NEW YORK (GenomeWeb) – An investigation into the prevalence of 17 breast cancer susceptibility gene mutations in more than 1,800 women with triple-negative breast cancer (TNBC) showed that the majority of susceptibility mutations show up in well-known BRCA genes.
However, the study also found variations in a handful of other genes in a smaller subset of TNBC patients, suggesting the need for additional research to pin down their frequency.
Researchers led by Fergus Couch at the Mayo Clinic published the study in the Journal of Clinical Oncology this week. The aim of the research was to confirm the prevalence of BRCA mutations in TNBC patients and get a better sense of which moderate- and high-risk mutations in non-BRCA genes show up in patients.
"Guideline recommendations for non-BRCA mutations for TNBC patients are really dependent on whether the result would change clinical practice. Right now there are not good age dependent risk estimates for breast, ovarian or other cancers for deleterious mutations in the non-BRCA1/2 genes," Couch told GenomeWeb. "This means that an individual found to carry a mutation will likely be told that they are at increased risk of breast, ovarian, or perhaps some other cancers, depending of the relevant gene, but the level of that risk will be unclear. As a result, few clear risk management or therapeutic strategies for TNBC patients or any individuals with mutations are available."
Couch and his team sequenced samples from 1,824 women for mutations in 122 DNA repair genes, including 17 known breast cancer susceptibility genes. The TNBC patients' samples and phenotypic information were gathered from 12 oncology clinics across the US, Germany, Finland, Greece, and the UK. According to the researchers, this is the largest effort to characterize disease predisposition genes in TNBC.
The researchers identified a total of 271 deleterious mutations, most of which were in BRCA genes, while a quarter were in 12 out of the 15 non-BRCA susceptibility genes. Patient samples didn't have mutations in three genes: CHEK2, CDH1, or STK11.
Among the close to 4 percent of patients who had mutations in non-BRCA genes, most occurred in genes involved in DNA repair pathways, such as BARD1, RAD51D, RAD51C, and BRIP1. TNBC patients with predisposition gene mutations tended to be younger and have higher-grade tumors than those without mutations.
"Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2," the researchers concluded in the paper. "Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives."
Approximately 15 percent of breast cancer patients have TNBC, a particularly aggressive type of the disease that occurs commonly in younger women and African Americans. TNBC patients have tumors that lack estrogen receptor, progesterone receptor, or HER2 expression. Absent these markers that drugs can target, there is an unmet need for treatments for this type of breast cancer, and as such, greater characterization of genetic markers associated with TNBC risk might inform treatment strategies.
Studies have already established that BRCA1 mutations show up frequently in TNBC patients. And because women of Ashkenazi Jewish ethnicity have a greater chance of being BRCA mutation carriers, they also tend to have TNBC characterized by BRCA1 variations. BRCA2 mutations are also known to occur in TNBC patients, but less frequently.
This data are in line with other studies suggesting that TNBC patients respond well to PARP inhibitors and DNA-damaging agents such as platinum drugs. For example, the adaptive multi-drug, Phase II breast cancer trial, I-SPY2, predicted that AbbVie's PARP inhibitor veliparib in combination with carboplatin and standard neoadjuvant chemotherapy in triple-negative patients has a 90 percent chance of success in late-stage trials. AbbVie is studying veliparib in BRCA-deficient breast cancer.
Additionally, Myriad Genetics has conducted a study showing that its homologous recombination deficiency assay can be used to predict which patients with early-stage TNBC and BRCA 1 and BRCA 2 mutations will likely respond to neoadjuvant, platinum-based treatments.
However, the study by Couch and colleagues suggested that TNBC patients may benefit from broader screening of mutations in genes other than BRCA, even though this needs to be further validated. The JCO study showed that patients with BRCA mutations tended to have a family history of breast and ovarian cancer, but those who had mutations in the other genes did not have a strong family history for these cancers. "Thus, many patients with TNBC with mutations in predisposition genes may not be identified by a family history of cancer," Couch and colleagues wrote in the JCO paper.
Additionally, close to 40 percent of predisposition mutations showed up in patients who were diagnosed with TNBC at ages younger than 40. The average age of diagnosis for TNBC patients with non-BRCA mutations was 48 years, compared to 44 years and 47 years for those with BRCA1 and BRCA2 mutations, respectively. Only 1.4 percent of patients were diagnosed with TNBC when they were older than 60 years and didn't have a family history of cancer had BRCA mutations. However, close to 8 percent with predisposition mutations but no family history of cancer were diagnosed between ages 50 and 60.
"We show that 8.5 percent of those TNBC with no family history and diagnosed between 40 and 50 years of age have mutations, and 7.5 percent of those without a family history diagnosed between 50 and 60 have mutations," Couch said. "It appears that some consideration could be given to changing the probability model age cutoff, especially since there are likely a few additional mutations in the form of missense and large genomic rearrangements that we overlooked that would push these percentages very close to 10 percent."
Given their findings, the researchers recommended "testing of all patients diagnosed at [ages under] 60 years, or even all patients irrespective of age or family history … especially if the cost of mutation screening were to decrease over time."
The findings of the study by Couch's team are in line with the National Comprehensive Cancer Network's guidelines, which recommend genetic testing and counseling for TNBC patients when there is a family history of cancer or if they have been diagnosed at 60 years or younger. These guidelines would miss only 1 percent of patients carrying mutations, according to the analysis by Couch and his team.
However, the UK's National Institute for Clinical Excellence recommends against testing TNBC patients if they are diagnosed after age 40 and they don't have a family history of cancer. This approach would miss 24 percent of mutation carriers, the researchers said.
"These are the best data we have so far" regarding the contribution of predisposition genes in TNBC patients, Harold Burstein, a medical oncologist at the Dana-Farber Cancer Institute and an expert for the American Society of Clinical Oncology, told GenomeWeb in an email.
He noted however, that some of the cancer centers that contributed patients' samples, may have more hereditary breast cancer cases, which would impact the rate of detected mutations. As such, he recommended that other groups treating TNBC patients from different populations try to gauge if TNBC mutation rates are similar to this study. Burstein serves on the NCCN's breast cancer panel, several ASCO working groups, and the CALBC Breast Committee.
To get a better sense of the non-BRCA markers implicated with TNBC, Couch said what's needed are "very large mutation screening studies with the intent of identifying enough mutation carriers in each gene to allow estimation of age related cancer risks. Once these risks are in place, studies can begin to define appropriate risk management strategies for these patients." He suggested conducting separate studies in the general population and then in high-risk families since "these groups are clearly at different levels of cancer risk." Some of these studies are beginning to be conducted in large research consortia, such as the NCI's ENIGMA consortium.