Myriad Data Supports Polygenic Score Value Even in Canonical Mutation Carriers

NEW YORK – Based on growing evidence, some of which was presented earlier this month at the San Antonio Breast Cancer Symposium, Myriad Genetics believes that polygenic risk testing can be valuable not just in women who test negative for mutations in well-known breast cancer risk genes, but could significantly affect risk estimates for some mutation carriers as well.

More specifically, the company has found that its polygenic scoring can make risk estimates more accurate in women of European ancestry who have pathogenic variants in genes considered to have high and moderate penetrance.  

Based on the results, Myriad said it is planning to make its riskScore PRS testing available to women of European ancestry who test positive for mutations in breast cancer genes, as well as the mutation-negative population to whom it already markets this analysis. This could potentially change the risk that is assigned to certain women, and in turn the implications for their oncologic and other medical care.

A company spokesperson said that the firm has not made any final decisions yet regarding whether, when it launches this new combined option, it will also offer riskScore retroactively to women who already had a gene mutation identified, or only to new customers.

But if it does offer PRS to women who had previous gene mutation results, there is a chance some would see their risk revised downward, based on the results seen in the study at SABCS. 

In the firm's presentation at SABCS, investigators shared data from a study that analyzed results from 152,000 women of European ancestry who received a myRisk Hereditary Cancer test, 141,000 of whom were negative for pathogenic variants, while the rest carried mutations in high and moderate penetrance breast, ovarian, and prostate cancer risk genes: BRCA1, BRCA2, CHEK2, ATM and PALB2.

Myriad's riskScore PRS incorporates 86 SNVs from across the genome, along with a risk assessment tool called the Tyrer-Cuzick model, to estimate a woman’s five-year and lifetime risk for developing breast cancer. The company initially validated the approach in  2017, launching it soon after as a no-cost, add-on option for women of European ancestry who have been tested with its gene mutation panel but were negative for pathogenic variants. 

"Up until now, the work that we've done on PRS has concentrated on women who didn't carry high and intermediate risk gene mutations," said Myriad Chief Scientific Officer Jerry Lanchbury.

"What we do [currently] in our clinical testing is to screen for mutations, report back the mutation status to the carriers, [which] represent about 10 percent or a bit less than 10 percent … and when we introduced PRS the idea was to give a result for the other 90 percent of the non-carriers," he explained.

Other companies adopting polygenic approaches for cancer have used a similar model. Ambry Genetics, for example, also performs polygenic testing for women with breast cancer, offering it as a free add on for its various gene mutation panels, but only for women who don't have a pathogenic gene variant.

But based on the results of the new study at San Antonio, it looks like polygenic scores can significantly modify the breast cancer risk for women with pathogenic mutations in single risk genes, too. 

According to Lanchbury, the study shored up what Myriad had already established in terms of the impact of polygenic scoring for those who are already eligible. "The data really emphasize the role [PRS] has in the non-carriers. You can see … that the risk associated [with cancer rises] up to about 60 percent in ... women with very, very high-risk PRS genotypes," he said. 

"But more important … was the effect the score has on modifying the risk associated with carrier status?" So, the firm is putting carrier status together with PRS and asking how the risk prediction is modified, he said.

For some mutation carriers in the study, adding polygenic information significantly increased the predicted risk of breast cancer, while in others, the calculated genetic risk went down with the combined approach.

The greatest PRS risk modification, the authors wrote, showed up in CHEK2, ATM and PALB2 mutation carriers. On its own, having a mutation in one of these genes confers a substantially lower risk than a mutation in other genes like BRCA1 and BRCA2 does. But coupled with high polygenic risk, some carriers of these lower penetrance mutations appear to have actual cancer risks approaching those of BRCA1 and BRCA2 mutations, and this higher risk would have potentially important implications for their clinical care.

This isn't the first look at how polygenic information may modify risk as indicated by gene mutations, Lanchbury said.

In a preprint published on MedRxiv the week before the SABCS meeting, for example, researchers from cancer risk testing firm Color and their academic collaborators presented data supporting polygenic factors as significant modifiers of the risk conferred by monogenic risk variants for breast cancer, colon cancer, or coronary artery disease.

Similar to Myriad's reported findings at SABCS, the MedRxiv study suggested that polygenic risk has an "additive effect," pushing the risk that would be expected based on single gene mutations either higher or lower.

"Modification [for BRCA risk mutations] have been discussed in the past by an international consortium, and there has been some work on a single mutation in CHEK2 showing that PRS modified that status," Lanchbury added. "The [big achievement] here is that we've done this PRS modification now for all CHEK2 mutation carriers in a very large sample, and these are also the first data showing modification of ATM risk and PALB2 associated risk by PRS," Lanchbury noted.

Elisha Hughes, lead investigator on the study and Myriad's director of bioinformatics, said in a statement that the findings suggest a potential to "significantly improve the precision of hereditary cancer risk assessment for women who test positive for mutations in the high and intermediate risk breast cancer genes."

"We are optimistic that this additional genetic information can help clinicians more accurately predict the risk of breast cancer and provide the best care for their patients in the future," she said. 

The company said it plans to publish the data in full in a peer-reviewed journal and then at some point make PRS testing available for mutation-positive US customers of European ancestry.

At the very least, Lanchbury said, "we believe this is the first step to changing practice for CHEK2 carriers ... because it's the most modifiable of those intermediate risk genes to the point that CHEK2 with a risky PRS is not an intermediate risk gene anymore. It's a gene whose risk for some women approaches that of BRCA2 and certainly of PALB2.

"What we need to do now is actually to combine these data with the Tyrer-Cuzick data: to bring in family history and age of onset, BMI, use of hormones, to really round out the package so that we're looking at as many of the risk variables that we understand as possible," he said. "This is the first step on that route and we're very, very committed to following through and eventually moving this into clinical practice when it's ready."

Other ancestry groups are still waiting for effective polygenic risk testing, not just for breast cancer, but in other areas where this type of combinatorial, genome-wide analysis is being investigated. At issue is the fact that databases of SNVs that provide a resource for mining a predictive polygenic score, or panel, were heavily skewed toward those of European ancestry when they were compiled.

Myriad has taken a proactive stance to the issue, conducting its own studies across different racial and ancestry populations to fill that data gap. As described previously, the company's plans to design specific PRS tests for both African-American, and Hispanic lineages, initially for those without risk-gene variants, though potentially — if the company can collect similar data to what it presented for the European PRS — to also help refine risk estimates for mutation carriers.

The firm has said before that it is a little further along in its development of a Hispanic-specific polygenic panel, presenting data at the 2018 SABCS meeting on initial validation work. 

"It's a sort of unfortunate numbers game as to where the public sector has put investment, and we're really trying very hard to redress that balance ... so that we can offer a more rounded package," Lanchbury argued. 

"That's required us to put really very significant amount of investment into these other ancestries and to try and raise the data level up to the level of European women. … Our numbers are still far behind ... and numbers within the public sector are still far behind that ... but [both tests] are on the horizon in the near future," he added.

With Myriad pledging to bring polygenics into its risk assessment for mutation carriers, the medical field will have to grapple with how exactly this information should or would change clinical practice. Investigators from the recent MedRxiv publication hypothesized, for example, that combined testing might be most useful in individuals who get a double-dose result, with both single-gene and polygenic risk. Knowing that they have both factors in play could potentially aid the difficult decision to seek out prophylactic mastectomy or other treatments.

Among other things, investigators hypothesized that having more refined risk estimates could also help increase adherence to cancer screening in those who really need it and de-escalate it for those who don't.

Because Myriad has not decided whether it will offer riskScore retroactively to women who already had a gene mutation identified or only to new customers, the question of the impact of risk re-estimation is only hypothetical. But if the company does allow women who had previous gene mutation results to get PRS, the impact of that could be complicated, for example, if women who already took more aggressive action find out their risk is lessened based on PRS information.

As Myriad and other companies have expanded the scope of cancer risk testing both in terms of genomic content and applicability, many access barriers still remain. Studies have found, for example, that significant numbers of women who meet screening requirements fail to receive testing even for high-risk, well-known genes such as BRCA1/2. Even setting aside polygenic algorithms, the clinical community also continues to debate which women should be tested and when, and whether single-gene tests or more comprehensive tests should be used.

"If you think about it, we started offering BRCA1 and BRCA2 testing in 1996, and there are still controversies around who should be tested," Lanchbury said. "And if you look at PALB2 ... its role in breast cancer was discovered in 2008 [or] 2009, and we're only now ... really seeing it accepted as a gene that should be tested in women with breast cancer.

"Hopefully we're learning as a community how to navigate this area. But the people who make these decisions are careful and conservative, and sometimes these decisions can take an awfully long time," he said.