October 27, 2017
6 min read

Genetic markers combined with family, clinical history may be next breast cancer ‘breakthrough’

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Ora Gordon

A breast cancer heredity test by Myriad Genetics, Inc., now combines genetic markers throughout the genome to a woman’s family and clinical history, according to a company-issued press release.

The new version of the myRisk test provides a numeric “riskScore” that helps determine a woman’s risk for breast cancer, as well as her need for further testing.

“This a breakthrough in terms of being able to provide more individual risk factors to women who have a family history of breast cancer,” Ora Gordon, MD, MS, medical director of the regional center for clinical genetics and genomics at Providence Health & Services, Southern California, told HemOnc Today. “It’s truly transformational in terms of the impact it’s going to have on women who have a family history and do not have [identifiable mutations] such as BRCA. It allows for the personalization of risk by combining novel genetic information with a woman’s family history and her own reproductive risk factors.”

The myRisk evaluation — which can be obtained through a blood sample or saliva swab — uses next-generation sequencing to analyze data from 86 biomarkers and 25 high-risk genes. The allele status of those markers is weighted and combined with patient clinical and family history data to produce breast cancer risk calculations at 5 years and for the remaining years of life.

A risk estimate of 20% or higher prompts specific modified medical recommendations, including consideration of more aggressive breast cancer screening and additional risk reduction measures. It may still be appropriate for women with assessed risk estimates below 20% to consider modified medical management based on other clinical factors or estimates from other breast cancer risk models.

The myRisk test includes sequencing and large rearrangement analyses performed on 25 high-risk genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM (large rearrangement only), MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Sequencing is performed for select regions of POLE/POLD1, and large rearrangement analysis is performed for select regions of GREM1.

Other risk assessments lacked clear guidance for women with a family history for breast cancer who do not harbor germline mutations.

“For somebody like me who practices in a high-risk clinic, if 90% of women with a family history of breast cancer test negative [for germline mutations], you can imagine how often I’m left wringing my hands not knowing whether I should manage this person as if they are still at elevated risk and have them undergo breast MRIs, which have high false-positives, are very costly and are burdensome,” Gordon said. “Do I consider putting them on medication — with its own risks — to prevent breast cancer?”


Gordon would like the ability to confidently differentiate between high risk and population risk.

“Way too often a woman undergoes testing, and when the BRCA and panel testing comes back negative, they are told by their doctors or they perceive themselves to be negative,” Gordan said. “[The riskScore] test is unique in that it is one giant step toward our quest for personalized medicine and putting the power of genetics and genomics into care.”

Impact of genetics

The essence of genetics is applying precision medicine to identify patients at risk before cancer or any other condition develops, according to Johnathan M. Lancaster, MD, PhD, chief medical officer at Myriad Genetic Laboratories and former professor of obstetrics and gynecology and oncologic sciences at University of South Florida.

Johnathan M. Lancaster

“For the first time, we’re able to give close to 100% of women an answer as to their risk, whether it’s positive or negative for BRCA1 or one of the other dominant susceptibility alleles,” Lancaster told HemOnc Today. “More importantly, for those 90% of women who receive a negative genetic test, they now have an answer to their quantifiable risk that enables them to take proactive measures to either diminish their risk for developing a cancer or to identify that cancer at an early and more curable stage.”

In addition to screening for multiple biomarkers and high-risk genes, myRisk measures single nucleotide polymorphisms against other risk factors, such as family history; body weight; and ages at menarche, first childbirth and menopause.

The multilayered breast cancer heredity test could be especially useful for women who have a family history of breast cancer but do not have mutations detected in previous screenings.

“What we’re left with in those women is trying to determine their true risk for breast cancer,” Gordon said. “Is it closer to a population risk, which would require routine mammograms? Or is there an elevated risk, in which we could avail all of the management strategies, such as MRIs, medication and optimizing lifestyle?”

Unless a woman has a strong family history of breast cancer or has tested positive for a BRCA1 or BRCA2 mutation, Gordon recommends women undergo hereditary breast cancer screenings when aged 30 to 40 years, adding that the results could help eliminate the need for unnecessary testing. The U.S. Preventive Services Task Force recommends biennial screening mammography for women aged 50 to 74 years.


“If a patient is at elevated risk, they should know before they’re in that high-risk window so that they can do the most they can in terms of prevention and optimizing surveillance for early detection,” Gordon said. “This gives clinicians the tool to be much better at targeting who really needs the high-risk screening.”

Such an approach may reduce false-positive and unnecessary testing by downgrading women’s risk.

“Theoretically, you could downgrade by 10% the number of women who think they are at high risk and would otherwise be shuffled through a high-risk protocol by getting breast MRIs,” Gordon said.

The red flags for hereditary cancer include multiple cancers in the family, early age at diagnosis in the family or individuals with multiple cancers.

However, genetic testing can be essential for diagnosing cancers that may be unrelated to family history, Lancaster said.

“Despite the fact we talk about this constantly and have been for many years, we know that 90% of the folks carrying these BRCA1-like genes are completely ignorant of the fact they are at a massively increased risk for cancer,” Lancaster said.

Determining value

Screening for single nucleotide polymorphisms adds incremental value to breast cancer risk models. But, without data, it is unclear how much added value myRisk provides to Tyrer-Cuzick models, according to Kevin S. Hughes, MD, FACS, co-director of the Avon Comprehensive Breast Evaluation Center, associate professor of surgery at Harvard Medical School, and medical director at Bermuda Cancer Genetics and Risk Assessment Clinic.

Kevin S. Hughes

The Tyrer-Cuzick model calculates the likelihood that a woman is carrying a hereditary breast cancer predisposition gene, as well as the likelihood she will develop breast cancer, based on family history, hormonal history, benign breast disease, BMI, age and genetic factors.

“I believe that genetic testing for known moderate- to high-risk genes is essential,” Hughes told HemOnc Today. “I believe running risk models like Tyrer-Cuzick on all patients is essential. Adding measures for SNPs will likely add discrimination to the Tyrer-Cuzick model, but I’m not sure how much, and at what cost. Is it cost-effective? I’m not sure without seeing the data. I will look forward to reviewing the published data.”

myRisk evaluations are covered by most insurance plans, including under the preventive care provision of the Affordable Care Act, with no out-of-pocket costs, according to Myriad.

The average out-of-pocket cost is $50 for individuals whose health plans have deductibles. Myriad also offers free testing for many uninsured and underinsured patients, and is assessing the need for similar genetic risk scores for colon, ovarian and prostate cancers.


“We focused initially on breast cancer because there’s a very high societal appreciation for the role of genetics and genomics in breast cancer,” Lancaster said. “There’s a massive cohort of individuals out there who either will undergo or have undergone genetic testing using the 10 or 11 known breast cancer genes and test negative. We perceive there is a real unmet clinical need for better quantifying risk in those germline-negative individuals with a family history of breast cancer.

“Our strategic decision was to start with breast cancer, but we’re certainly following the science very closely, and we have an interest in potentially pursuing other tumor types moving forward,” Lancaster added. – by Chuck Gormley

For more information:

Ora Gordon, MD, MS, can be reached ora.gordon@providence.org.

Johnathan M. Lanca ster, MD, PhD, can be reached at jlancaster@myriad.com.

Kevin S. Hughes, MD, FACS, can be reached at kshughes@partners.org.

Disclosures: Gordon reports a consultant role with Myriad. Lancaster reports employment with Myriad as chief medical officer. Hughes reports honoraria from Myriad Genetics, Veritas Genetics and Focal Therapeutics, and is a founder of and has a financial interest in CRA Health.