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A form of breast cancer shown to disproportionately affect young African American women has also recently been found to have an increased incidence in Hispanic women. Called "triple-negative" breast cancer because its cells lack the receptors for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), it cannot be controlled with drugs such as tamoxifen or trastuzumab that target these receptors, limiting the effective treatment options for patients.

Triple-negative breast cancer primarily consists of a molecular subtype called the basal-like subtype. Different molecular subtypes of breast cancer can now be identified in patients by gene-expression profiling.

The first hints that molecular subtypes of breast cancer may not be distributed equally among populations in the United States emerged several years ago, and in 2006, results from the Carolina Breast Cancer Study (CBCS) showed that 39 percent of premenopausal African American women diagnosed with breast cancer had basal-like disease, compared with 14 percent of postmenopausal African American women and 16 percent of non-African American women of any age. In early 2007, a study from the California Cancer Registry confirmed the higher incidence of triple-negative breast cancer in young African American women and also identified a smaller but significant increased prevalence in Hispanic women.

Researchers are now attempting to answer the complex question of why this unequal distribution among various racial and ethnic groups exists. "The obvious question, if you recognize that there are subtypes of breast cancer," said Dr. Lisa Carey, medical director of the University of North Carolina Breast Center and lead author of the CBCS paper, "is to stop saying 'what causes breast cancer?' and say 'what causes different subtypes?'"

Intriguing data from the Nurses Health Study, the Women's Health Initiative, and smaller studies suggest that risk factors might be different for different subtypes of breast cancer. Follow-up results from the CBCS and from a large, population-based breast cancer case-control study conducted in Poland identified elevated waist-to-height ratio, excess weight gain since childhood, lack of breast-feeding after pregnancy and use of lactation suppressants, and several other variables as potential risk factors for basal-like breast cancer.

Now researchers led by Dr. Sarah Gehlert, director of the Center for Interdisciplinary Health Disparities Research (CIHDR) at the University of Chicago, have begun a unique, multidisciplinary study looking at the social environment (including crime) and other community factors that contribute to social isolation, reported perceptions of stress, and levels of salivary cortisol - a hormone involved in the response to stress - in a group of African American women in Chicago to determine if stress and social isolation contribute to breast carcinogenesis. "It's a completely integrated model," explained Dr. Gehlert.

"We realized from our animal work that social isolation was a very significant feature" in tumor development, said Dr. Gehlert. Their study hypothesis, she explained, is that "women who live in areas with…a lot of violent crime, and who live in unsafe housing, without a lot of community support to make it easier to deal with that stress, will be more likely to have sporadic mutations and will have [worse outcomes] with breast cancer."

An important part of this integrated model is the collection of tumor tissue from participants. Interim results from the study have already found glucocorticoid receptors in tumors of women who reported high stress levels, indicating that an altered stress response may contribute to failure of apoptosis and lead to tumor growth.

The tissue collected will be analyzed by Dr. Olufunmilayo Olopade, professor of medicine and human genetics at the University of Chicago and one of four project leaders in CIHDR. Dr. Olopade's previous work with African women in Nigeria and Senegal has shown an even higher incidence of estrogen-negative breast cancer than that found in African American women. Her laboratory is now deeply involved in determining if genetic mutations similar to BRCA1 and BRCA2 may contribute to the disparity in triple-negative disease under study by CIHDR.

Work is also now beginning across the U.S. to better understand the impact of triple-negative breast cancer in the Hispanic population. "We're concerned about this triple-negative phenomenon and whether Mexican Americans are also facing a similar [disparity]," explained Dr. Melissa Bondy, professor of epidemiology at the University of Texas M.D. Anderson Cancer Center. Dr. Bondy and her colleagues are starting a study to examine risk factors for triple-negative breast cancer in Mexican American women living in Texas and Arizona, and Mexican women from Northern Mexico and from the city of Guadalajara.

The next steps for researchers will be to figure out ways to help these populations reduce their risk and to develop new treatment options for triple-negative breast cancer, which are limited to traditional surgery, radiation therapy, and chemotherapy.

"The whole point [of the Carolina Breast Cancer Study] was…to figure out what the population frequencies were of these different subtypes and what some of the clinical associations were so that we could design trials for them," said Dr. Carey.

Dr. Carey's group and others around the country are now involved in large, multi-institution clinical trials testing therapies for triple-negative breast cancer. Drug regimens being examined in these trials include the antiangiogenesis agent bevacizumab given before surgery; new, targeted drugs that interfere with cell-signaling pathways other than those triggered by the estrogen, progesterone, and HER2 receptors; and platinum-based chemotherapy drugs, which may be effective in triple-negative disease.

By Sharon Reynolds