You may or may not have heard the name Kathleen Maxian, but it is likely you have encountered women like her in your practice without knowing it. Kathleen has been featured in several news stories lately, including in the New York Times and on CNN. Her sister, Eileen Kelly, was diagnosed with breast cancer at age 40 and underwent testing for BRCA1 and BRCA2 (BRCA1/2) gene mutations. She was found to be negative. Two years later, Kathleen was diagnosed with ovarian cancer. Ultimately, Eileen and Kathleen were found to carry a BRCA mutation that is only detected by BART, a test that looks for large genomic rearrangements in BRCA1/2. According to Maxian’s surgeon, “If BART had been done from the beginning, it could have saved Kathleen from getting ovarian cancer.” 1 So why wasn’t BART performed on Eileen’s initial genetic test? To understand the science behind Kathleen’s story, the history of clinical BRCA testing needs to be examined.
Overview of BRCA1/2 Testing
The majority of hereditary breast and ovarian cancer is linked to 2 genes, BRCA1 and BRCA2. A woman with a BRCA1/2 mutation has up to an 87% chance of developing breast cancer and up to a 40% chance of developing ovarian cancer in her lifetime. Other cancers associated with mutations in the genes include male breast cancer, prostate cancer, pancreatic cancer, and melanoma. The genes were first identified in the early 1990s, and patents followed. In 1996, Myriad opened a $30 million laboratory and began marketing 3 tests for BRCA1/2 analysis.2 Some of Myriad’s patents will expire in 2014; however, the company believes patent protection should last at least until 2018.3
Today, Myriad Genetics offers several versions of the BRCA1/2 test: Single Site BRACAnalysis, Multisite 3 BRACAnalysis, Comprehensive BRACAnalysis, and BRACAnalysis Rearrangment Test (BART). The Single Site test is used to test for a known mutation in a family, while the Multisite 3 test looks for the 3 most common BRCA mutations in individuals of Ashkenazi Jewish descent. Myriad’s standard test, Comprehensive BRACAnalysis, consists of sequencing of exons and flanking regulatory regions, as well as a panel for 5 rearrangements in BRCA1. The 5 rearrangements in BRCA1 were added to the test on August 12, 2002. Of interest, the first large rearrangements in BRCA1 began appearing in the literature in 1997.4,5
As the 5 rearrangements do not account for all large deletions and duplications in BRCA1/2, BART was launched in 2006. BART utilizes quantitative multiplexed fluorescent polymerase chain reaction to detect genomic rearrangements in BRCA1/2 that are typically missed by traditional sequencing. In August 2006, Myriad began performing BART as a reflex test on individuals meeting their defined clinical criteria. On May 14, 2007, Myriad converted from a reflex test to a concurrent test. For individuals who do not meet Myriad’s defined criteria (Table), the BART component can be added for a fee. As of November 2011, most insurance companies do not cover the cost of the BART component.
How Common Are Mutations Detected by BART?
It is difficult to assess the frequency of large genomic rearrangements in families at risk for BRCA1/2 mutations, as most studies have focused on families at the highest risk of carrying a mutation. BRCA2 rearrangements are reported to be less common than BRCA1 rearrangements. Depending on ethnic background, studies report 0% to 36% of BRCA1 mutations are genomic rearrangements; however, these studies do not necessarily exclude the genomic rearrangements found by the BRCA1 large rearrangement panel.5
In 2006, Walsh and colleagues reported that 12% of families with 4 or more cases of breast and/or ovarian cancer found to be negative by BRCA1/2 sequencing harbored a large genomic deletion or duplication in BRCA1/2.6 A recent retrospective chart review conducted at Massachusetts General Hospital of patients undergoing BART analysis demonstrated 2 in 5 individuals with a mutation did not meet Myriad’s defined criteria and 1 in 5 only met criteria because information on third degree relatives was obtained. They suggest that “when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR [large genomic rearrangements] testing so that the results are the most comprehensive and reliable.”7
According to Myriad Genetics, “there is, on average, a less than 1% chance that BART will identify a mutation in a patient who has already had a negative result from Comprehensive BRACAnalysis.” 8 BART currently detects approximately 7.5% of mutations, while Comprehensive BRACAnalysis detects 92.5% of all mutations. However, the ancestry of the patient is also important. For patients of Latin American/ Caribbean ancestry, Myriad Genetics states that 20% of the mutations found were detected by BART.9 However, it is important to note, ancestry is not taken into account in Myriad’s defined clinical criteria for complimentary BART.
Applying Knowledge to Clinical Practice
Take-home messages regarding BART testing:
- Not every individual with a BRCA mutation detectable only by BART will meet Myriad’s defined clinical criteria for complimentary BART (eg, Kathleen Maxian)
- Family history and genetic testing options are dynamic. Patients should be encouraged to alert healthcare providers about changes in their family history. Additionally, they should be encouraged to contact their genetic provider on an annual basis as genetic testing options may change—even for the same gene (case 2)
- Familial mutations should be confirmed via a test report. Although a family may meet Myriad’s defined criteria for BART analysis, not every individual in the family may meet criteria for concurrent BART analysis (case 1)
A 68-year-old female presents for genetic counseling due to her history of breast cancer at age 65 and family history of breast cancer. Family history includes a sister diagnosed with bilateral breast cancer at age 35 and 42, mother diagnosed with breast cancer at age 90, maternal aunt diagnosed with colon cancer in her 60s, maternal first cousin diagnosed with breast cancer at age 45, a maternal first cousin who underwent risk-reducing mastectomies, and maternal first cousin diagnosed with ovarian cancer in her 40s. Additionally, the patient tells you that her nieces had some genetic testing based on the cousins, and results were negative. Comprehensive BRACAnalysis is performed, and the patient is asked to contact her family members to obtain additional information about cancers and possible genetic testing results.
The patient is found to be negative via Comprehensive BRACAnalysis. However, she was able to obtain additional information. Her maternal aunt, diagnosed with colon cancer in her 60s, actually had ovarian cancer. Ad - ditionally, the cousin who underwent the risk-reducing mastectomies and her sister did carry a mutation in the BRCA1 gene. The patient brings copies of various family members’ results to the counseling session. The mutation in the family is a large deletion of the BRCA1 gene, which is only detected by BART. Her test result and the test results of the nieces did not include this component, as they did not meet Myriad’s defined criteria for complimentary BART. Ultimately, the patient is found to carry the familial mutation in the family and states she plans on contacting her nieces to alert them to the fact that their test result did not include testing for the familial mutation.
Sandy was diagnosed with breast cancer at age 32, and was recently diagnosed with ovarian cancer at age 58. Her family history includes a mother, 2 maternal aunts, 2 maternal cousins, and a maternal grandmother with breast cancer, all diagnosed at younger than 50 years of age. Because of this extensive family history with cancer, Sandy underwent genetic counseling in 2000. She sought it for her own risk assessment as well as for her 3 daughters. At that time, testing consisted of sequencing of BRCA1/2, and she was found to be negative. In 2002, Sandy underwent 5-site testing and was again found to be negative. Her daughters are managed as having high risk, and 1 daughter opted to proceed with risk-reducing mastectomies. Upon Sandy’s diagnosis of ovarian cancer, this daughter contacted her certified genetic counselor (CGC) for guidance on her ovarian cancer risk. The CGC explained that there is a new component of the BRCA test called BART and suggested that her mother consider having the test performed. Sandy opted to pay out-of-pocket for the test as her insurance carrier did not cover the test and she was not eligible for Myriad’s complimentary BART analysis. Sandy was found to carry a large genomic rearrangement in BRCA1.
- Cohen E. When breast cancer tests get it wrong. CNN Health. http://www.cnn.com/2011/10/27/ health/brca-genetic-testing-ep/index.html. Updated October 27, 2011. Accessed November 23, 2011.
- Gold ER, Carbone J. Myriad Genetics: In the eye of the policy storm. Genet Med. 2010;12(4 suppl): S39-S70.
- Pollack A. Despite gene patent victory, Myriad Genetics faces challenges. New York Times. Published August 24, 2011. http://www.nytimes.com/2011/ 08/25/business/despite-gene-patent-victory-myriadgenetics- faces-challenges.html?_r=2&pagewanted= all. Accessed November 23, 2011.
- Puget N, Torchard D, Serova-Sinilnikova OM, et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 1997;57:828-831.
- Petrij-Bosch A, Peelen T, van Vliet M, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997;17:341-345.
- Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295:1379-1388.
- Shannon KM, Rodgers LH, Chan-Smutko G, et al. Which individuals undergoing BRACAnalysis need BART testing? Cancer Genet. 2011;204:416-422.
- Myriad Genetics. BART Brochure. Fact sheet 02/11. http://www.myriad.com/lib/brac/BART%20 one%20sheet.pdf.
- Myriad Genetics. BART Prevalence Table and FAQ. http://www.myriad.com/lib/brac/BART-tablefaq.pdf.