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New Research Approaches Explored
Seminar Examines Cancer in Women

By Carla Garnett

Photos by Bill Branson

On the Front Page...

From body size to pathology standards, from high-tech advances to potential vaccine policy, a recent Women's Health Seminar looked at new ways of looking at cancers affecting women.

Its role in diabetes established, obesity is also being examined as a cancer risk factor. Dr. Rachel Ballard-Barbash, associate director of NCI's Applied Research Program, discussed anthropometrics — the study of body measurements — and how body size and shape may increase women's chances of getting cancer.

Continued...


NCI's Dr. Rachel Ballard-Barbash

"Why are we concerned about this? I think most people are aware that the United States is leading the world in its epidemic of obesity, with the exception of a few small islands in the Pacific," Ballard-Barbash explained. "In that regard, women in particular are at increased risk."

More than 35 percent of U.S. women can be classified as obese; more than 60 percent of U.S. men and women are said to be overweight.

The relationship of body size and cancer was first considered in the 1930s and 1940s, she noted. The science has evolved from studies of excess energy intake and calories to examining the effects of metabolism and hormones.


"Most recently people have questioned whether being in a state of positive energy balance — where one is eating more than one is burning — leads to a state that may increase risk for cancer," she said. Early research examined weight as a measure of body size, but that did not account for the wide ranges of height. Body mass index, or BMI, a measure of weight adjusted for height, has been used most commonly since the early 1980s. By the early 1990s, researchers began to look at body fat location, and most recently, weight gain in later years of life has been examined. Muscle mass and bone density are also under consideration.

Ballard-Barbash summarized results from several hundred studies: Heavier women are at increased risk of endometrial, postmenopausal breast, colon, kidney (renal cell), esophageal (adenocarcinoma) and thyroid cancers. Risks for several of these cancers are also increased among women with increased central body fat (the popularly termed "apple-shaped" body) and with large amounts of weight gain during adult life. Mortality from a number of cancers is also increased among heavier women with most of the evidence related to breast cancer.

Women who are heavier at breast cancer diagnosis and gain large amounts of weight during treatment have poor survival and increased likelihood that the breast cancer may recur. The effect of increased body fat on estrogen production, particularly among postmenopausal women, is being examined as one major explanation of these findings. Other mechanisms being examined in humans include effects of insulin-like growth factors, levels of various hormone-binding proteins, and other insulin-related measures.

In addition, she noted, even moderate physical activity appears to reduce risk for colon, breast and endometrial cancers in women, and for colon cancer in men. The most dramatic reduction of risk was seen in men who reported vigorous physical activity.

"The standard guidance," Ballard-Barbash concluded, "is to avoid weight gain that commonly occurs during adult life by adopting a physically active lifestyle and energy-appropriate eating habits...In terms of physical activity, general recommendations to accumulate 30 minutes a day of physical activity may not be enough. Many studies suggest we need up to an hour a day of actual exercise."

Dr. James Connolly, director of anatomic pathology at Beth Israel Deaconess Medical Center, suggested setting clearer standards for pathologists who examine mammogram and biopsy results.


Dr. James Connolly

Interpretations of test results vary widely in this field, he said, and establishing universally accepted benchmarks may be critical for a cancer such as ductal carcinoma in situ (DCIS), in which often trace evidence of diseased cells and their locations can determine diagnosis, extent of surgery and prognosis. The problem with the current classification system, Connolly said, is that definitions for subtypes are not uniform and many lesions have mixtures of subtypes.

"With so many varying definitions, looking at the various studies and trying to make recommendations is a nightmare," he explained, showing slides of cancer cells that pathologists can and often do read differently. "Not everyone's low grade is the same...The reason things like definition and classification are important is because in the past all patients with DCIS have been treated with mastectomy. Now we're trying to select which patients can be treated with breast conservation."


DCIS, a precursor to invasive breast cancer, often does not appear as a solid mass in tests, but shows up as tiny tumors along the vein-like ducts in the breast. This presents challenges for determining whether and where disease has spread and for complete removal of tumors via lumpectomy.

Surgeons like to use a pie-chart image of the segments of the breast, wherein they could simply remove cancerous slices without affecting healthy tissue, Connolly said. Unfortunately, the breast ductal system is not nearly that simple. To illustrate his point, he showed a slide of the ductal system that resembled a large number of interconnecting, looping highways, wherein removal of a diseased "road" would be nearly impossible to accomplish without somehow affecting a neighboring road or a road that feeds into it.

"It varies from woman to woman, but there are anywhere from 6 to 11 ductal systems," Connolly explained, "and they branch. They overlap one another. So you could have a pathologic slide that shows normal ducts and lobules, then cancer...The anatomy is very complicated, and varies from one woman to another."

Another complication is deciding whether a DCIS is growing contiguously. In other words, using the roadways analogy, if DCIS is found at two or more intersections, has it grown along the road between the points or is removal of the intersections adequate surgical treatment?

"Distribution in the breast, histologic features, size and adequacy of excision seem to be important considerations in selecting appropriate therapy for patients with DCIS," he concluded. "There are difficulties in assessing each of these factors and the relative importance and interaction among them are not well-defined. We want to find better methods to determine extent of invasion, better methods to assess biologic potential, and agents to suppress progression to invasion."

Dr. Elise Kohn, chair of the gynecologic malignancies faculty at NCI's Center for Cancer Research, explained how recent technological advances can aid diagnosis and treatment.


Dr. Elise Kohn

"There's clearly an issue that we have to understand how to identify patients who have the highest risk of having the worst cancers," she said. "Wouldn't it be great if we could identify those women and men at a time before they have severe disease, maybe even at a time before the cancer has truly transformed? If we start to mix and match our technologies, we're going to make that progress."

Defining cancer as "a disease of deranged, dominating or defective protein pathways and networks," she described the group's work in proteomics as four-fold: early detection, protein network profiling, individualized therapy and target discovery.


"One of the biggest challenges is finding the correct needle in a haystack," she said. "Ovarian cancer is a relatively rare disease among rare diseases. One in 2,500 postmenopausal women may get ovarian cancer in her lifetime."

Using mass spectroscopy with artificial intelligence, the group is trying to find the unique "signature" of ovarian cancer in blood before women have to undergo ultrasounds or biopsies.

Kohn said artificial intelligence programs now allow scientists to teach computers what to look for in tiny blood samples — whether protein patterns appear normal or cancerous. In early results, Kohn's group was able to detect stage I disease, the most curable stage.

"The goal is to identify patients quickly who are high-risk and move them through to evaluation, to find the disease — whether it's breast cancer, ovarian cancer or others — at an early and treatable stage," she said. "In ovarian cancer, early detection has a high frequency of cure and good outcome. It would make a big clinical impact."

Kohn also briefly described technology scientists are using to monitor how therapies destroy or starve malignancies. By seeing how such drugs as Gleevec attack cancers, researchers hope not only to design better medicines, but also to explain why some treatments do not work in some patients and why some patients on similar therapies relapse.

"We think these approaches allow us to start personalizing how we approach patients for diagnosis and also therapy," she said.

Dr. Douglas Lowy and his research group are on a quest for vaccines to attack the human papillomavirus (HPV) and cervical cancer. It has been shown that virtually all cervical cancers are caused by HPV, a virus that accounts for one-third of all cancers attributable to infectious agents. More than 600,000 cases of cancer worldwide per year can be traced to HPV.

Dr. Douglas Lowy and his group are researching vaccines to attack the human papillomavirus (HPV) and cervical cancer.

"Cervical cancer is the number two cancer in developing countries, whereas it is a less common cancer in the U.S. and other developed countries," said Lowy, deputy director of NCI's Center for Cancer Research. "The principal difference is attributable to having high quality Pap screenings in the developed world, whereas this is not available in developing countries."

Cervical HPV infection is extraordinarily common, even in the U.S., Lowy pointed out. About 10 million cases per year are estimated in this country, but the large majority are subclinical, or very early stage abnormalities. In fact, only 2 million of the infections ever rise to low-grade disease and only 15,000 advance to invasive cancer. At any point after infection, cure of infection (and thus prevention of cancer that might have resulted) is possible.

Lowy and his NCI colleagues developed the technology for the current candidate prophylactic HPV vaccine, composed of virus-like particles. Overviewing proof-of-principle efficacy trials with this vaccine approach, conducted by pharmaceutical companies Merck and GlaxoSmithKline, Lowy stressed that "these efficacy trials have shown that an HPV virus-like particle vaccine can protect young women from the acquisition of new persistent HPV infection." However, he added, larger trials and longer follow-up are needed.

"The results suggest that there is safety, immunogenicity and efficacy so far, but there are a lot of other issues that need to be addressed," he said. Further research is needed, for example, to determine how long the vaccine's protective effects last.

Realistically, Lowy cautioned, even if vaccination proves widely effective, it will take more than 20 years to reduce incidence of cervical cancer.

"The major benefits of a preventive vaccine in countries with effective Pap screening are a reduction in the number of abnormal Pap results, reduction in follow-up costs in such cases, and fewer cervical cancer cases in women who do not undergo regular Pap screening," he concluded.

To view the entire ORWH seminar online, visit Past Events at http://videocast.nih.gov/.


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