June 4, 2013
A high proportion of black women with breast cancer carried inherited mutations considered damaging in a study using next-generation sequencing, according to a presentation at an Oral Abstract Session on Monday. Most of the mutations identified were in BRCA1 or BRCA2, but 21% of women had mutations in other genes with well-defined, clinically meaningful cancer susceptibilities.
This study (Abstract CRA1501) was the first comprehensive screen of all known breast cancer susceptibility genes among black women using next-generation sequencing, said presenter Jane E. Churpek, MD, of The University of Chicago. The BROCA assay was used to screen for 42 genes, including 18 known breast cancer susceptibility genes. This single genomic test was capable of detecting all classes of genomic variants in all of the screened genes.
Black women diagnosed with breast cancer are less likely to survive the disease than white women, Dr. Churpek noted. Differences in tumor biology may contribute to this disparity, she said, as black women are younger at diagnosis, have a higher grade and stage of disease at diagnosis, and more often develop triple-negative or basal-like breast cancers than white women. In addition, even when given the same treatments in clinical trials, black women have worse overall survival than white women.
The study population included 511 black women with breast cancer identified from The University of Chicago’s cancer risk and general breast cancer clinics between 1992 and 2011. After exclusion of subjects who were related and those for whom adequate DNA was not available for analysis, 249 patients were included in the study. Of these, 27 had a known BRCA1 or BRCA2 mutation, and 222 underwent targeted genomic capture and next-generation screening.
The screening identified 58 clearly damaging inherited mutations in six genes in 56 (22%) patients. Of the total mutations, 79% were in the BRCA1 (20 patients) or BRCA2 (26 patients) genes, and 21% were in other genes, including ATM, CHEK2, PALB2, and PTEN.
Three women had more than one inherited damaging mutation. Notably, two of these women reported no family history of breast cancer, and all developed disease at an early age.
The proportion of patients with mutations, particularly in BRCA1, increased in patients with younger age at diagnosis. A second breast or ovarian cancer diagnosis was strongly associated with mutation, mostly in BRCA1 and BRCA2. Patients with triple-negative or grade 3 breast cancer were also more likely to have mutations.
Mutations were present in 32% and 40% of subjects with a family history of breast or ovarian cancer, respectively. Those with a family history of pancreatic cancer were also more likely to carry a mutation. However, even in those with no family history of these cancers, mutations were present in approximately 12% of subjects.
“Our study shows how comprehensive modern genomics approaches like BROCA, which can examine multiple genes at once in a single lower cost test, will allow a more efficient and cost-effective approach to genetic testing so that we can better determine who is at risk and have the potential to impact public health,” Dr. Churpek concluded.
Discussant Judy E. Garber, MD, MPH, of the Dana-Farber Cancer Institute, noted that germline mutations in genes other than BRCA1 and BRCA2 have recently been identified in other study populations. “We have to be committed to learning as much about these alternations in this additional group of genes as we have been to BRCA1 and BRCA2,” she said.