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Researcher Presents Promising Early Results on Color Cascade Testing Uptake at ACMG Meeting

CHARLOTTE, NC (GenomeWeb) – An early analysis of data from the Color Genomics Color Family Testing Program suggests it is possible to get relatively robust uptake of cascade testing for hereditary cancer risk when cost is decreased and access is simplified.

At the American College of Medical Genetics and Genomics annual meeting on Friday, Allison Kurian presented uptake patterns and test outcomes for first-degree relatives (FDRs) of pathogenic variant carriers who were invited for cascade testing during the first year of Color's family program — part of the firm's population genomic screening effort.

Kurian, a medicine and health research and policy investigator at Stanford University and policy director for Stanford School of Medicine's women's clinical cancer genetic program, noted that the program provides the opportunity to follow cascade testing uptake in a new way.

"What does it look like when we empower carriers to invite relatives [for testing]? I don't think we've seen anything like that in the US before," Kurian said in an interview.

"I think it's been very helpful, particularly in settings where relatives live far away, where maybe they lack insurance coverage, where cost might be a problem," she added. "The reception [to this cascade testing program] has been special in terms of thinking about different models of how these things are done."

Through the Family Testing Program initiative — funded by the BRCA Foundation with matching funds from Color — Color offers FDRs of known hereditary cancer risk carriers a panel sequencing test that profiles for coding sequences and large rearrangements in 30 cancer-associated genes (including BRCA1, BRCA2, CHEK2, MLH1, MSH2) for just $50.

That reduced price tag stands even if the index individual's testing was done through another lab, provided that lab was CLIA-certified, explained Color Genomics' Head of Research Alicia Zhou, who said "a lot of people do apply with results from other sequencing labs."

Between late September 2016 and September 2017, Color invited nearly 2,300 FDRs to participate in cascade testing, Kurian reported, based on applications from 741 carriers and 360 FDRs. Of those, 1,084 individuals — or 48 percent of the FDRs who were invited — opted for screening.

That uptake rate compares favorably with previously reported cascade testing studies, Kurian noted. In the US, she explained, past research from specialty cancer genetics clinics suggests roughly one-third of FDRs choose to undergo cascade testing.

In the Color program, Kurian and her colleagues found that FDR test uptake was significantly higher in women than in men. FDRs of carriers with syndromic pathogenic variants were also a bit more likely to take part in the cascade testing.

Overall, the highest rates of uptake occurred among FDRs of individuals carrying pathogenic variants in high-profile genes such as BRCA1/2 or in CHEK2, in which worrisome mutations are thought to be relatively common.

Consistent with predictions, which put the risk of inheriting the same mutation at 50 percent in first-degree relatives of known carriers, the team identified pathogenic variants in 48 percent of first-degree relatives participating in the cascade study so far.

Another 41 percent of participating FDRs were negative for pathogenic variants, Kurian said, while 8 percent had at least one variant of uncertain significance in any of the genes profiled. In addition, she noted that 5 percent of the FDRs carried pathogenic variants not found in the original carrier relative, including mutations affecting other genes.

In the future, the team is interested in exploring the lower rates of secondary cascade testing — that is, tests offered to relatives of the original FDRs. At the moment, that rate is roughly 12 percent, though she noted that future cascade tests in these relatives of relatives may not have been captured during the time period considered, leaving room for that proportion to rise over time.

The researchers also hope to get a better sense of how well FDRs with pathogenic variants understand those results and the screening steps and outcomes they go through in the future. Similarly, they expect that it will be possible to integrate clinician response to, and expertise in, the tests.

Based on results so far, Zhou said it may be necessary to consider new strategies for engaging FDRs who opted against participating, particularly male family members or FDRs from different age groups. She noted that Color has decided to continue its cascade testing program indefinitely, even after current funding runs out.

"Given the success of the program, we've actually decided at Color to continue the program," she said, "and not just for hereditary cancer, but also for [familial hypercholesterolemia]."

More broadly, the clinical genetics community continues to debate the feasibility, economics, technical challenges, and potential harms associated with widespread population genomic screening on healthy adults who do not have FDRs with known pathogenic variants. A panel of experts from across the US came together to discuss some of those issues during a Saturday morning session at the ACMG conference.