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Healthy Nevada Researchers Consider Impact of Low Genetic Breast Cancer Risk on Screening Guidelines

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NEW YORK – An analysis of more than 25,000 women included in the Healthy Nevada Project suggested that patients with a low genetic risk of breast cancer may be able to safely defer mammogram screening up to 10 years after the recommended screening age of 40 years.

The researchers suggested that identifying this low-risk group with genetic screening could help conserve healthcare resources and reduce patient anxiety around cancer screenings. In a recent draft guideline, the US Preventive Services Task Force lowered the recommended age for starting biennial mammograms to 40. As such, researchers involved in the Healthy Nevada Project decided to investigate whether patients at low risk of developing breast cancer could be identified with similar genetic testing methods used to stratify high-risk patients.

"We logically asked what the impact is [of the guideline change] given our propensity for overdiagnosis within the health system and how difficult it is to maintain equity across the population," said Joe Grzymski, senior author of the study and principal investigator of the Healthy Nevada Project. The authors noted in their paper, which was published in JAMA Oncology, that the proposed guidelines update would require screening for an additional 20 million women.

"If you're doing genetic analysis on a population for risk assessment, it might be time to start stratifying people into red, yellow, and green [categories] rather than just high risk and everybody else," he continued.

Within the framework of the Healthy Nevada Project, Grzymski and his colleagues analyzed genetic and electronic health record (EHR) data from 25,591 enrolled women. Researchers worked with the population genomics firm Helix to conduct genetic sequencing of participants' blood or saliva samples using the Helix Exome+ assay, which covers more than 20,000 genes with whole-exome sequencing and about 300,000 common single nucleotide polymorphisms (SNPs) outside of the exome, including the 313 SNPs used to determine PRS.

The researchers classified women as low risk for breast cancer if they lacked pathogenic variants and variants of uncertain significance in genes associated with high risk of breast cancer — BRCA1, BRCA2, PALB2, ATM, and CHEK2 — and had a polygenic risk score (PRS) that put them in the bottom 10 percent of the population for breast cancer risk. Average-risk patients could have either a variant of uncertain significance in a high-risk gene or a PRS that put them in the top 90 percent of the population for breast cancer risk. High-risk patients were those with pathogenic variants in one of the previously noted breast cancer-associated genes.

Using this stratification method, 2,338 women, or 9.1 percent, were classified as having a low risk of developing breast cancer in the study cohort. Additionally, 410 women, or 1.6 percent, were classified as having a high risk of developing breast cancer, and 22,843 women, or 89.3 percent, were deemed average risk.

Looking at the EHR data, researchers found that a significantly lower percentage of women had a breast cancer diagnosis in the low-risk group across all ages compared to the average-risk group.

To determine whether mammogram screening could be deferred for the low-risk group, the researchers then calculated the cumulative risk of breast cancer at five and 10 years after the guideline-recommended age to begin mammograms. At age 45, five years after the recommended start of mammography, 0.69 percent of average-risk women had been diagnosed with breast cancer. The low-risk group did not reach this same threshold of diagnosis until age 51.

At age 50, 1.41 percent of the average-risk group had gotten a breast cancer diagnosis, but the low-risk group did not reach that same percentage until age 58. At age 70, the highest age that the researchers calculated breast cancer risk, the cumulative risk of a diagnosis was 3.7 percent for the low-risk group versus 9.9 percent for the average-risk group.

While the researchers concluded in the paper that this low-risk group could potentially defer mammograms, Grzymski clarified that they aren't necessarily saying they should.

"We are suggesting that there is a group of individuals who have a much more delayed onset of these cancers compared to the normal-risk population," he explained. "It doesn't mean that no women in the low-risk group ever developed cancer. It means that for the prevalence [of breast cancer diagnoses] to equal the normal-risk category, you have to move the low-risk group forward eight to 10 years."

Knowing whether a patient is at low genetic risk can also help clinicians more precisely guide patients on their prevention strategies, he added. "It allows them to change their calculus about what prevention [strategies] certain women should be focused on," he said.

Potentially delaying mammograms for the low-risk group could reduce the burden of mammogram screening on health systems and reduce overdiagnoses or unnecessary surgeries that can result from over-screening. In a study published last year, researchers from Yale Cancer Center compared breast cancer incidence between a group of older women who had screening and those who did not and concluded that about a third of older women screened for breast cancer were potentially overdiagnosed because their cancers were unlikely to have become symptomatic or caused health problems.

Another study from 2022 found a breast cancer overdiagnoses rate of 15.4 percent in a cohort of 35,000 women who received their first mammogram between ages 50 and 74. The researchers estimated that 6.1 percent of the overdiagnosed cases were instances where women had indolent preclinical cancer, while 9.3 percent of women had a progressive preclinical cancer and would have likely died of an unrelated cause before they would have been clinically diagnosed with breast cancer.

Grzymski also pointed out that having the ability to identify a low-risk group and guiding screening accordingly could help reduce patient anxiety around screenings. "There is a reluctance in the population to be stratified into the high-risk category," he said. "Many people don't want to know if they're high risk or if they have a BRCA1/2 mutation."

The novel idea from this paper is that patients can be at low risk for breast cancer and that this could influence a less-intensive screening approach and could make more patients willing to be screened in the first place, Grzymski said, by giving them a chance to learn something positive from testing rather than only finding out if they're at high risk.

"If you could say 9 percent of women can be safely stratified as [being at] low risk of breast cancer, folks may want to join a population study or get genetic screening because they're really interested to know, for example, if their daughter might inherit a low-risk status," he explained. "My hope is that this paper might alleviate anxiety for certain people and that might also help them continue to maintain a preventative mindset."

Grzymski argued that wider genetic screening for cancer risk could improve health and individualize recommendations while contributing to research that will better refine cancer risk and screening practices.

"Population-level genetic screening inherently marries family medical history without having to rely on the incredibly complicated dynamics of family structure," Grzymski said. "There are countless examples of folks who don't know who their parents are, who don't talk about health, or who don't talk about why or how family members died. Genetics cuts through all of that, so it's a sharper scalpel for assessing family risk."

The Healthy Nevada Project is ongoing, Grzymski said, and the researchers will continue exploring the data to try to inform a "more comprehensive risk assessment program."

In a preprint of another study from this same project, researchers have assessed different genetic risk screening approaches, including the role of loss-of-function variants in breast cancer risk-associated genes and the PRS model, in identifying women at a high risk of hereditary breast cancer. The Healthy Nevada Project aims to ultimately enroll 250,000 participants in Nevada and explore participants' hereditary risks for breast and ovarian cancer, heart disease, and Lynch syndrome-associated cancers.