Myriad’s riskScore test for breast cancer risk adds a second layer of precision

Just 10 percent of women with a family history of breast cancer test positive for one of the 11 genes directly associated with disease risk. Myriad’s new riskScore assessment caters to the other 90 percent.

On Wednesday, day two of the 2017 San Antonio Breast Cancer Symposium, Myriad Genetics unveiled pivotal validation data in support of its new riskScore genetic test, designed to quantify a woman’s five-year and lifetime risk of developing breast cancer.

In practice, it’s a follow-up test. The riskScore test is indicated for women with a family history of breast cancer that don’t carry mutations in any of the major genes, such as BRCA1/2. Instead, it looks at over 80 point mutations (SNPs) that have a more complex relationship with the disease.

To understand the product’s value, picture this scenario:

A woman in her late 30’s schedules an appointment with her obstetrician/gynecologist. She’s concerned, now that she’s getting older, about her risk of developing breast cancer. Several of her aunts and her paternal grandmother all developed the disease in their 60s and 70s, she tells the doctor. Surely there’s a genetic component?

The standard course of action is to order a gene panel test to determine whether the patient has a mutation in one of 11 genes known to directly impact breast cancer risk. However, for better or worse, the patient tests negative for all of them. She goes home with no answers.

Johnathan Lancaster, chief medical officer of Myriad Genetics, has seen this play out many times before as a practicing ob/gyn doctor.

“They’ve come to their physician with a strong family history and yet, 90 percent of women in that scenario test negative for the breast cancer genes,” Lancaster explained in a phone interview.

That’s where riskScore comes in.

It dives deeper into so-called ‘polygenic’ traits; multiple genetic variants that may increase risk in the presence of other mutations or lifestyle factors. For this reason, the results are combined with the well-established Tyrer-Cuzick model, which takes into account person-specific variables (such as the use of hormone replacement therapy), alongside family history.

Put together, riskScore and the Tyrer-Cuzick model deliver a combined residual risk score (cRRS) specific to each patient. In the validation study of 1,617 women without the 11 major breast cancer genes (990 women with breast cancer and 627 controls), Myriad found the SNPs added “significant breast cancer risk discrimination” above and beyond what is achieved with the Tyrer-Cuzick model alone.

Being able to precisely quantify a person’s five-year and lifetime risk of developing breast cancer is useful and actionable in several ways. The obvious benefit is for patients at high risk of the disease. In the U.S., breast cancer is the second most diagnosed cancer and the second leading cause of cancer death in women. Early detection is key.

Many groups, including the American Cancer Society and the American Congress of Obstetricians and Gynecologists, recommend that if a woman has a greater than 20 percent lifetime risk for breast cancer, she should be offered magnetic resonance imaging (MRI) alongside her annual mammography exam. Adding a breast MRI increases detection sensitivity compared with mammography alone.

On the flipside, the combination of a genetic panel, the riskScore test, and the Tyrer-Cuzick model can identify women who have a lower than average risk of developing breast cancer. Alongside the validation study, Myriad presented data on Wednesday from a separate analysis of the combination testing approach, which delivered lifetime risk estimates that ranged from 0.88 percent to 66.4 percent. If a patient has a less than one percent chance of developing breast cancer, her screening regimen can be less.

Lancaster believes that positive news is often a missed opportunity. Doctors, particularly oncologists, tend to focus on what to do, not what not to do, he said. Yet the potential benefits of knowing a patient is at lower risk are huge.

“There’s the cost-saving, the unnecessary medical interventions, the appropriate utilization of healthcare resources at a population level; but there’s also the individual patient and not just their clinical management… but also I think the anxiety level impact, the emotional impact,” Lancaster said.

Many women endure weeks of anxiety around every mammography exam, he noted, aware that this could be the year that clinicians find a cancerous growth. They might be at elevated risk based on family history, but they have no idea how concerned they should be.

In some ways, this makes the addition of riskScore a significant milestone for the field. It means genomics is evolving from studying single mutations that independently increase disease risk, to a more nuanced reading of many genetic and lifestyle variables that combine in an individualized way.

While several academic teams have published studies highlighting the value of polygenic testing in recent years, none appear to have commercialized and validated their tests to this extent. Due to the sheer volume of data required, Myriad used external databases to develop its test.

The catch right now is that riskScore has only been validated for women of European descent. Lancaster stressed that this is not due to any decision-making at Myriad, but simply because genome-wide association studies (GWAS) that have identified the crucial SNPs tend to be in Caucasian populations.

“We are to a certain extent limited by what’s out there, by what research has been done,” he said. “But as the data accumulates, we certainly will embrace the opportunity to expand, not just into other ethnic groups but also into other disease types.”

Cancers with a strong hereditary component will likely be next on the list. That might include prostate, ovarian, and pancreatic cancers.

At the same time, Lancaster laments that some genetic tests, such as those for colon cancer, are woefully underutilized. Indeed, it doesn’t matter how sophisticated the genetic tests become, the information is only worthwhile when patients and doctors embrace it. (Myriad currently sells a genetic test for colon cancer.)

In the meantime, women with a family history of breast cancer can order Myriad’s existing myRisk Hereditary Cancer test; a 28-gene panel that identifies patients with an elevated risk for eight hereditary cancers. If patients test negative for the 11 breast cancer genes included in the panel, Myriad will follow-up with the riskScore assessment free of charge, using the initial sample. To understand each woman’s personal risk, the results will then be paired with the Tyrer-Cuzick model.

Photo: Flickr user NIH Image Gallery