NEW YORK — Polygenic risk scores could help refine screening recommendations for women at risk of developing familial breast cancer but who do not have pathogenic BRCA1 or BRCA2 variants and potentially women more broadly.
While pathogenic BRCA1 or BRCA2 variants greatly increase the risk of familial breast cancer, not every family with a history of breast cancer harbors those risk variants. Other families may have more moderate risk variants such as ones in ATM, CHEK2, and PALB, or even other risk factors.
This has prompted researchers to wonder whether polygenic risk scores (PRS) that bundle common genetic variants that affect disease risk together could be applied to breast cancer and shift breast cancer screening more generally to be based on someone's personal risk, rather than their age. Currently, the United States Preventive Services Task Force recommends that women between 50 years and 74 years old who are at average risk of breast cancer get a mammogram every two years, though women under 50 years old may also opt for screening based on their personal circumstances.
"Instead of an age-based screening program, we would go to a risk-based screening program where you would first determine the risk of women and then invite them to tailor-made kind of screening," Peter Devilee, a cancer genetics professor at Leiden University Medical Center in the Netherlands, said.
He and his colleagues reported in the Journal of Medical Genetics last month that the addition of a more than 300-variant-strong PRS to a commonly used clinical risk algorithm would change screening recommendations for about a third of women. Similarly, researchers from University of Pennsylvania School of Medicine found in the journal Breast Cancer Research and Treatment that the same PRS could predict both breast cancer diagnosis and prognosis.
Studies like these "are building the evidence base that [PRS] might be something we think about for predicting breast cancer risk," Anne Marie McCarthy, an epidemiologist at UPenn, said.
In their study, Devilee and his colleagues tested the effect of folding a PRS encompassing 313 variants into a family history-based risk assessment. They did so using a cohort of 3,918 breast cancer cases from 3,492 Dutch families with a history of disease but without BRCA1 or BRCA2 risk variants and 3,474 Dutch population controls. They then calculated their cohort's lifetime risk of developing disease using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a family history-based risk assessment tool, both with and without the added PRS information.
Including the PRS information would have changed screening recommendations for about 30 percent of the women in the cohort. As Devilee noted, these guidelines rely on different thresholds of risk to recommend different screening options. Someone with higher risk, for instance, might be advised to have more frequent checkups or undergo mammograms more often or starting from a younger age than others with more typical risk.
The portion of women for whom screening recommendations would have changed depended on which guidelines and corresponding cutoff thresholds were used. If US National Comprehensive Cancer Network recommendations were used, then screening recommendations would have changed for 27 percent of the cohort with family history of disease, while if UK National Institute for Health and Care Excellence recommendations were followed, then recommendations would have changed for 36 percent of the cohort and for 34 percent if the Netherlands Comprehensive Cancer Organization guidelines were followed.
Further, this added PRS information also changed recommendations for individuals in the cohort with moderate risk variants for breast cancer. About a quarter of individuals with pathogenic variants in ATM and about 18 percent of those with pathogenic variants in CHEK2 also changed risk category based on NICE or IKNL guidelines. They did not switch groups based on NCCN guidelines due to its single cutoff threshold.
At the same time, screening recommendations also shifted for between 39 percent and 58 percent of the population controls, again depending on which screening guidelines were followed.
"We have shown that if you use those thresholds … [and] if you now start using the new system, that would change for quite a few women," Devilee said.
These findings suggested to Devilee that how screening recommendations are generally made could shift even for the general population away from an age-based approach to a personal risk-based approach.
"That's something that's been discussed widely," he said, adding a trial in California, the Women Informed to Screen Depending On Measures of risk (WISDOM) study, is addressing this question.
Meanwhile in a separate study, UPenn's McCarthy and her colleagues examined whether the same PRS could predict breast cancer risk over a shorter period of time. That team focused on the two years following a negative mammogram. "We know it predicts long-term risk. Does it predict short-term risk as well?" McCarthy asked.
In their analysis of a cohort of 3,657 women, they found that the PRS could predict breast cancer diagnosis within those two years as well as the risk of poor prognosis breast cancer.
"So together, this is all evidence that's helping us to determine whether polygenic risk scores might help us make decisions about when women should be screened, how often they should be screened, when should they start screening?" she said. "Should they be screened just with mammography, or should they consider breast MRI, which has better sensitivity? That's the goal that both this paper and my paper were aimed at, [just] coming at it with slightly different angles."
Devilee said the next challenge is to get these risk calculations into the clinic, and he is seeking funding from the European Union for that.
He added, though, that studies have shown that screening breast cancer works. "In the general population, there are very good data that these programs actually reduce mortality from breast cancer — and so we know that the screening as such works," Devilee said.
But whether more personalized screening is a further improvement is not yet clear. That is what the WISDOM study, which aims to enroll 100,000 women to either undergo the usual mammogram screening for breast cancer or screening based on an assessment of their personal risk that encompasses genetics, family history, and breast density, is currently looking into.
"Hopefully, it's going to be as good or maybe even better than the current age-based" approach, Devilee said, noting that the results of the trial are expected in about four years. "That is something that we are eagerly awaiting."