Kate Johnson

June 06, 2013

CHICAGO, Illinois — Black women with breast cancer are more likely than women in the general population to have genetic mutations linked to their disease, and a significant proportion of those mutations extend beyond the common BRCA1 and BRCA2 mutations, a new study has found.

In the first comprehensive analysis of all known breast cancer susceptibility genes in a black cohort, mutations were most prevalent in women with early-onset disease, triple-negative disease, or a family history of breast, ovarian, or pancreatic cancer.

The study results were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

The findings suggest that broader genetic screening than is currently clinically available might be warranted in high-risk black patients and their families, said study author Jane Churpek, MD, a hemotologist/oncologist at the University of Chicago.

"New techniques that allow us to comprehensively screen multiple genes — including BRCA1 and BRCA2 — in a single test will allow cost-effective and efficient genetic testing, which is currently not clinically possible," said Dr. Churpek. However, "right now, BRCA1 and BRCA2 cannot be included in those panels because there is a patent on those genes. Therefore, for many patients, genetic testing is a multistep, multiexpense process."

The study involved 249 unrelated black breast cancer patients who received genetic counseling at the University of Chicago Cancer Risk and Breast Cancer Clinic from 1992 to 2011.

The median age of the women at diagnosis was 43 years, so these patients were younger than the average breast cancer patient, noted Dr. Churpek.

Of these women, 56 had an additional cancer diagnosis (41 with previous breast cancer, 7 with ovarian cancer, and 14 with other).

The majority of tumors (78%) were infiltrating ductal carcinomas, 38% were grade 3, 44% were estrogen-receptor positive, 14% were HER2/neu-positive, and 27% were triple negative.

A family history of breast or ovarian cancer in a first- or second-degree relative was reported by 57% of women, "but importantly, almost 40% of our group did not have any close relatives with breast, ovarian, or pancreatic cancers," she said.

Genetic testing was done using a special BROCA assay that uses targeted genomic capture and next-generation sequencing of 42 genes, including all 18 known breast cancer susceptibility genes.

BRCA Testing Allowed for Research Purposes

Myriad Genetics owns the patent on the BRCA genes, as previously reported by Medscape Medical News, which means that BRCA testing is not normally allowed as part of an assay, said Dr. Churpek. However, it was allowed in this BROCA assay for research purposes. "Thus, a single test was used to comprehensively analyze all of these genes," she explained.

In the study, 22% of the women had "a clearly damaging mutation," said Dr. Churpek. In general, only 5% to 10% of all breast cancers are thought to have a hereditary component.

Of the mutations, 79% were BRCA1 or BRCA2. "However, we also found that 21% of the mutations we identified were in other genes with defined cancer risk, including ATM, CHEK2, PALB2, and PTEN."

Almost all of the mutations identified were unique, "meaning that each woman inherited a mutation that was not seen in the other women," she said.

Techniques that look at only a few sites and a few genes will not be adequate. Dr. Jane Churpek

"This work highlights the genetic diversity in this population and emphasizes that techniques that look at only a few sites and a few genes will not be adequate for this population," she added

Dr. Churpek explained that a greater proportion of mutations was associated with younger age at diagnosis — "this was mostly driven by BRCA1 mutations."

"In contrast, BRCA2 and other mutations remained relatively constant with age. Thus, if we focus our efforts on testing young women, we will pick up the majority of BRCA1 mutations but we have a greater chance of missing BRCA2 and other mutations," she said.

As expected, women with a second cancer diagnosis were more likely to have mutations (almost 50%), as were those with triple-negative or grade 3 cancers (almost 30%) or a family history of breast or ovarian cancer (almost 30%).

"Of note, those with a family history of pancreatic cancer were nearly as likely to carry a mutation as those with a family history of breast or ovarian cancer. This highlights the importance of this tumor in the family history," she said.

Even among those with no family history, "12% still carried mutations. This reminds us that family history alone is not the sole criterion for predicting who will have mutations," she noted.

Broader Screening Might Be Justified

The high rate of mutations identified in the study, as well as the significant number of non-BRCA mutations, suggests that panel-based screening beyond the BRCA mutations might be justified, Dr. Churpek told Medscape Medical News.

"In most patients with breast cancer only, BRCA1 and BRCA2 are the best place to start with the current system, because our data show that these 2 genes account for the majority (79%) of mutations in high-risk black women," she said. "If that test is positive, no other testing needs to be done.

However, if BRCA testing is negative, gene panels with most cancer susceptibility genes have become available in the last year. "For efficiency and cost, we now consider doing a panel, but only in the right clinical settings," depending on family and personal history, she explained.

To test for all the gene mutations analyzed in this study, either the BROCA panel or the BreastNext panel (Ambry Genetics) would be required, she said.

"Our work highlights the fact that a modern genomics approach like BROCA will allow comprehensive screening of all genes at once. It is hoped that this will include BRCA1 and BRCA2 in the future, which will allow a more efficient and cost-effective approach to genetic testing than is currently possible," she concluded.

"We can now more efficiently define the proportion of breast cancer patients that has inherited mutations that allow us to better predict who is at risk, prevent second cancers, and do primary prevention for at-risk family members," she explained.

This research also "underscores the need to raise awareness and increase access to genetic counseling and genetic testing services, especially for underserved populations who have not been able to effectively use these services in the past," Dr. Churpek added.

Useful Information

"This is really useful information for genetic counselors to discuss with their patients prior to genetic testing. We like to be able to give patients an accurate assessment of the chance that they will have a positive finding with genetic testing, and this study provides some very helpful data," said Lisa Madlensky, PhD, CGC, a cancer geneticist and director of the family cancer genetics program at the Moores Cancer Center, University of California, San Diego. She was asked by Medscape Medical News to comment on the findings.

Dr. Madlensky said the results show that in addition to BRCA1 and BRCA2, "the CHEK2, ATM, PALB2, and PTEN genes are appropriate sequencing targets in this population. Conversely, this study provides evidence that the other genes on the panel are not likely to emerge as major contributors to hereditary breast cancer risk."

"This study reinforces the recommendation that select breast cancer patients be referred for a genetics workup," Dr. Madlensky added. "Women with triple-negative breast cancers or multiple primary cancers, young breast cancer patients, and patients with a family history clearly have an increased likelihood of a genetic cancer predisposition. Most of the published data on the yield of genetic testing has come from women of European ancestry. We now have additional data that apply to a more diverse patient population."

Dr. Churpek, her coauthors, and Dr. Madlensky have disclosed no relevant financial relationships.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract 1501. Presented June 3, 2013.


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