1. Samson, Kurt

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In July, the National Cancer Institute (NCI) announced the launch of the largest breast cancer study ever in African-American women, probing biological factors and genetics, including whole genome sequencing, which might help explain racial disparities in higher mortality rates in black women.

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Breast cancer mortality is much higher among African-American women than in their Caucasian counterparts, even if they share the same socioeconomic status and live in similar areas. While overall survival rates have steadily improved over the past several decades in white women the same has not been true among black women. They are more likely to die of breast cancer than others, possibly because they appear to be more susceptible to aggressive subtypes like triple-negative disease, which progresses quickly and is very difficult to treat.


The new Breast Cancer Genetic Study in African-Ancestry Populations is based on years of cooperation between investigators with the African-American Breast Cancer Consortium, the African-American Breast Cancer Epidemiology and Risk (AMBER) Consortium, and the NCI Cohort Consortium. In the new initiative researchers from a number of institutions who have studied breast cancer in black women will share biological specimens, and resources, including data from 18 previous studies, for an overall study population of 20,000 black women with breast cancer.


"This effort is about making sure that all Americans-no matter their background-reap the same benefits from the promising advances of precision medicine," said Douglas R. Lowy, MD, Acting Director of NCI, in announcing the new study.


"Exciting new approaches to cancer prevention, diagnosis, and treatment ring hollow unless we can effectively narrow the gap of cancer disparities, and this new research initiative will help us do that," he said. "I'm hopeful about where this new research can take us, not only in addressing the unique breast cancer profiles of African-American women but also in learning more about the origin of cancer disparities."


The reasons for such racial disparities are unclear, but some studies have suggested they might be the result of a complex interplay between genetic, environmental, and societal factors, including reduced access to health care.


Large studies are needed to comprehensively examine all of these, which is why the NCI is supporting this and several other research projects.


"This $12 million grant-in combination with previous investments-should help to advance our understanding of the social and biological causes that lead to disparities in cancer among underserved populations," said Robert Croyle, PhD, Director of NCI's Division of Cancer Control and Population Sciences (DCCPS), which is administering the grant. "A better understanding of the genetic contributions to differences in breast cancer diagnoses and outcomes among African-Americans may lead to better treatments and better approaches to cancer prevention."


"A number of studies have suggested that genetic factors may influence breast cancer disparities, so we're hopeful that this project can help to shed further light on this matter," said Damali Martin, PhD, Program Director for the DCCPS Genomic Epidemiology Branch. Martin's office is working directly with the grant recipients as well as the consortia groups that have been researching black women and breast cancer.


"This large cooperative study is essentially about how genetics might play a critical role in racial differences in breast cancer among black women," he told Oncology Times. "The first will be a genome-wide search for common variants, but this is not enough to detect different subtypes that might exist between races. Instead we will conduct whole-genome sequencing of 20,000 black women with breast cancer and an equal number who are cancer-free. This will be a direct comparison of variants within breast cancer tumors and normal women."


He said the group will also compare the findings with data from women of European descent who have breast cancer, looking for differences and similarities.


"We are just getting started on this 5-year study and we will hopefully have all of the genetic and risk factor data available after 5 years. Then they'll look at potential environmental data," he explained.


As data comes in the information will become available in a number of different forms-at meetings and among community groups, Martin continued. "There is a policy at NIH that all genetic sequencing data from grants has to be deposited into the database of Genotypes and Phenotypes, or dbGaP, that is available for researchers anywhere to access."


Unfortunately, he said, there will not be enough participants to look at the triple-negative breast cancer subtype because only around 13 percent of participants have that form of cancer.


"But we do hope to get some clues about it."


A Vital Role for Black Institutions

The grant has been awarded to Wei Zheng, MD, PhD, Vanderbilt University, Nashville, as well as others at major universities across the country. Minority scientists from other institutions, including one historically black college and university medical school, will play an important role, just as they have been in previous research that this study builds upon.


For example, the Southern Community Cohort Study, a contributing study for this grant, represents a 15-year partnership between Vanderbilt and historically black Meharry Medical College, also in Nashville. The grant will also provide training opportunities for scientists from minority populations.


In an interview with Zheng, he noted that while whole-genome sequencing for participants will be free, such testing for black women who might be concerned by any of the study's findings will be significantly more expensive.


"It is important however that even though such tests can be expensive for individuals, studies indicate that they are cost-effective in the long run," he said. "Our hope is that eventually what we will learn from this research will reduce mortality in black women. What are the biological factors? What are the genetic factors? In time we hope to have some answers."


Although the information that might be learned about triple-negative cancer will be small, he said that it is very important to remember that there is no targeted treatment yet even though black women have twice the risk of developing tripe-negative cancer than white women.


"But overall, the risk of breast cancer in African-American is about the same as in women as a whole, or even a little lower than in white women."


Examining Breast Cancer

"Black women do not get breast cancer more often, but when they do it tends to be more aggressive, especially in younger women," noted Tuya Pal, MD, an Associate Professor at the University of South Florida's Moffitt Cancer Center, Tampa.


"We believe that this due to both biological and non-biological factors, including being diagnosed at a later stage," she told Oncology Times, noting that poorer access to health care and not having adequate insurance are just two of the non-biological factors believed to be contributing later-stage diagnosis.


"When we ask black women about this, they give different reasons. But there is a general misunderstanding among the general population. Most people think of cancer as being biological or due to well-recognized risk factors, but with breast cancer we know that non-biological factors also play a big role in higher mortality rates among black women."


The new NCI study should help oncologists treating breasts cancer patients as well as cancer researchers get a much clearer picture of these risks, she said. "It will provide data from a significantly larger cohort of black women that we have ever had before. With bigger cohorts we get more meaningful data."


Pal also told Oncology Times that while there have been whole genome sequencing studies in black women-albeit much smaller cohorts, researchers and groups participating in the NCI study will be able to go beyond the large whole genome sequencing data and examine single nucleotide polymorphisms, or SNPs.


SNPs are the most common genetic variation, with each one representing a difference in a single DNA building block, or a nucleotide. There are about 10 million SNPs in the human genome. They can act as biological markers to help researchers locate genes associated with disease, because when a SNP occurs within a gene they can play a direct role in disease by altering that gene's function.


"Researchers will be able to look at SNPs for disease associations. Once they are done looking at the known genetic mutations in the BRCA group they can look at possible other mutations and these might shed better light on why black women may be more susceptible to these more aggressive cancers," Pal noted.


Christine Ambrosone, PhD, Professor and Chair of Cancer Prevention and Control, as well as Senior Vice President of Population Sciences, Roswell Park Cancer Institute, in Buffalo, N.Y. They are part of the AMBER consortium, which studies why African-American women are more likely than white women to be diagnosed with more aggressive breast cancer subtypes.


She told Oncology Times that the consortium is especially interested in modifiable risk factors for aggressive breast cancers.


"It had been dogma in breast cancer research that having children reduces the risk of breast cancer, although the majority of these studies were conducted among older white women who are more likely to get ER positive breast cancer," she said.


"A few smaller studies have looked at risk factors separately for ER+ and ER negative breast cancer and have found while having children reduced the risk of ER+ breast cancer, it actually increased risk of ER- disease, and, importantly, breast feeding reduced that risk."


AMBER has pooled DNA from its studies and had genotyping performed for thousands of genetic variants and identified certain gene loci that appeared to increase risk, particularly of ER- breast cancer.


"To date, researchers have not yet identified mutations or rare variants similar to BRCA that could explain the higher prevalence of ER- breast cancer among African-American women," Ambrose said.


Although to date AMBER has not addressed socioeconomic factors, it is likely that women with fewer resources may be diagnosed at later stages, she continued.


For example, for many rural African-American women, if they do not have personal vehicles, public transportation may not be available or cancer screening centers nearby. However many cancer centers operate mobile mammography units to go to areas where screening is not readily available, Ambrose noted.


"Among African-American women, reproductive characteristics appear to be most important factor in increased risk of aggressive breast cancer. With AMBER we also showed that early age at menarche independently increased risk of ER- breast cancer, while for ER+ tumors, risk associated with menarche was only increased if there was a longer span between menarche and first birth."


On average, she said, African-American girls have menarche approximately 1 year earlier than white girls, which, in addition to having more children and not breastfeeding, could also be associated with their greater risk of ER- disease.


"The NCI funded project will have participation of almost every study of breast cancer in African-American women in the U.S.," she said. "This cooperation among researchers willing to pool their data is very important in our being able to identify genetic factors that could be putting African-American women at higher risk of ER-breast cancer.


Kurt Samson is a contributing writer.