In May 2013, nearly 20 years after the discovery that mutations on the BRCA1 and BRCA2 genes could lead to a higher risk of breast and ovarian cancer, A-list Hollywood actress Angelina Jolie garnered widespread attention for announcing that she had mutations on these genes. In most people, these genes produce tumor suppressor proteins that repair DNA problems as they crop up, but some inherited mutations mean these genes don't work properly, leading to a significantly elevated risk for breast cancer. A 2017 JAMA study estimated that 72 percent of women who inherit a harmful BRCA1 mutation and 69 percent with a harmful BRCA2 mutation will develop breast cancer by age 80. Hoping to reduce her risk, Jolie underwent a prophylactic double mastectomy to remove both breasts.
Although BRCA gene mutations are only implicated in about 5 to 10 percent of breast cancer diagnoses, Jolie's announcement focused major attention on inherited genetic mutations, leading many women to seek genetic testing. One study released in December 2016 found that Jolie's revelation led to a 64 percent increase in women being tested for genetic mutations on the BRCA1 and BRCA2 genes.
In general, people are becoming more aware of how genetics influence disease risk. Leigha Senter-Jamieson, associate professor of genetics and licensed genetic counselor who specializes in cancer genetics at the Ohio State University College of Medicine, says that across the board, interest in genetic testing has increased in recent years. "The number of genetic tests that we've ordered over the years just continues to grow. Part of that is a really good thing – people are engaging with their families, asking questions about their family history and want to be proactive and take steps that could prevent cancer or reduce risk."
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Such testing is typically done with the help of a genetics counselor, a licensed health care provider who can combine laboratory results with individualized advice about other risk factors to develop a tailored risk profile. But that's no longer the only way to find out whether you have a mutation on your BRCA1 or BRCA2 genes.
In March 2018, the FDA authorized the marketing of direct-to-consumer genetic testing kits from genetics testing company 23andMe that look for three mutations on the BRCA1 and BRCA2 genes. Now, consumers can order a test kit and send a saliva sample back to the company for testing. Within a few weeks, an individual report returns with information about whether and which mutations were detected.
Dr. Jeffrey D. Pollard, 23andMe's director of medical affairs, says these kits aim to help consumers get a better understanding of their individual risk profile for developing breast cancer. "The report is called the BRCA1 and BRCA2 selected variance report. And it specifically looks at three genetic variants on BRCA1 and BRCA2 genes that are associated with an increased risk for developing breast and ovarian cancer." He says these three variants are the most common ones associated with breast cancer and are found "in folks with Ashkenazi Jewish heritage. That doesn't mean you have to have that specific ancestry to actually benefit from the test, but we did select those three variants based on how well established they are and how much is known about the significant risk that they do impart on folks who carry them," he says.
In addition to providing this individualized information to consumers, Pollard says 23andMe also offers other resources and information to help answer questions. The reports sent to consumers discuss risk and what the results mean, making clear that just because a variant was not detected does not mean the consumer has zero risk for breast cancer. For individuals who receive positive results, the reports also note that even if a variant was detected, it doesn't necessarily mean the individual will develop breast cancer and the company offers resources to help individuals get more information about how to best approach their specific situation.
"I like to think of it as we're creating a very soft landing for our customers. We provide a lot of detailed information that's both educational and informative," Pollard says. Consumers can opt into whether or not they want to see the report and then when results are revealed, it's "couched with resources, references and additional helpful information so that they can really comprehend and understand the value and get benefit out of the report itself." Consumers must also complete an educational module before receiving results, he says. For some consumers, these tests offer an inexpensive and convenient way to get a sense of their inherited genetic risk for breast cancer.
However, many genetics counselors have raised concerns over the use of these do-it-yourself testing kits, saying the raw data they produce can't equal the more in-depth and contextualized information and advice a licensed genetics counselor can provide, and could actually cause harm.
Dr. Louanne Hudgins, professor of pediatrics at Stanford University Medical Center and president of the American College of Medical Genetics and Genomics, says one concern is that because these reports are provided without an individualized analysis of the patient's family history and other risk factors, they can give a false sense of security to some people. "It's not done in context. The reason why we think it's so important that it's done in context is because the specific testing that's indicated is informed by the patient's clinical history and the patient's family history," meaning the testing a genetics counselor can offer might look for different variants than those sought by direct-to-consumer kits.
Another issue she cites is the limited nature of the direct-to-consumer testing. Although the three variants the 23andMe test looks for have been linked to a higher risk of developing breast cancer, there are potentially thousands of variants that could elevate cancer risk. She says these tests don't "test for all the mutations in both of those genes, let alone the plethora of other genes that we know now are associated with breast cancer. One of the major concerns is that people would get a false sense of reassurance that they don't carry a mutation, and that might affect their plan for surveillance." In other words, Hudgins fears that some consumers will cease undergoing regular screening for breast cancer after receiving a negative test result because they think they're in the clear.
Senter-Jamieson agrees, saying "the concern is that unless you understand that nuance, [that a clear report doesn't mean zero risk] you might think, 'I've had genetic testing and I had a negative result. [I'm safe.]' When really you haven't even scratched the surface yet." She says it takes both the lab results and an assessment of a person's other risk factors to arrive at a clear sense of risk and the basis for an action plan regarding how to reduce that cancer risk. She says such efforts may include additional testing and screening. Lifestyle changes such as quitting smoking, controlling obesity and limiting alcohol intake may also improve your overall risk profile, because it isn't just genetic susceptibility that leads to breast cancer. Other factors may also come into play.
At the other end of the spectrum, false positives could be a problem, too. Hudgins points to a recent study published in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics, that found up to "40 percent of the variants that were reported by the direct-to-consumer laboratories were actually false positives," leading her to conclude "it's just a screening, and it may not even be very good screening." That study included results from several companies, not just 23andMe, and looked at testing results for more than just BRCA gene variants.
However, Pollard, says 23andMe's results are more accurate than that, noting that the FDA would not have authorized the marketing of these products for BRCA gene mutations if they were highly inaccurate. "The accuracy of our testing was over 99 percent when you compared our results to Sanger sequencing, the gold standard for testing." Sanger sequencing is the most widely used method for DNA sequencing and the method used in the study.
Still, false positives are part and parcel of screening for all types of cancer and they can happen. "Even if you have a really nice report that gives you some information, it might miss things that are in your family history and either over- or under-estimate your risk," Senter-Jamieson says.
If you're considering ordering an at-home genetics test, Hudgins urges you to consider visiting a genetics counselor instead. "If you are concerned about your risk for cancer, especially if you have a positive family history or there's anything in your own personal history that puts you at increased risk, I would strongly recommend that you see a cancer genetics provider," Hudgins says.
If you've already completed a direct-to-consumer test, regardless of whether you received a positive or a negative result, Senter-Jamieson says that's also an excellent time to visit with a genetics counselor. "All of us in cancer genetics are willing and do provide assessment of those reports that you already have. You can take that report to somebody and ask, 'Are we missing anything?' 'Do I need other genetic testing?' 'How do you interpret this in the context of my family history?' And the 4,000 of us who practice in the United States are getting really used to doing this," she says, as the popularity of these testing kits grows.
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