relationship between diet and physical activity and chronic disease in particular is in great need of better methods and more study.”

Prentice, along with Fred Hutch nutrition experts Drs. Marian Neuhouser, Johanna Lampe and Lesley Tinker and other Fred Hutch colleagues are working on one such method: Instead of asking study volunteers to remember and record everything they eat, the scientists are searching for diet “biomarkers” in the blood and urine, signals that would tell them more reliably how much fat, carbohydrates or other nutrients a person consumes on a daily basis.

Beyond these three significant clinical trials on prevention research, which concluded in 2005, the WHI’s observational study continues to track women’s lifestyle factors and their influence on health.

Scientists from Fred Hutch and around the country use WHI data, as well as the 5.3 million blood and urine samples donated by WHI volunteers, to conduct hundreds of spin-off studies that have yielded numerous insights on women’s health, running the gamut from new ways to combat menopausal symptoms, to genes that influence height, to effects from heavy metal exposure.

“In the last several years, we’ve been transitioning to be a scientific resource for a much broader range of questions,” Anderson said. At Fred Hutch alone, the range of those questions is enormous. As techniques have recently emerged to more easily and rapidly examine the DNA and proteins present in blood, the WHI’s bank of millions of samples has proven even more useful.

For example, breast cancer epidemiologist Dr. Christopher Li has used WHI blood samples to search for markers of breast cancer.

Dr. Christopher Li
Dr. Christopher Li

Public health scientists Drs. Nicole Urban and Martin McIntosh used WHI specimens to study biomarkers of ovarian cancer. Drs. Ulrike Peters and Charles Kooperberg have identified many new genetic links to explain mysterious cases of inherited colorectal cancer.

Epidemiologist Dr. Alex Reiner has studied the genomes of African American and Hispanic participants of the WHI to find genetic links to diseases, height and body mass index in these minority groups.

Attempting to ease menopausal symptoms, LaCroix and Anderson are conducting a series of trials to find alternatives for women.

Recently, they found that the antidepressant escitalopram reduces hot flashes, and they are also evaluating yoga and other exercise, and some other drug treatments.

Dr. Polly Newcomb, head of Fred Hutch’s Cancer Prevention Program, and cancer prevention researcher Dr. Scott Adams are delving into links between heavy metals and breast cancer.

They are looking for traces of the common heavy metal cadmium and 18 other metals and elements in urine samples of WHI volunteers to investigate whether women with higher levels of metals are more likely to develop breast cancer, as some of Newcomb’s previous work has suggested.

“I’m sure that when it was designed, the WHI founders never in a million years thought that a researcher would come along and ask to evaluate cadmium in their study,” Newcomb said. “It just shows you how rich a resource the WHI is.”

Women’s Health Initiative by the numbers

20,000: Decrease of breast cancer cases in U.S. women per year since 2002 due to changes in clinical practices based on WHI findings.

5 million: U.S. women who stopped taking 
combined hormone replacement therapy 
in the year following the WHI discovery that 
these drugs increase the risk of breast cancer. Prescriptions for this type of hormone therapy dropped from 15 million to 10 million in 2003.

161,808: Women around the U.S. who 
volunteered for the WHI trials and observational study, making it the largest trial of women’s health in the U.S.

1993: First volunteer enrolled.

2013: First WHI volunteer to turn 100.

229: Number of WHI spin-off studies conducted around the country, ranging from genes that influence height to links between air pollution and heart disease to ways to detect breast cancer earlier.

5.3 million: Blood and urine samples from WHI volunteers that are used in these studies.

747: Scientific articles stemming from WHI.

$625 million: Funding from the National 
Institutes of Health to support the WHI’s first 15 years.

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