The case for replacing age-based breast cancer screening with personalized risk-based screening is gaining strength — with recent studies showing the approach is feasible and has the potential to save more lives.
In one, a modeling study published last month in JAMA Network Open, researchers estimated the effects of various screening strategies that were based on a woman’s 5-year absolute risk for breast cancer. They found that some of the approaches would avert more breast cancer deaths and reduce false positives than standard age-based screening.
Those results came on the heels of a large, real-world randomized trial — the WISDOM study — presented at the San Antonio Breast Cancer Symposium (SABCS) and published in JAMA in December. Researchers showed that risk-based screening was acceptable to women and noninferior to annual mammograms over 5 years.
Some observers said that if ongoing trials confirm the value of risk-based approaches, decades of age-based mammography could soon give way to precision screening.
From One Size to Tailored
While there are already separate screening guidelines for women at a very high risk for breast cancer (such as those with pathogenic mutations), for most women screening is one-size-fits-all, with recommendations for either annual or biennial mammography starting around age 40.
That’s too much screening for some women but not enough for others, and there’s a need to incorporate risk stratification more broadly, according to Laura Esserman, MD, a breast cancer surgical oncologist at the UC San Francisco.
In the WISDOM trial, Esserman and her colleagues randomly assigned more than 28,000 US women to either annual mammography from age 40 to 74 or risk-based screening. In the latter group, screening intensity was tailored to a woman’s estimated 5-year risk for invasive breast cancer — based on an earlier version of the BCSC risk calculator, along with a polygenic risk score derived from at-home test kits.
Trial participants were placed into one of the four risk categories: Those at the highest risk had a 5-year breast cancer risk of 6% or more on the calculator, or carried a high-risk pathogenic variant, and they were assigned to alternating mammography and MRI every 6 months plus counseling on risk reduction.
Women deemed to be at elevated risk (the top 2.5% for their age group) were assigned to annual mammography starting at age 40. Women considered average risk (a 5-year risk of about 1.3%) were assigned to biennial mammography starting at age 50. (Most study participants, about 63%, fell into this category.)
Finally, there was the lowest-risk group of women in their forties with a 5-year risk of below 1.3%. They were told to delay screening until their risk reached 1.3% or they reached age 50.
Despite long-standing concerns that less-frequent screening in some women will miss aggressive disease, WISDOM had reassuring findings: At 5 years of follow-up, there were 21 vs 31 stage IIB or worse cancers in the risk-based vs annual screening group — corresponding to rates of 30 vs 48 per 100,000 person-years.
No stage IIB or higher cancers were found in the highest-risk women, indicating earlier detection of clinically significant disease, Esserman said.
Overall, there were fewer mammograms in the risk-based group, while rates of mammography, MRI, biopsy, and cancer all increased with increasing risk, as expected with risk stratification.
“This is the kind of data we needed to have confidence that an approach like this can work,” Esserman said. “I think this is the beginning of a major change in the way we screen for and prevent breast cancer.”
Other breast oncologists who attended Esserman’s SABCS presentation agreed.
“We have to do better when it comes to screening,” Virginia Kaklamani, MD, of UT Health San Antonio MD Anderson Cancer Center, told Medscape Medical News. “WISDOM is a great study to show that this is feasible and that the outcomes are good. I think risk-based screening is going to be a great approach.”
Eric Winer, MD, director of the Yale Cancer Center in New Haven, Connecticut, called the study “the most important thing we’ve heard at this conference.”
“This is absolutely great,” he said. “[It] should be the new standard.”
The findings also suggest that patient demand for a personalized approach could be substantial, Esserman said: WISDOM included an observational cohort of more than 18,000 women who declined randomization, and 89% chose risk-based screening.
Modeling Adds Support
In the JAMA modeling study, investigators examined the outcomes of various mammography screening approaches in a simulated cohort of women aged 40-74 years with no history of breast cancer. They used the current version of the BCSC calculator to categorize the women as low, average, intermediate or high risk. (Women at very high risk due to factors such as pathogenic mutations were not included.)
The team plugged their simulated population into two validated breast cancer models to test three age-based and 47 risk-based screening strategies against age-based biennial screening as recommended by the US Preventive Services Task Force.
Overall, they found that nine risk-based approaches were as good as or better than age-based screening at preventing breast cancer deaths, while yielding fewer false positives.
In one strategy, for example, low-risk women underwent biennial screening from age 55 to 74; average-risk women had biennial screening starting at age 50, followed by annual screening from age 60 to 74; intermediate-risk women underwent biennial screening from age 45 to 54, followed by annual screening through age 74; and high-risk women had biennial screening from age 40 to 49, switching to annual mammography through age 74.
That approach boosted the number of averted breast cancer deaths by 6% (from 6.8 to 7.2 per 1,000 women), while reducing false positive recalls by 13%.
“As personalized medicine advances, risk-based screening is poised to become a cornerstone of breast cancer prevention,” wrote the investigators, led by Oguzhan Alagoz, PhD, of the University of Wisconsin–Madison.
An accompanying editorial agreed that the study, along with WISDOM, offer visions of how breast cancer screening can be reshaped.
It “demonstrates the potential benefit of nuanced, periodically reassessed risk-based screening,” wrote Lydia E. Pace, MD, of Brigham and Women’s Hospital, and Marybeth Hans, PA-C, of Beth Israel Deaconess Medical Center, both in Boston.
Caution Urged
While risk-based screening shows promise, there are also concerns about moving forward too quickly. In response to the WISDOM findings, the American College of Radiology (ACR) pointed to numerous limitations of the trial.
One was “substantial nonadherence” to assigned screening protocols. For example, although women in the risk-based screening group had fewer mammograms, the reduction was less than the researchers anticipated because women in the two lower-risk groups screened more often than recommended.
The ACR also noted that the total number of cancers detected — about 260 in each arm — is smaller than expected and may not truly represent the screening population.
“This trial has not proven the [risk-based] approach to be better than current recommendations,” the group said.
In their editorial, Pace and Hans raised some real-world issues, including possible challenges in incorporating breast cancer risk assessments into routine primary care.
They also stressed that risk-based screening would have to be carefully deployed to ensure it doesn’t worsen existing disparities in breast cancer deaths — particularly the 40% higher mortality among Black women than among White women.
“If risk-stratified approaches are taken, ensuring that risk calculators perform equally well in different racial and ethnic groups is imperative,” the editorialists wrote.
Regarding WISDOM, Esserman acknowledged the trial’s limitations, and she emphasized that it offers a first draft for risk-based screening, not a finalized protocol.
“This is the beginning,” she said, “not the end.”
What Comes Next
The fundamental questions of exactly how to risk-stratify women and how to tailor screening according to risk are still being explored.
In WISDOM, the researchers used a previous version of the BCSC calculator that incorporates breast cancer history, age, race, family history, prior biopsies, and breast density.
The follow-up WISDOM 2 is updating its risk assessments. It’s using the current BCSC calculator — which adds menopausal status, BMI, and age at first birth to risk estimates — as well as refined genetic risk scores, including signatures that predict triple-negative breast cancer and breast cancer in Black women.
The trial will also include women as young as 30 years and has a goal of enrolling 50,000 participants, including at least 10,000 Black women (who made up only 6% of WISDOM participants). Artificial intelligence will be used to improve image interpretation.
In addition, results from the WISDOM trials will be pooled with findings from a similar, international randomized trial, called MyPeBS, to help zero in on the best risk-based approaches. Initial MyPeBS results are expected in early 2028.
For Esserman, the implications of this research extend beyond mammography intervals to challenging the long-held assumption that more cancer screening is better.
“More isn’t better. More is just more,” she said. “Smarter is better.”
Esserman reported having no relevant disclosures. Alagoz reported being the owner of Innovo Analytics LLC and receiving personal fees from Exact Sciences outside the submitted work.
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