Health Disparities: Genetics Plays An Important Role In Cancer Detection, Prognosis Among Minorities

Gene expression differences in primary breast tumors from African American and Caucasian Women

Researchers have found that gene expression in breast tumors differs between African-American and Caucasian patients in ways that might help explain why the disease is more deadly in African-American women and why it strikes these women at an earlier age. Although more Caucasian women are diagnosed with breast cancer overall, their cancers tend to be less aggressive and generally occur later in life, investigators report.

Researchers at the Windber Research Institute in Windber, PA, found 65 genes were differentially expressed between tumors in the two racial groups. Of these, 28 genes were more highly expressed in African-American patients and 37 genes had lower expression. Although most of the genes have not been previously linked to cancer, some are known to be associated with tumor progression or suppression.

"This study suggests that in addition to the socioeconomic and health care factors that have been found to play a role in breast cancer outcomes, there may also be molecular differences that contribute to the more aggressive clinical features of breast tumors in African-American women, compared with Caucasian women," said lead investigator Lori Field, Ph.D., a postdoctoral fellow in the women's health research program at the institute.

According to Field, African-American women have the highest mortality rate from breast cancer among ethnic groups in the United States. "With further study, these genes may prove to be promising new molecular targets to which new therapies can be developed to better treat the breast tumors in African-American women as well as improve outcomes in this population," Field said.

The research is part of the Clinical Care Breast Project, a federally mandated and funded collaboration between the Windber Research Institute and Walter Reed Army Medical Center in Washington D.C. In this study, the researchers obtained breast tumor samples from 26 pairs of African-American/Caucasian women, who were matched in age and breast cancer stage, as well as in the care they received from Walter Reed. They obtained RNA from these samples to produce gene expression profiles, which they then compared between the groups.

Field's team found a significant difference between the two groups in the RNA produced by 65 genes. Some of the molecules that were more highly expressed in the African-American patients function in signal transduction (the SOS1 gene), cell division and growth (PSPH gene) and cell proliferation (TSPO gene), Field says. RNA expression that was lower in African-Americans included genes linked with transcription (ZNF228), protein transport (SCAMP4) and the PSD3 gene, "which is believed to be involved in suppressing cancer metastasis," Field said. Low levels of PSD3 have been linked to poor outcome and tumor progression in ovarian cancer.

Field cautions that the findings need to be validated in an independent set of breast tumors using other techniques.

Gene expression profiling reveals tumor immunobiological differences in prostate cancer between African-American and European-American men

Prostate cancer appears to be distinctly different in African-American men compared with European-American men, according to researchers at the National Cancer Institute (NCI) who found significant differences in expression of numerous genes in tumor samples taken from the two racial groups.

Many of these genes were related to inflammation and immune system regulation, suggesting that pathogens could be involved in race/ethnic differences that lead to the development of these tumors, the researchers say. Some of the genes were also linked to cancer spread.

Although further study is needed to confirm their hypothesis of possible viral involvement in cancer, the team believes that these novel findings could help explain why both the incidence of, and death rates from, prostate cancer are increased among African-American men.

"We don't think the worse outcomes we see in African-American prostate cancer patients are due to issues of socioeconomic and sociodemographic differences alone," said lead author, Tiffany Wallace, Ph.D., a postdoctoral fellow in the Laboratory of Human Carcinogenesis at the NCI. "So we are trying to understand if differences in genetics and biology play a discernable role, and this study suggests they do."

NCI researchers obtained gene expression profiles from tumors removed during surgery from 33 African-American and 36 European-American patients using gene microarray technology. They also obtained samples of surrounding non-tumor prostate tissue from seven of the African-American and 11 of the European-American patients. They then compared the combined tumor profiles to profiles from non-cancerous tissue, and similar differences in tumor marker expression that other research groups had already detected.

Sorting the samples according to race, they found the differences in gene expression. Of significance was over-expression of indoleamine-2,3-dioxygenase, an immune system modulating enzyme that tumors use to subvert immune-system surveillance, and the "self" antigens HLA-E and HLA-G that additionally inhibit immune responses through different mechanisms.

"These genes are well-known contributors of immunologic tolerance in tumors," she said. Additionally, there was a distinctive interferon signature in gene over-expression in the African-American patients, which is associated with an immune system response against foreign invaders such as viruses.

One puzzling finding: genes that activate the immune system and genes that suppress it were both more highly expressed in the African-American patients. Wallace says this suggests the immune system is fighting the cause of the cancer, which could be a pathogenic invader. Alternatively, the discovered gene signature may reflect merely the presence of a chronic low-level inflammation that is more prevalent in the tumors of the African-American patients, she says. It could also mean that prostate tumors in these men have ways of suppressing the immune system, which explains why their tumors are more aggressive, she adds.

"Something is different in the tumor microenvironment between the group of patients we studied and it has to do with tumor immunobiology," Wallace said. "We are intrigued with these findings, which we are continuing to research."

A tracking and feedback registry to reduce disparities in breast cancer care

A tracking and feedback registry following breast cancer surgery reduces racial disparities in follow-up treatment and may ultimately affect clinical outcomes, researchers report.

Following surgery, women with breast cancer have numerous subsequent treatment options, but minority women are less likely to obtain further treatment than white women, previous studies have found.

Nina Bickell, M.D., M.P.H., an associate professor of health policy at Mount Sinai School of Medicine, suspected this was partly because referring surgeons had no way of keeping track of their patients in order to encourage follow-up care. So Bickell, Kruti Mohan, M.P.H., a senior project manager at Mount Sinai, and colleagues set up a tracking and feedback registry whereby surgeons at six medical centers were notified by phone and letter whether or not their patients subsequently visited an oncologist. By the end of the study, there was an increase in oncology consultations and a decrease in underutilization of adjuvant treatment.

"With this intervention, we were attempting to target the 'system failures,' cases in which the surgeon recommended treatment, the patient did not refuse, but care did not ensue," Mohan said. "We found that once surgeons were made aware that their patients were not using available therapy, they felt compelled to intervene and were equipped with the appropriate data to take action."

Use of consultations increased from 85 to 96 percent in minority women, and 82 to 97 percent in non-minorities. Overall, women were more likely to take advantage of treatment options, particularly chemotherapy and hormone therapy. Among African-American and Hispanic women, underuse of radiotherapy decreased from 23 to 10 percent.

Following the intervention, race no longer played a significant role in whether or not women connected with a subsequent oncology consultation (OR=1.20; 95% CI, 0.69-2.08) or took advantage of therapy (OR=1.13; 95% CI, 0.73-1.75).

"This could reduce the racial disparity in breast cancer treatment and subsequently impact health outcomes," Mohan said. "We conducted this tracking and feedback process at six centers, but it has the potential to be expanded to other institutions, perhaps in an automated fashion."

Is recent decline in breast cancer incidence equal across different US racial groups?

Adding data to an ongoing debate about the causes of a recent decline in breast cancer incidence, researchers report that the decline is confined to white women and may be due to their use of hormone replacement therapy to treat symptoms of menopause.

"Non-Hispanic whites were more likely to use hormone replacement therapy, and had similar percent reduction of discontinuation after the [U.S. Food and Drug Administration] warned about its link to breast cancer in 2003, so the benefit of a reduction in breast cancer was more pronounced," said Dezheng Huo, M.D., Ph.D., research associate professor in the Health Studies Department at the University of Chicago.

Between 2002 and 2003, scientists observed a sharp decline in breast cancer incidence in the United States but only among women older than 50 years who had estrogen-receptor positive cancer. Reasons for the decline have been hotly debated in the research and medical community.

Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results Database, Huo and colleagues calculated rates of breast cancer between 2000 and 2004 to confirm that the reductions were restricted to a certain breast cancer type and to determine whether or not the reductions were similar across racial and ethnic groups.

"The sharp reductions seen in Caucasians aged 50 to 69 years were not seen among other ethnic groups," Huo said.

Between 2000 and 2002, the rate of invasive breast cancer among Caucasians was stable. The greatest reduction, 2.41 percent per quarter, was seen toward the end of 2003. In the same year, the rate of invasive breast cancer among African-American women increased 0.07 percent per quarter, decreased 0.14 percent per quarter in American Indian/Alaskan Natives and decreased 0.46 percent per quarter in Asian American/Pacific Islanders.

For the rate of in situ breast cancer, an early stage disease, the rate was stable among Caucasians, African Americans and American Indian/Alaskan Natives. Among Asian American/Pacific Islanders, the rate of in situ breast cancer increased slightly from 2000 to mid 2002 by 2.09 percent per quarter, and decreased by the end of 2004 by 3.2 percent per quarter.

Application of nanotechnology for enhanced early detection of prostate cancer in African-American men

Once limited to the electronics industry, semiconductor material may hold the key to improving the detection of prostate cancer among African-American men. Nanotechnology using quantum dots made from semiconductor material allowed researchers to detect the presence of six biomarkers associated with prostate cancer.

If proven in clinical studies, the nanotechnology will enable physicians to diagnose prostate cancer at earlier stages, which is particularly important for African-American men.

"African-American men appear to have the highest rate of prostate cancer incidence in the world," said Catherine M. Phelan, M.D., Ph.D., an assistant professor in cancer prevention and control at H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla. " In addition, their prostate cancer mortality rate is twice as high as the rate for white Americans."

Early detection is crucial. Among African-American men diagnosed with early stage prostate cancer, five-year survival rates are almost 100 percent. For men diagnosed with more advanced disease, five-year survival rates are 29 percent, according to Phelan.

To improve early detection, Phelan and her colleagues investigated quantum dot antibody conjugates. Quantum dots (QD) measure 5-20 nanometers in diameter. For comparison, a human hair measures 100,000 nm in diameter. The small size of the QDs results in new optical properties that allow observers to determine the size and energy of the QD and where it will emit light along the color spectrum.

"Smaller QDs are higher energy and emit in the blue part of the spectrum, whereas the larger-sized but lower-energy QDs emit light in the red part of the spectrum," Phelan explained.

"If you want to look at a particular known protein in the blood, such as prostate specific antigen (PSA), you can attach the specific antibody for that protein to the QD and, using a laser, observe where the emission peak lies in the color spectrum. The height of the peak represents the amount of protein in the blood sample," she said.

Phelan and her colleagues targeted established prostate cancer biomarkers: PSA, kallikrein 2 (KLK2), kallikrein 14 (KLK14), osteoprotegerin (OPG), antip53Ab, caveolin-1 (Cav-1) and interleukin-6 (IL-6). Using an African-American prostate cancer case-control collection, the researchers observed that the bioconjugated QDs displayed a spectral shift of the maximum position on average by 4 nm in comparison with nonconjugated QDs.

"The benefit of the observation may lie in the fact that the shift is different for each antibody, thus will show a peak at different wavelengths," the researchers reported.

Phelan said there are two main advantages to QD technology over current methods, such as measuring PSA. First, the optical properties of QDs allow protein detection at lower levels when the tumor is in its earliest stages. Second, the technology offers the ability to detect multiple biomarkers, which will be more effective than a single biomarker.

"The technology can be used for detection of any cancer in any ethnic group," Phelan said. The biomarkers in the study are unique to African-American men with prostate cancer, but the baseline levels of the proteins may differ among ethnic groups.

The technology could also be used to detect risk of recurrence, although the biomarkers may be different than for early detection, she said.