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Large Study Confirms High Frequency of ER-negative Breast Cancer in African American Women

Tuma, Rabiya S. PhD

doi: 10.1097/01.COT.0000297235.30011.31
Breast Cancer Symposium

SAN FRANCISCO—African American women have a higher rate of breast cancer mortality despite an overall lower incidence of disease relative to Caucasian women. That difference may be due in part to tumor biology rather than to disparities in health care access as previously hypothesized, according to data from a retrospective study of more than 170,000 women reported here at the Breast Cancer Symposium.

The meeting is cosponsored by the American Society of Breast Disease, American Society of Breast Surgeons, American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Surgical Oncology.

Several small studies have already reported that African American women are more likely to have estrogen receptor (ER)-negative tumors and more aggressive disease at diagnosis than white women. These new data confirm those results.

“This is a huge database that really solidifies some information that we had hints of earlier,” said Julie R. Gralow, MD, Associate Professor of Medicine at the University of Washington School of Medicine, the moderator of a news briefing that featured the study.

“The fact that the basic biology of the breast cancers being diagnosed in African American women [differs] as compared with white American women is fascinating. The ER negativity is holding true for any age, any stage at diagnosis, and any income level. It really speaks to there being a different biology in many of these women that we have to address. It is not just access to care, access to treatment, and other factors that have been implicated in the past.”

“Landmark progress has been made in the management of endocrine-responsive breast cancer and in breast cancer chemoprevention,” said the researcher who presented the results, M. Catherine Lee, MD, Clinical Lecturer in the Department of Surgery at the University of Michigan Comprehensive Cancer Center. “However, this preponderance of ER-negative cancer in African American women poses an inherent biological barrier to benefiting from these advances.”

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Refocus on Education

Dr. Lee emphasized that based on these data, education, especially with regard to breast cancer screening, needs to be a primary focus in dealing with breast cancer disparities.

The researchers—senior author was Lisa A. Newman, MD, MPH, Associate Professor and Director of the University of Michigan Breast Care Center—analyzed tumor and patient information from the National Cancer Data Base, a registry that includes information from 1,600 hospitals across the United States. The team looked at information on 170,079 cases of in situ and invasive breast cancers diagnosed in 1998 and included in the registry. Of those, 90.3% of the women were white and 9.7% were black. (Other ethnic groups were not included in the study.)

Comparing those two patient groups, the team found that African American women were diagnosed at an earlier age, at a mean age of 57, compared with age 62 in white women.

Black women were also diagnosed less frequently with early stage disease—only 29% of the women had Stage I disease compared with 42% of whites. The median tumor size was 2.0 cm in black women compared with 1.5 cm in Caucasian women.

As Dr. Gralow pointed out, African American women were more likely to have ER-negative tumors regardless of disease stage compared with white women. In Stage I disease, 30.8% of black women had ER-negative disease vs 16.9% in whites, in Stage II it was 42.2% vs 26.2%, in Stage III it was 46.9% vs 32.4%, and in Stage IV it was 45.5% vs 30.6%.

The trend held up as well across all ages at diagnosis. Of the women diagnosed before the age of 45, 52.3% of black women had ER-negative disease vs 35.2% in whites; in women diagnosed between ages 45 and 60, the percentages were 41.1% vs 25.6%; between ages 61 and 80 they were 29.1% vs 16.9%, and in women diagnosed above age 80 the rates were 24.5% vs 15.2%.

Income did not influence the likelihood of being diagnosed with ER-negative disease in either population. Across all income levels, African American women had a rate of ER-negative disease that ranged between 37.2% and 39.0%, and the rate for Caucasian women was 21.9% to 25.3% across all income levels.

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TNFα Pathway Links Inflammation, Angiogenesis, & Breast Cancer

The inflammatory protein tumor necrosis factor alpha (TNFα) gives rise to an enzyme that inactivates two tumor-suppressing genes, ultimately triggering production of new blood vessels to nourish breast cancer cells, researchers at the University of Texas M. D. Anderson Cancer Center reported in the August edition of Cell.

“This is a completely new pathway for inflammation-induced cancer and may provide new targets for clinical intervention,” senior author Mien-Chie Hung, PhD, Professor and Chair of the Department of Molecular and Cellular Oncology, said in a news release describing the chain of events found in the study, whose first author was doctoral student Dung-Fang Lee.

Inflammation has been shown in recent years to be linked to breast, liver, and gastrointestinal tract cancers. The research team set out to discover whether angiogenesis plays a role in cancer formation related to TNFα.

“What we found is a previously unrecognized role for IKKβ, a protein kinase activated by TNFα,” Dr. Hung said. IKKβ inactivates a cancer-suppressing protein complex, which frees a cancer-inducing pathway to generate new blood vessels to supply tumors.

The chain of events is as follows, the researchers explained: TNFα activates IKKβ, which as a kinase works by attaching phosphate groups to other proteins. IKKβ, phosphorylates tuberous sclerosis 1 (TSC1) blocking it from working with tuberous sclerosis 2 to repress the mammalian target of rapamycin (mTOR) pathway.

With the tumor suppressors inactivated, mTOR is freed to produce vascular endothelial growth factor (VEGF), which creates new blood vessels to feed breast cancer.

The team confirmed the lab findings in mice, and then continued the research by analyzing breast cancer tumors from 116 patients—those whose tumors had the TSC1/TSC2 tumor-suppressor complex blocked by phosphorylation did not survive as long as those with an active TSC1/TSC2 (46% survival rate at 60 months vs 65%).

Rapamycin is a powerful immune system suppressor used to protect organ transplant recipients against rejection of their new organs by suppressing mTOR. Rapamycin and similar mTOR inhibitors are in early clinical trials for several different cancers, and one drug, temsirolimus, has been approved to treat renal cell carcinoma.

Dr. Hung's lab is exploring the possibility that this TNFα-driven activation of mTOR is the molecular link between obesity and heightened cancer risk. Obese mammals have high levels of TNFα secreted by their fat cells. Dr. Hung noted in the news release that the Cell paper is part of an ongoing effort to define the cancer-inducing activity of IKKβ and the related IKKα. He has found that the two, known to have a cancer-inducing effect working together, also have separate effects individually.

The latest research showed that IKKβ, does its damage working in the cytosol of the cell, and together, the two kinases previously were known to free the oncoprotein nuclear factor kappa B from the cytosol, allowing it to move to the nucleus and activate genes that promote cancer growth.

Research leading to the Cell paper was funded by grants from the NCI, the Kadoorie Charitable Foundations, the National Breast Cancer Research Foundation, the US Army Breast Cancer Research Program, the Hsu Endowed Memorial Scholarship, and the Andrew Sowell-Wade Huggins Scholarship from the University of Texas Graduate School of Biomedical Sciences, the Taiwan Merit Scholarship from the National Science Council of Taiwan, and M. D. Anderson's Odyssey Scholarship.

© 2007 Lippincott Williams & Wilkins, Inc.
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