The Role of Hormone Replacement Therapy

Another recently recognized risk factor is hormone replacement therapy (HRT), which also appears to act synergistically with alcohol. A 2002 Boston-based Brigham and Women's Hospital study found that using HRT for five years combined with having 1.5 drinks daily doubles breast cancer risk. Physicians have prescribed HRT to treat menopausal discomfort since the 1940s, and use skyrocketed in the 1960s and early 1970s when HRT was heavily promoted as a means to prevent bone loss, and as a way to remain "feminine forever," to quote the title of a popular book of the era.

HRT may figure prominently in the Marin breast cancer equation. A 2001 telephone survey of 4,821 Marin residents conducted by the county found that 43 percent of the women age 60 and over had taken HRT for five years or more. In fact, in the 1970s high rates of HRT use by Marin women led to the discovery by epidemiologists that the estrogen-only form of HRT popular at the time was a risk factor for cancer of the endometrium, a tissue that lines the uterus. The malignancy, while much less common than breast cancer, was more common in Marin than elsewhere. The combination of estrogen and progestin that has gained prominence in the decades since reduces the risk of endometrial cancer. However, in the past two years major study reports have made it clear that this form of HRT also increases a woman's risk for heart disease, stroke and breast cancer.

There are two broad categories of breast tumors, a key consideration in evaluating the possible link between HRT and excess Marin breast cancers. Estrogen receptor (ER)-positive tumors harbor many estrogen receptor molecules within their cells and grow in response to the hormone. ER-negative tumors lack the receptor and grow independently of estrogen. Certain drugs that resemble estrogen but that block its action in the breast -- tamoxifen and raloxifene, for instance -- are effective in treating or preventing only ER-positive tumors. Similarly, certain risky exposures may favor the formation of one type of tumor over another.

In ARFS, HRT use was the same for women with or without cancer -- about 55 percent. But UCSF breast oncologist Shelley Hwang, using a combination of ARFS and cancer registry data, later discovered that the cancers afflicting women in the study who took HRT were more likely to be ER-positive than the cancers of women who did not use the therapy.

"The increased risk of breast cancer seen in women of higher socioeconomic class may be due to the widespread use of hormone replacement therapy," Hwang says. She plans to compare tumor and normal tissue samples from the cancer cases in ARFS with tissues obtained from breast cancer patients treated at San Francisco General Hospital Medical Center, a lower-income population in which only about 5 percent of women have used HRT, she says.

Hwang's finding is made more provocative by results of another recent study, led by Chris Benz, a researcher with the Buck Institute for Age Research, located on the northern border of Marin County, who is also a UCSF faculty member and oncologist. After reviewing Marin breast cancer cases recorded in the regional cancer registry, Benz found that ER-positive breast cancers among postmenopausal women account for all the county's excess breast cancers. (The incidence of ER-negative breast cancers was no higher than average.) From his review of other studies Benz also concludes, "There is an almost perfect correlate for developing ER-positive breast cancer, and that's socioeconomic status."

Wrensch and Clarke and Erdmann (now at the University of Michigan) are conducting additional research to find out how much of Marin's excess breast cancer can be attributed to alcohol and HRT, and whether high SES will remain an independent risk factor and proxy for unknown hazards after these more recently recognized risks are added to the mix. In its own investigation of the demographics of breast cancer, the Marin Cancer Project has contracted with UCSF's Family Health Outcomes Project to conduct a study comparing cancer in Marin to "peer" counties across the US.

Wrensch remains intrigued by the role of SES and its possible associations with personal environmental risk factors. Among the possibilities raised by Wrensch and the activists and scientists with whom she collaborated during ARFS were lawn and household pesticides, chemicals emitted by cooking and other household activities and furnishings, hormonal effects arising from nighttime light exposure, cosmetics, chemical residues from dry cleaning, new car upholstery, women's indoor work environments and too little immune system exposure to germs early in life. However, local residents citing concerns most often mention outdoor pollution, which remains a high research priority among activists.

Setting the Agenda

Scientists wary of activist-driven research agendas frequently point to the whopping $30 million spent on studies of environmental toxicants and breast cancer on Long Island -- studies that were either negative or inconclusive. The politically mandated research arose from activist concern over higher-than-average breast cancer rates in this high-SES region. Blood samples were analyzed for any associations between breast cancer and exposures to certain long-banned chemicals that nonetheless persist in the body and that are among the easiest to measure -- DDT, chlordane, dieldrin and PCBs. Despite the results, many activists are unconvinced, arguing that the studies' designs were flawed and that the wrong chemicals were studied.

Similarly, even if the elevated rates in Marin County are eventually explained by demographics, local activists say they will remain concerned about the half of breast cancers in Marin and across the country that cannot be explained by known risks. "I think we have studied traditional risk factors to death," says Janice Barlow, executive director of MBCW. "It's worth it to put research money into the environment; it's an area that has been understudied." Unlike traditional, reproductive risk factors, which women can do little or nothing to change, Barlow says, "If you do find causes that are environmental, you can modify and prevent them."

Robert Hiatt, director of population sciences for the UCSF Comprehensive Cancer Center, offers a careful endorsement. "Most of the scientific literature now has not shown any relationship to environmental agents," he says. "But there are hundreds of thousands of chemicals out there. We have to be cautious about just looking under the lamppost for the keys."

Few of these chemicals have been studied for their health effects. The Breast Cancer Fund, the Marin Cancer Project and MBCW all advocate the "precautionary principle," and are encouraging local governments to favor safe alternatives to untested and toxic chemicals in regulating commerce and contracting. Last year San Francisco became the first big US city to pass a precautionary principle ordinance.

Advocates also share researchers' enthusiasm for bringing molecular biology into epidemiological studies. The Breast Cancer Fund and MBCW advocate statewide "biomonitoring" for manmade chemicals in breast milk. To help establish priorities for research on health effects, the US Centers for Disease Control and Prevention recently has begun conducting surveys to measure levels of more than 100 known or suspected toxicants, including many cancer suspects, in the blood and urine of more than 2,000 adults and children throughout the country. Breast cancer activists are interested in many chemicals on the list, including trace metals, polycyclic aromatic hydrocarbons, and two classes of chemicals that mimic hormones: Phytoestrogens and phthalates, common in plastics and beauty products.

In most cases, however, the CDC's measurements are unlikely to accurately reflect exposures from long ago, a key consideration in using epidemiology to track cancer causes, especially -- considering the adolescent window of vulnerability -- breast cancer causes. "A lot of these things don't remain in the body, and their effects could have been manifested very early," Hiatt says. "You also need to understand cumulative dose, and it's a huge problem to go back from the time of cancer diagnosis and try to understand exposures that people had 20 or 30 years before. That's part of the rationale for looking at young girls."

In response to the concerns of breast cancer advocates, the NCI and the National Institute for Environmental Health Sciences have funded a new national research network, which includes the Bay Area Breast Cancer and the Environment Research Center, led by UCSF. Among the collaborators are Kaiser Permanente of Northern California, Lawrence Berkeley National Laboratory and MBCW, as well as advocacy groups from Bayview Hunters Point -- a largely poor, minority neighborhood in San Francisco -- and Alameda County, in the East Bay.

With the help of the advocates, clinicians and researchers will survey families and begin collecting data and blood from 400 seven- and eight-year-old girls. They plan to monitor physiological, hormonal and biochemical changes as the girls grow, and to keep tabs on genetic variables and nutritional or other personal environmental exposures that might influence developmental changes and later risk for breast cancer. Unfortunately, the grant is not large enough to support extensive biomonitoring of human subjects.

Also participating in the study is UCSF's Zena Werb, a leading cell biologist who has spent years in the lab studying how normal and cancer-associated changes in breast tissue occur. Working with mice, Werb will investigate how specific dietary components or environmental exposures, yet to be chosen, affect cellular, biochemical and genetic changes in the developing and mature mammary gland.

Hiatt, the principal investigator for the study, says that in deciding which chemicals to investigate in more detail, the main considerations are, What are people concerned about? What can you measure? What can you afford? and What makes sense biologically? He emphasizes the importance of having community input while planning and conducting studies, even though the impact on the science is unpredictable. Scientists and advocates may not start out with the same expectations and goals, or even share the same language -- terminology that is beautifully precise to a scientist may be mere jargon to an advocate.

For their part, advocates are leery of serving as window dressing. "Advocates don't just want to be used to make science more convenient," says the Breast Cancer Fund's Rizzo. "We need to be there at the beginning, we need to be there at the middle, and we need to be there at the end."

If the collaborators ultimately identify industrial toxicants as culprits, then presenting the scientific data won't be the last step; the enactment of measures to protect public health will be the true goal. In the meantime, women in Marin will keep worrying, wondering about the nature of the unseen serpent let loose in paradise.

Losing Paradise - Page 1