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WHAT MAKES SOMEONE HIGH RISK FOR BRCA1 BRCA2 MUTATIONS?

HOW MUCH RISK ARE WE TALKING ABOUT?

WHAT ARE THE POSSIBLE RESULTS OF THE TEST?

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Physicians began peering into our genes over a decade ago to look for mutations that increase the risk of breast and ovarian cancer. Last week, Myriad Genetics Inc., a Salt Lake City-based biopharmaceutical company, began mass-marketing this genetic test, called BRACAnalysis, to the general public.

Taking a test that tells you whether you have increased risk of getting cancer might seem like a good thing. But some genetic experts say it may not be, and worry that Myriad’s campaign will prompt people to make important medical decisions based on ad copy, rather than sound medical advice.

Unlike pharmaceutical ads and labels, which are reviewed by the Food and Drug Administration and the Federal Trade Commission, genetic test advertisements are not subject to any federal oversight, experts say. Concern that the content of the ads may be misleading has prompted an investigation by Connecticut's attorney general.

Mark Robson, a medical oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, sums up the concern this way: "I to some extent agree with the premise of the Myriad campaign which is that we're not identifying all those who could potentially benefit from the information. But the great majority of women with breast cancer are not going to carry this predisposition.” Experts say that of the women diagnosed with breast cancer this year, about 5 percent will have the mutation.

“There's a danger that many people will be concerned they carry the mutation and the flip side is that there may be people who would be falsely reassured when they don't have the predisposition," says Robson, who is also the clinic director of clinical genetics service at MSKCC.

Gregory Critchfield, M.D., president of Myriad Genetics, stresses that a consumer cannot order BRACAnalysis directly—a physician must order the test, which should help weed out people who are unlikely to have the mutation. “The BRACAnalysis public awareness campaign is designed to encourage women with breast and ovarian cancer running in their families to talk to their doctors about their risk. The most important part is that conversation with a healthcare professional,” Critchfield said in an interview. Myriad’s position is that only a small percentage of people with an inherited risk factor know about it and this campaign will likely encourage more people to take the test to find out.

BRACAnalysis, which costs about $3000 for the full analysis, looks for variations in the DNA of two genes—BRCA1 and BRCA2. The BRCA1 and BRCA2 sequences are the blueprints for proteins that protect against breast and ovarian cancers. By reading the sequences of the parts of the genes that code for the protein, Myriad can identify potentially harmful variations in the genes.

Certain variations, called deleterious mutations, in BRCA1 and BRCA2 can prevent the genes from making functioning proteins. These mutations significantly increase the risk of getting breast or ovarian cancer: A woman with a deleterious variation has 56 to 87 percent risk of developing breast cancer by age 70, compared with a 7 percent risk in the general population. For ovarian cancer, the risk of getting the disease is 2 percent in the general population, while women with the mutation have a 27 to 44 percent risk, according to Myriad.

Not all variations in these two genes, however, are necessarily harmful. "There's over 1000 different variants that have been described already in each of these genes," says Lawrence Brody, a senior investigator at the National Human Genome Research Institute. Some of these variations (the deleterious ones) are known to increase cancer risk, others are known to not increase risk, and a third category of variations are not well-understood.

This category, "variants of uncertain significance," are the results that physicians and geneticists would be hard-pressed to usefully interpret. "Typically many of us view the middle ground as essentially uninformative. If we see that kind of report we say, 'OK, we're not at a point of knowing what that means, let's go back to your family history,'" says Sharon Plon, professor in the departments of pediatrics and human genetics and the director of the medical scientist training program at Baylor College of Medicine in Houston, Texas.

Even if a patient’s test results unambiguously point to higher cancer risk, what she should then do may not always be obvious. The options are limited: the patient can increase surveillance for breast cancer (by getting full body MRIs instead of mammograms), or decide to get her breasts or ovaries removed.

Sharon Plon—who advises patients on whether to get genetic tests like this one--says that the test is most useful for people with a specific family history. Good candidates for the test are women who have had close relatives (mothers and sisters) with early-onset breast cancer, women with ovarian cancer in their family, families in which multiple family members have had breast cancer, and women who have had multiple instances of breast cancer. In fact, the best candidates for the test are those already diagnosed with breast or ovarian cancer, Plon says. If they are found to have a deleterious variation, their relatives can then be tested for that specific variation—a cheaper and less-involved analysis.

As the cost of genome sequencing goes down, it's feasible that more genetic tests that look for genes with less significant risks may be marketed. But do people want to know such hazy predictions? As for the BRCA1 BRCA2 test, the president of Myriad says business is booming. “The number of tests every year continues to grow every year very strongly. This is becoming something people know a lot about and are expressing a lot of interest in,” says Critchfield.

Brody is less certain. "Information seeking does seem to be a natural tendency," Brody says, "but if it doesn't help you in any way... it's unlikely that it will become widespread." A look at the results of Myriad's campaign may be the best indication of whether or not people really do want to know their genetic horoscopes.

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