Understanding Breast Cancer

Breast cancer is among the diseases most feared by women and for good reason: An estimated 178,700 new invasive cases, plus another 30,000 or so in situ, will be diagnosed among women this year, and 43,900 will die of the disease, making it second only to lung cancer as a cause of cancer-related death. CSPH researchers are looking into the causes of breast cancer and how to prevent it.

According to Geoffrey Howe, Ph.D., head of the Division of Epidemiology and a world-renowned breast cancer expert, CSPH research has focused on the effects of environmental, lifestyle and genetic factors on breast cancer risk. The scope of research is wide, encompassing international as well as local studies that range from radiation to lineage.

The Metropolitan New York Registry of Breast Cancer Families, now centered at CSPH, will soon have an important impact on research both at the School and around the world. Sponsored by the National Cancer institute, the registry is part of an international consortium with sites in Australia, toronto and the United States.

Eligible families, recruited at each of the six participating New York medical centers and through community organizations, provide blood and urine samples, confidential family histories and other personal data. Participants who have had cancer are also asked to allow the registry to obtain tumor tissue samples. There are close to 500 families in the registry now; the goal is 1,600.

The registry’s biological samples and other data will be a unique resource for cancer researchers worldwide who are studying extended families with a high incidence of breast or ovarian cancer. Genetic factors are thought to be responsible for only 5 to10 percent of breast cancers, says Ruby T. Senie, Ph.D., principal investigator of the registry. “We need to look at the interaction between genetic and other environmental or lifestyle factors in participating families.”

“We realize we’re in a very early stage of genetic understanding,” Senie notes. “The first gene was found in 1994, but we hope to identify more.” She adds that the ultimate goal is to reduce incidence through understanding, and one way the registry will do this is by keeping participating families informed of relevant study findings through newsletters and seminars.

Regina Santella, Ph.D., the registry co-investigator, has the critical task of directing the Biomarker Core Facility, which processes and stores blood and urine samples for clinical and epidemiological studies. Santella oversees quality control as well as state-of-the-art laboratory processes. for example, if a family has a particularly interesting history, their lymphocytes can be “transformed”—or grown in culture—to provide a limitless source of DNA.

Long Island Study

Long Island Breast Cancer Study Project Principal investigator Marilie Gammon, Ph.D., meets regularly with LIBC Network members to discuss community concerns. From left: Ellen Triosi, Susan Teitelbaum, M.P.H. (study project coordinator), Dr. Gammon, and Dee McCabe.

The Biomarker Core Facility also plays a key role in the Long Island Breast Cancer Study Project (LIBCSP). Led by CSPH, this multi-disciplinary, collaborative effort among New York City and Long Island researchers, the National Cancer institute and the National institute of Environmental Health is examining the role that environmental factors play in the development of breast cancer. The project was mandated by an act of Congress in response to the efforts of local breast cancer activists. “This study is unique,” says principal investigator Marilie Gammon, Ph.D.“I don’t know of any other epidemiological study funded in this way.”

Using blood stored at the Core Facility, as well as tissue samples, Santella will utilize the tools of molecular epidemiology to determine whether exposure to polycyclic aromatic hydrocarbons (PAH) increases the risk of breast cancer. (PAH are environmental pollutants produced when anything organic is burned. Common examples are burning heating fuel and contaminants produced when charcoal-broiling a steak or hamburger.) She will measure actual DNA damage caused by carcinogens. Scientists believe that this technique provides more precise information than simply asking women about their exposures (see page 27).

In addition to PAH, the Long Island study will examine whether certain pesticides or other environmental contaminants, primarily organochlorine compounds, increase the risk of breast cancer. LIBCSP researchers are also trying to identify women’s concerns about exposures to air pollution and to help resolve whether cigarette smoking is linked to breast cancer.

On the prevention side, the study will assess whether physical activity lowers the risk of breast cancer. Says Gammon: “I’ve had a long-term interest in physical activity and breast cancer because there aren’t many things you can tell women they can do to modify their risk.” Although some studies, including one of her own, have not demonstrated a link, she remains optimistic. “An explosion of studies have been reported and the preponderance of data is showing a decrease in risk.”

Although data collection for the Long Island project is finished, results are not expected until 1999 because of the extraordinary nature of the samples and the complex analyses required. “This study is pushing the envelope in terms of materials being collected,” says Alfred Neugut, M.D., Ph.D., LIBCSP co-principal investigator. “Our questionnaire takes a much more detailed environmental exposure history from the women themselves. and for a large sample of women—those who have lived in their houses more than 15 years— we’ve collected soil from the garden or yard as well as dust samples and tap water from their homes.”

Radiation and Risk

Apart from LIBCSP, Neugut studies whether radiation treatment for breast cancer raises the long-term risk of developing secondary malignancies. He has found that women smokers have a significant increase in risk—as high as 40-fold—of getting lung cancer and that all women treated with radiation have a higher likelihood of developing esophageal cancer. Neugut is continuing this work with detailed studies in Connecticut.

Ruby T. Senie, Ph.D., principal investigator of the Metropolitan New York Registry of Breast Cancer Families, now centered at CSPH.

Howe has taken another approach to studying the link between radiation and breast cancer. His research focuses on 30,000 Canadian women whose treatment for tuberculosis in the 1930s and 1940s involved regular monitoring with a fluoroscope (an x-ray machine), a procedure that exposed them to substantial doses of radiation. By linking their medical records with national mortality and cancer incidence records, Howe and his colleagues have analyzed the relationship between the radiation dose the women received and their subsequent risk of breast cancer. “This is probably the most definitive study of the risk of radiation exposure for breast cancer,” he says. “Women with the highest doses of radiation had 30 to 40 times the risk of breast cancer.” Significantly, the study also demonstrated a dose-response relationship for radiation—the greater the exposure, the higher the risk—a cornerstone of epidemiologic research.

Mammography Benefits Outweigh Risks

Both Howe and Neugut are quick to point out that their research should not lead women to eschew mammography or radiation treatment for breast cancer; in either case, the benefits outweigh the risks. The same applies to Howe’s study of the effects of radiation, which is being expanded to determine whether certain women are more likely to develop breast cancer after radiation exposure because of genetic susceptibility.

Of course, it’s not enough to identify genetic and environmental causes of breast cancer; the ultimate goal is to develop prevention and treatment strategies. Bernard Weinstein, M.D., and his colleagues at Columbia-Presbyterian’s Herbert Irving Comprehensive Cancer Center have identified a factor they hope will prove useful. They have found that in about 60 percent of women with breast cancer, there are increased levels of a protein called cyclin D1. Although the body produces this protein as a normal part of the process called “the cell cycle”—where cells prepare to replicate DNA and then divide—its overproduction contributes to the abnormal proliferation of cancer cells. Significantly, in laboratory studies, Weinstein found that inhibiting the overexpression of cyclin D1 also inhibits the growth of tumor cells. “This suggests that developing inhibitors of cyclin D1 could be a new approach to cancer therapy or even prevention, targeted to women with this abnormality,” he says. “In the past, drugs were hit or miss; advances in basic research like cyclin D1 give us hope that we will have a more rational way to design anti-cancer drugs.”

Helping women understand the implications of various treatment choices is the focus of Victor Grann, M.D., M.P.H.,’97, who changed the direction of his career as a practicing oncologist to be director of health outcomes research at the Comprehensive Cancer Center following his completion of the Division of Health Policy and Management’s health outcomes track.

In a groundbreaking study, Dr. Grann explored the outcomes of four approaches available to women who test positive for BRCA1 or BRCA2 genes. (Both genes raise the risk of breast and ovarian cancer.) Using a decision analysis computer model, he examined survival benefits, quality of life and cost-effectiveness for surveillance (being watched carefully), prophylactic mastectomy, prophylactic oophorectomy (removal of ovaries) or combined mastectomy and oophorectomy. He found that a 30-year-old woman could extend her life by as much as 4.5 years if she chose to have both procedures. A prophylactic mastectomy added 3.4 years, while a prophylactic oophorectomy contributed only .9 years to an average woman’s life. Unfortunately, for many women there is a negative impact on quality of life of having these surgeries at such an early age.

All three surgeries were cost-effective when compared to other treatments. “But the message is not that you should take the cheapest,” explains Grann. “Instead, insurance companies should pay for these procedures if women choose them. What frightens me is that people will look at this and say, ’Oh, you can extend life in a 30-year-old women by 4.5 years, so every woman should have both procedures.’ But these are average group survival rates; they are very different from what one individual might gain, and it’s not necessarily a bad thing if a woman chooses not to have prophylactic surgery.”

CSPH researchers are hopeful about untangling the web of factors that cause breast cancer. Says Gammon: “During this decade, we’ve identified a lot of new areas to explore, avenues that didn’t even exist in the 1980’s. Prior to the 1990’s, no one was willing to look at environmental risk factors. The research on physical activity is very promising and so is working with molecular markers.”

Weinstein is optimistic that this research will translate into concrete benefits: “We’ve had major advances in the subset of cancers that are hereditary, a small but important group. and if we get more solid information on the role of dietary and environmental factors, we can guide women to preventive strategies. Things are very hopeful.”