A genomic profiling study of African American women with breast cancer who werereferred for genetic counseling at The University of Chicago, supported, in part, by the National Institutes of Health, the Breast Cancer Research Foundation, and Komen for the Cure,finds that about one in five carries an inherited abnormality in at least one of 18 genes associated with breast cancer susceptibility. The study results were presented at the 49th Annual Meeting of the American Society of Clinical Oncology(ASCO), being held in Chicago, Il, May 31 – June 4, 2013 and is the first comprehensive screening among African American women of all 18 known breast cancer susceptibility genes using new methods called targeted genomic capture and next-generation sequencing.

Mutations like these were more prevalent among women with aggressive triple negative breast cancer, early onset disease, and a family history of breast and ovarian cancer. The findings suggest that broader genetic screening may be beneficial for these women and their family members.

Compared to other ethnic groups, African American women have increased rates of early onset and aggressive triple negative breast cancer, as well as poorer survival once diagnosed with breast cancer. Researchers have suspected that inherited variations in genes linked to breast cancer may contribute to these differences. This research adds evidence in support of this hypothesis. While most prior studies have focused on BRCA1 and BRCA2 gene mutations, this is the first comprehensive study among African American women of all known genes associated with breast cancer susceptibility.

A study of African American women with breast cancer who are at higher risk finds that more than 20% of those women have inherited abnormalities in at least one of the 18 known breast cancer susceptibility genes.


?Our study confirms the importance of screening for mutations in breast cancer susceptibility genes in all African American breast cancer patients diagnosed by age 45, those with a family history of breast or ovarian cancer, or with triple-negative breast cancer before age 60,?said lead study author Jane E. Churpek, MD (photo 2), an assistant professor of medicine atThe University of Chicagoin Chicago, Ill. “For many years, we’ve seen breast cancer take a heavy toll on African American women, and this study begins to resolve unanswered questions about what’s driving these disparities.While larger studies are needed to confirm our results and compare them to other populations, we hope our findings will lead to increased awareness about potentially life-saving genetic screening for African American women with a personal or family history of early onset or aggressive forms of breast cancer, and their relatives.?

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Genomic DNA from 249 unrelated African American women with breast cancer was analyzed for the presence of mutations in 18 breast cancer susceptibility genes using an assay called BROCA, which utilizes new tools called targeted genomic capture and next generation sequencing. Overall, 56 out of 249 patients (22%) had at least one clinically relevant mutation. Most of these women carried a single mutation.

The researchers noted that because the women in the study were selected from among those referred for genetic counseling, they were at higher risk for carrying an inherited mutation than the general African American female population. However, the researchers were nonetheless surprised by the high rate of mutations, given that only 5-10 percent of all breast cancer cases are thought to have a hereditary component.

Inherited damaging mutations were found in BRCA1, BRCA2, CHEK2, PALB2, ATM, and PTEN genes. Mutations were most common among patients with triple negative breast cancer (30%), patients diagnosed before the age of 45 years (27%), patients with a second primary cancer in the breast (49%), and patients with a family history of either breast or ovarian cancer in a close relative (30%).

“We expected the women in our study to have a higher risk of carrying an inherited mutation than typical breast cancer patients,? Churpek observed, ?but some of their risk factors?diagnosis by age 45 or triple-negative breast cancer?also are more common among African American women.?

Once diagnosed with breast cancer, African American women have lower survival rates. Regional variations in survival suggest that much of the difference may be driven by reduced access to screening and optimal care, but there is mounting evidence, including this study, that differences in tumor biology, such as a higher rate of inherited mutations in genes that increase the risk of aggressive forms of breast cancer, also play a role. In those cases, delay of diagnosis can prove deadly.

Founder mutations
The majority of the mutations were unique, meaning that the specific inherited change in the genetic code identified in each woman was seen only in that woman. This is in contrast to other populations, such as the Ashkenazi Jewish population, in which one in 40 individuals carry one of three specific mutations in the BRCA1 and BRCA2 genes.

In populations with a high prevalence of these so-called founder mutations, genetic testing begins with these specific sites rather than by sequencing the entire gene or genes, since these mutations account for the majority that one will find in that population, thus allowing a more cost-effective approach. This study confirms that such an approach would not be adequate for African American women, because of the great diversity in the inherited mutations.

?These results argue for increased screening for mutations in African American women diagnosed with breast cancer at a younger age, with triple negative breast cancer, and/or with a family history. Since such testing may lead to life-saving interventions for their family members, these data underscore the need to overcome barriers to genetic testing for breast cancer risk among African American women,? said Andrew D. Seidman, MD, ASCO spokesperson and breast cancer expert.

Risk assessment
Cancer risk assessment and genetic testing for BRCA1 and BRCA2 gene mutations is currently routinely recommended for women with a personal history of early onset breast cancer or ovarian cancer or with a strong family history of breast and/or ovarian cancer. Uptake of this test has been higher in women who belong to an ethnic group with a known high prevalence of these mutations such as Ashkenazi Jewish women but mutations in these genes occur in all racial/ethnic groups. Given the high proportion of mutations identified in this study, the researchers said these findings make a case for exploring broader genetic screening among ethnic minorities who have been understudied thus far.

?In every population, but especially among those with greater genetic diversity, we often detect changes in genes that may not yet have been studied clinically,? Churpek said. ?Some people question the utility of using gene panels like BROCA, as we don?t always know how to counsel a patient without sufficient data on the clinical consequenc
e of every variant found, but unless we start learning about them now we will never know.?

Next generation sequencing assays, like BROCA, allow assessment of multiple genes from multiple people at the same time, making them more efficient and cost-effective than traditional genetic screening technologies. In addition, these tools can detect all the different types of abnormalities in the genetic code, which previously required multiple methods. The authors stated that this type of testing is clinically available and costs about the same amount as current BRCA1 and BRCA2 testing, but like all risk-related genetic testing is best performed through professionals trained in cancer risk assessment who can help individuals understand their own risk of developing cancer, what type of testing is appropriate for them, how to interpret the information each test provides, and how best to reduce their risk.

Current proven strategies for breast cancer risk reduction and early detection for women at increased risk include preventative surgical removal of the ovaries and/or breasts, risk-reducing medications, and more intensive screening with breast MRI. However, the authors noted that the recommendation for use of each of these strategies must be personalized based on each woman’s specific risk, genetic mutation status, and her own personal preferences about which of these options is right for her.

For more information:
Abstract #CRA1501: Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next generation sequencing.
Oral Abstract Session: Cancer Prevention/Epidemiology
Authors:Churpek JE, Walsh T, Zheng Y, Casadei S, Thornton AM, Lee MK, Churpek M, et al.
Date: Monday, June 3, 2013, 8:15 ? 8:30 AM CDT
Location: Room: S100bc

Photo 1:Inherited genetic mutations could lead more African Americans to develop early-onset and ?triple-negative? breast cancer, an aggressive and difficult-to-treat form of the disease. Photo 2: Jane Churpek,Section of Hematology / Oncology Assistant Professor of Medicine. Photo Courtesy: The University of Chicago Medicine.

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