Studies show feasibility, potential of cascade testing for cancer-associated pathogenic variants
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Melissa K. Frey, MD, does not believe a woman who has just been diagnosed with ovarian cancer should be responsible for telling her relatives they also may be at risk.
“A woman with a new diagnosis of ovarian cancer is often recovering from surgery, starting chemotherapy, and dealing with the financial implications of the disease and its treatment,” Frey, assistant professor of obstetrics and gynecology in the division of gynecologic oncology at Weill Cornell Medicine, told Healio. “She might be thinking about her own genetic mutation and potential risk for other cancers. So, I think to ask her at the same time to reach out to family members to recommend and help organize testing is too much of a burden.”
Genetic testing among relatives of patients with cancer-associated pathogenic variants — commonly known as cascade testing — has an uptake rate of 30% or less, according to historical studies. The low uptake may be due to difficulties locating at-risk relatives (ARRs) and facilitating testing for these individuals, as well as a lack of communication.
“To understand how well we’re doing at this, we needed to determine the proportion of individuals who get tested and will then tell their relatives about the need to be tested,” Kenneth Offit, MD, chief of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “One of the great surprises I’ve discovered in my years in cancer genetics is that families really don’t communicate this information very well.”
Offit and Frey spoke with Healio about separate but related studies they and their colleagues conducted to examine the feasibility and value of cascade testing and its potential as a substitute for population-wide screening.
Finding the variants
The study by Offit and colleagues examined genetic testing at the time of cancer diagnosis and familial diffusion of genomic risk information as a potential alternative to population-wide testing.
“We wanted to see if there was a more rapid way to identify and inform all of the individuals and families in the U.S. that are carrying mutations that predispose them to cancer,” he said. “The most obvious way to do that is just test the entire population. We know that is doable, but there are enormous costs to doing that, and there are also enormous complexities to doing that.”
The researchers began by using a multiple linear regression model to calculate the number of people in the United States with pathogenic variants in one of 18 cancer susceptibility genes.
“We calculated that number to be 3.9 million people,” he said. “We know that more than 90% of these people don’t know they are carrying these mutations. So, the question is, how do we identify these people, other than testing all of them directly?”
Offit said the model assessed a combination of two approaches as an alternative to population-based testing: testing of patients at the time of cancer diagnosis and familial cascading of results.
They found that the time to detect the cancer-predisposing pathogenic variants was influenced by the degree of cascade to first-, second- and third-degree relatives; family size; mutation prevalence among patients with cancer; and the percentage of patients with cancer sequenced. A representative scenario that served as a base case assumed a 7% rate of pathogenic variants across cancer types, an average family size of three per generation, and 15% of incident patients with cancer undergoing peridiagnostic germline testing in the U.S. In this scenario, researchers found that the time to detect all 3.9 million people with the variants would be 46.2 years if 10% of all first-, second- and third-degree relatives were tested for familial mutations, 22.3 years if 25% were tested and 13.6 years if 50% were tested, but only 9.9 years if 70% of relatives were tested.
The results showed familial cascade and peridiagnostic testing could represent a viable alternative to population-based testing, according to the researchers.
“It’s much, much easier to find a mutation by testing a relative with a known mutation,” Offit said. “Also, one of the major advantages is we only test a relative for the mutation that we know about.”
However, he said this approach hinges on relatives informing one another of their genetic risk.
“Our key challenge is, if we could improve family communication, could we actually find all of the mutations that exist?” he told Healio. “So, the questions here are, how successful do we need to be in getting family members to talk to one another, and can we help this process by digital aides available, for example, via internet education?”
‘We have to do better’
Frey said after discovering the low rate of cascade testing, she became interested in why family members of mutation carriers were not taking advantage of this information.
“I realized it’s very hard to communicate this information; it’s complex and scary news that even some physicians would have trouble communicating,” she told Healio. “So, I thought this could be a really good way to get the medical team involved; it’s easier for us to communicate these topics.”
Frey also considered other potential barriers those with cancer-predisposing mutations may face in conveying genetic testing information to at-risk relatives. One significant obstacle could be that family members live far away.
“These relatives can’t just come with the patient to a genetics appointment, and even if you send them the genetics report, it’s hard to find a genetic counselor to explain it,” Frey said. “Most primary care physicians are still not ordering genetic testing. So, I suddenly understood why the low rate of testing is not at all shocking.
“I found this unacceptable,” Frey added. “We have the opportunity to prevent cancer by finding these mutations, so we have to do better.”
In their study, Frey and colleagues examined the feasibility of a novel method of cascade testing that included telephone genetic counseling and saliva testing.
The researchers identified 114 at-risk relatives of 30 adults newly diagnosed with an autosomal dominant hereditary cancer syndrome during the preceding year. They successfully contacted 95 (93%) of the relatives, 66 (70%) of whom completed genetic testing. Of those who completed testing, 27 (41%) carried the familial variant.
According to surveys administered at the time of testing and 6 months later, the at-risk relatives reported low levels of anxiety, depression and distress and high levels of satisfaction with testing.
“Even more exciting was that when we called these relatives back at 6 months, many of them had already had risk-reducing surgery or risk-reducing interventions like screening mammograms or prostate evaluations,” Frey told Healio. “What that means is that these relatives who were interested in testing were able to not only complete it, but also to use it proactively to take risk-reducing measures.”
Frey noted that in her study, she personally reached out to the relatives, adding that such an approach would not be sustainable in a real-world setting.
“The goal of this study was really just to prove that this is a feasible strategy,” she said. “The next step is to try to find something that is scalable.”
Offit said Frey’s study showed the impressive potential of physician-directed outreach in facilitating cascade testing, whereas his study demonstrated how dramatically and rapidly cascade testing could identify all mutations in the U.S. population.
“She proved that you can do it, that you can get this level of cascade up to 60% to 70% by enhanced physician outreach,” he said. “So together, these two papers are quite interesting. On the one hand, you have a pilot study that shows we can do it, and in the other, we show the power of the experiment as a vital public health intervention.”
References:
For more information:
Kenneth Offit, MD, can be reached at 1275 York Ave., New York, NY 10065.
Melissa K. Frey, MD, can be reached at 525 E. 68th St., Suite J-130, New York, NY 10065.
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