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BRCA testing has 'clear role' for triple-negative breast cancer
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The high prevalence of deleterious mutations in predisposition genes in patients with triple-negative breast cancer unselected for family history suggests germline genetic testing for BRCA1 and BRCA2 mutations may be appropriate in this population, according to study results.
However, further analyses of non-BRCA genes are needed to assess their utility in this setting, researchers wrote.
Fergus J. Couch, PhD, of the department of laboratory medicine and pathology at Mayo Clinic in Rochester, Minn., and colleagues evaluated data from 1,824 women with triple-negative breast cancer who were enrolled on one of 12 studies. All women were unselected for family history of breast or ovarian cancer, and most were non-Hispanic white (97%). The median age of the population at diagnosis was 51 years (range, 22-93).
Among the 1,510 patients with available data on family history, 34% (n=514) had one first- or second-degree relative with breast cancer, and 4% had a family history of ovarian cancer.
Researchers conducted germline DNA sequencing to identify the frequency of mutations in 17 predisposition genes. Overall, researchers identified 271 deleterious mutations in 14.6% of the population.
A majority of the mutations occurred in BRCA1 (57%) or BRCA2 (18%). Mutations in one of the other 15 genes occurred in 3.7% of patients, the most common of which were PALB2 (n=21), BARD1 (n=9), BRIP1 (n=8), RAD51D (n=7), RAD51C (n=6) and RAD50 (n=6).
Patients who harbored deleterious mutations were significantly younger at diagnosis (45 years vs. 52 years; P˂.001) and were more likely to have higher-grade tumors (P˂.001) than patients with wild-type genes.
A significant proportion of BRCA1 mutation carriers had a family history of breast cancer (50%; P˂.001) or ovarian cancer (18%; P˂.001). BRCA2 mutations were associated with a family history of ovarian cancer (13%; P˂.001). However, mutations in non-BRCA1/2 genes were not associated with a family history of breast or ovarian cancers.
“BRCA1 and BRCA2 mutation testing has a clear role for patients with triple-negative breast cancer, many of whom will meet the current probability threshold guidelines,” Couch and colleagues concluded. “However, although inclusion of other susceptibility genes in the genetic testing panel is already a widely adopted strategy, it is important that clinical care providers appreciate the current lack of robust estimates of penetrance for many of these genes.”
Disclosure: See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Adam M. Brufsky, MD, PhD, FACP
Many new agents that alter cellular DNA repair in breast cancer, such as olaparib, are either in clinical trials or coming to market. Additionally, evidence for the benefit of prophylaxis — either surgical or medical — in women with an inherited predisposition to breast cancer is accumulating. With these two issues in mind, it becomes increasingly important to more precisely define the subgroups of women who are predisposed genetically to breast cancer, and in whom the use of DNA repair altering agents to may have benefit.Typically, these women have been determined by a strong family history of breast and/or ovarian cancers, and mutations in the BRCA1 and/or BRCA2 genes. In a population sample of women aged younger than 50 years with breast cancer, the incidence of mutations in these genes is about 5%. However, about 15% to 20% of women have a strong family history of breast cancer without a known BRCA1 or BRCA2 mutation, suggesting other unknown genetic factors at work. Additionally, many breast cancers that arise on a background of genetic susceptibility are triple-negative breast cancer (TNBC). The questions thus become: How many women with TNBC actually have a germline mutation in a gene involved in DNA repair and, in particular, how many of these women have a mutation in a gene that is not BRCA1 or BRCA2?
The article by Couch and colleagues is an attempt to address this question. A large sample of women with TNBC (n = 1,824) had germline whole-exome DNA sequencing for 122 genes involved in DNA repair and 17 genes involved in predisposition to breast cancer. Mutations that had a predicted deleterious effect on the translated protein were found in 14.6% of these women. The majority of these mutations (11.2% of the total) were found in BRCA1 or BRCA2. Another 1.2% of women had germline mutations in PALB2, and another 0.3% to 0.5% had germline mutations in other DNA repair genes.
This very interesting article leads to several conclusions with clinical implications. Given that nearly one in seven women with TNBC — regardless of age — had germline mutations in a DNA repair gene, screening of all women with TNBC for inherited susceptibility to breast cancer becomes a reasonable option. Second, about 25% of the mutations found in this analysis were in genes other than BRCA1 or BRCA2, suggesting that there is indeed a need to better characterize genetic risk of breast cancer incidence in women who carry these mutations. Finally, given that the cost of this whole-exome analysis is relatively inexpensive, it should be an option whenever DNA repair agents such as olaparib (and others) are considered for the management of metastatic or unresectable TNBC.
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