May 4, 2015

New Study on ‘Very Hot Topic’ in BRCA Testing

Genetic testing with a new multigene panel not only delivers more information about breast cancer risk but also assesses deleterious BRCA1/2 mutations as accurately as BRCA testing alone, according to a new study presented at the American Society of Breast Surgeons (ASBS) 16th Annual Meeting.

Data for 966 patients were retrospectively analyzed at three sites within a single institution. Full panel testing was performed on 337 patients; 629 were tested only for BRCA mutations.

There was no statistical difference in the rate of detecting BRCA1/2 mutations between women who tested with a full panel and those who underwent limited BRCA testing (3.6% vs 4.0%)

Similarly, there were also no statistical differences between the two groups in detecting variants of uncertain significance (VUS) in BRCA genes (3.3% vs 4.0%).

“This is a very hot topic in a field that has been exploding,” said study author Nimmi S. Kapoor, MD, a surgical oncologist who practices at Breastlink Laguna Hills and Breastlink Orange, in California. “This area of testing is in rapid evolution.”

Speaking at a press briefing, Dr Kapoor pointed out that advancing technology allows for rapid sequencing, and increasing knowledge about hereditary links to breast cancer has revealed the involvement of genetic mutations beyond BRCA 1 and 2. With the 2013 Supreme Court ruling of Association for Molecular Pathology v. Myriad Genetics, women at risk for hereditary breast and ovarian cancer are now able to undergo expanded multigene panel testing that includes BRCA1/2, rather than in sequence after initial BRCA1/2 testing.

“But the big question is that when we have newer methods of tests, we need to know if they are safe,” said Dr Kapoor. “Are we going to miss mutations, or are we still going to find the same mutations as our previous methods? And also, what more can we gain if we actually look at other genes?”

More Mutations Detected

To evaluate the rate of pathogenic BRCA1/2 mutation detection and VUS detection between previous restricted methods of gene testing and newer multigene panel testing, Dr Napoor and colleagues collected retrospective data from 966 patients who underwent genetic testing between January 2008 and September 2014.

All of the women were evaluated by a breast surgeon and/or a risk assessment counselor to see whether they met the criteria for genetic testing, as determined on the basis of National Comprehensive Cancer Network (NCCN) guidelines.

The results for patients who underwent limited BRCA1/2 testing, including multisite testing (Ashkenazi panel) or full BRCA sequence testing, with or without large rearrangement testing (limited testing group), were compared with the results for those who underwent a multigene panel that included a minimum of five breast cancer–related genes, including BRCA1, BRCA2, PTEN, TP53, CDH1, and up to 28 cancer-related genes.

“There was no statistical difference in BRCA detection, so we knew our test was safe,” said Dr Napoor.

In the multigene panel group, 3.9% of patients (n = 14) were also found to have non-BRCA pathogenic mutations, and an additional 13.4% had non-BRCA VUS.

In the panel group, mutations in PALB2, CHEK2, MUTYH, and ATM were the most common non-BRCA mutations identified (n = 10; 2.8%). The most frequent non- BRCA VUS was in the ATM gene (n = 11; 3.1%).

“We found mutations in some commonly known genes, like the PALB2 gene, which was recently publicized in the New England Journal of Medicine as being associated with both breast cancer risk and pancreatic cancer risk,” said Dr Napoor. “But we also found mutations in genes that are less well known, such as CHEK2 and ATM. These genes confer a risk, but they are not well studied yet.”

However, an important issue is that these recently discovered genetic variants may pose unanswered questions about cancer risk. “A lot of the problem with testing is the variability and the unknown,” commented Julie A. Margenthaler, MD, an associate professor in the Division of General Surgery at the Washington University School of Medicine, St. Louis, Missouri, who is also moderator of the briefing.

“We do have guidelines from the NCCN as to what to do with BRCA if you are positive for a mutation, but other mutations, such as CHEK2 and AM, do not have these established guidelines,” she told Medscape Medical News. “Entering the unknown becomes scary for the patient and the clinicians providing the test. Personally, I think it is important to ask the questions, and without asking them, we will never get those answers.”

American Society of Breast Surgeons (ASBS) 16th Annual Meeting. Presented April 30, 2015.

— Roxanne Nelson


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