New research launched with WHI biological samples

The Women's Health Initiative is having a sequel.

The National Heart, Lung and Blood Institute in January awarded a dozen contracts worth a total of $18,679,000. The money will fund researchers, many of whom have not previously worked on the initiative, to spend the next two years analyzing more than 5 million blood and other fluid samples. These biologicals were collected during the 15-year project that randomized more than 68,000 postmenopausal women to various hormonal and dietary interventions. Thousands more participated in the observational arms.

"When big studies end, the samples are often forgotten. These are too valuable. We are determined that we will not let that happen," said WHI Project Officer Jacques Rossouw, MD. "What comes out of this may be as important as what the WHI contributed in the past."

The hope is that these efforts, which will not require any additional human participation, will better explain the WHI's findings, particularly those related to hormone therapy.

These samples will be used to look at how initial, naturally occurring levels of estradiol and sex hormone-binding globulin affect hormone therapy's impact on cardiovascular disease, blood clots, dementia and fracture. Another project will attempt to determine the influence of hormone metabolism on the incidence of hip fracture and breast cancer.

A paper in the July 17, 2002, Journal of the American Medical Association linked hormone therapy to an increased risk of breast cancer, stroke and heart attack, ending the dream that this was a strategy to protect women from cardiovascular disease. Now, out of the dozen projects, these two are expected to produce the most immediately useful information.

"The idea is to try to explain the biology behind the results," said Lewis Kuller, MD, DrPH, principal investigator on one of the projects and professor of epidemiology at the University of Pittsburgh. "Is there a difference in metabolism of estrogen that may explain the WHI's findings? That can have important implications if we can find the metabolite that is contributing."

Several projects also will explore some of the seemingly counterintuitive findings about diet, such as those published in February 2006 issues of JAMA, the New England Journal of Medicine and the Archives of Internal Medicine. These findings among study participants showed that low-fat diets had no impact on heart disease and cancer risk. Calcium and vitamin D preserved bone, but not as much as previously thought.

To explain these results, researchers will examine the role of fat cell proteins in developing cancer or stroke and look for mechanisms that translate physical activity into a reduced risk of coronary heart disease. Another project will try to determine which nutrients improve health.

Answering new questions

The existence of such a large collection of samples along with extensive clinical data on many women means that researchers also will tackle questions they couldn't consider when the WHI began in 1991. One project, for instance, will look for biomarkers that could indicate breast cancer long before it shows up on a mammogram.

"Mammography has reduced mortality, but it does have certain limitations with sensitivity and specificity. Anything to improve that would be helpful. We hope to identify markers that will detect breast cancer early and provide better risk prediction," said Christopher Li, MD, PhD, lead researcher on that project and an associate member of the Fred Hutchinson Cancer Research Center in Seattle.

Other projects will hunt for proteins and genes associated with increased risk of coronary heart disease, stroke, breast cancer, colon cancer and hip fracture.

"It's probably multiple different genes that work with environmental factors to create risk," said Rebecca Jackson, MD, professor of medicine and associate director for clinical research at The Ohio State University in Columbus. "Now we have the technology to look across the entire genome to find them, and we could find new targets potentially for therapy."

For example, Dr. Jackson will be investigating the links between genetics and fracture to identify more accurately whose bones will break, regardless of bone mass, and who is in more urgent need of medication.

"Pharmacologic intervention is expensive and not for everybody," she said. "We want to be able to focus on these individuals most likely to get the greatest benefit."

Women's health experts praised the fact that these samples will continue to provide useful information to help physicians.

"It's exciting that we could be able to fine-tune the data from the WHI and hone in better on who may really benefit from hormone therapy and who might not," said Ann Honebrink, MD, medical director of Penn Health for Women in Radnor, Pa.

Another dozen contracts for biological sample work will be awarded next year.

Additionally, about 80% of WHI participants continue to be followed. This effort is expected to continue until 2010, and several more papers from this study's human side are due to be published before the year is over.