Risk-based breast cancer screening noninferior to annual mammograms

medwireNews: Risk-based screening for breast cancer, guided by age and population-based genetic testing, is noninferior to annual mammography for the identification of stage IIB and more advanced disease, indicates research published in JAMA.

However, the risk-based approach did not significantly reduce the co-primary endpoint of biopsy rate among participants, report Laura Esserman (University of California, San Francisco, USA) and co-authors.

Writing in an editorial, Nancy Baxter (The University of Sydney, New South Wales, Australia) and Kelly Anne Phillips (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) agree that “[t]he WISDOM trial increases confidence in the safety and feasibility of risk-based screening,” but say that “because of low adherence to screening recommendations in this large, pragmatic trial, the effectiveness remains uncertain.”

The WISDOM study included 28,372 US women aged 40–74 years (mean 54 years, 77% non-Hispanic White) with no history of breast cancer or ducal carcinoma in situ (DCIS) who were randomly assigned to undergo screening tailored to their individual risk of the disease (n=14,212) or annual mammography (n=14,160).

The risk-based group were classified into four subgroups using the presence of nine high-penetrance pathogenic variants, a polygenic risk score, and the Breast Cancer Surveillance Consortium version 2 model for predicting 5-year risk of invasive breast cancer, based on age, race/ethnicity, family history, benign breast disease, and breast density.

Two percent of these participants were considered to be at the greatest risk of breast cancer, with a 5-year risk of at least 6%, presence of a high-penetrance pathogenic variant, and/or receipt of mantle radiation. These women were scheduled to undergo alternating mammography and magnetic resonance imaging (MRI) at 6-month intervals plus risk-reduction counseling.

A further 8% of women were classified as having an elevated risk based on being in the top 2.5 risk percentile by 1-year age category, extremely dense breasts before age 50 years, at least a 1% risk for developing estrogen receptor-positive breast cancer based on genetic susceptibility, or high-risk pathogenic variants without a family history. These women were scheduled to receive annual mammography and counseling.

The majority (63%) of participants were considered to be at average risk based on age 50–74 years, or age 40–49 years with a 5-year risk of at least 1.3%, and were assigned to receive biennial mammography.

And the remaining 27% were classified as being at low risk for breast cancer based on an age of 40–49 years or at least 75 years with a 5-year risk of below 1.3%, or age 70 and older with a 5-year breast cancer risk of below 2.2% plus a 50% or greater 10-year risk of mortality based on comorbidity; the younger women were not scheduled to undergo screening until age 50 years or until the risk reached the 1.3% threshold and the older participants to stop screening.

Over a median of 5.1 years of follow-up there were 523 cancer diagnoses, of which 78% were invasive and 22% stage 0 (DCIS).

There was no significant difference in the rate of stage IIB or more advanced breast cancers in the risk-based versus annual screening groups, at 21 versus 31 cases per 100,000 person–years, therefore meeting the noninferiority criteria. And although the rate increased with increasing risk category, there were no stage IIB or more advanced diagnoses in the highest risk subgroup, the researchers note.

However, there was no significant difference in the rate of biopsy in the risk-based group versus annual screening group, at 943 versus 1029 per 100,000 person–years. Nevertheless, women in the highest, elevated, average, and low-risk subgroups had “markedly” different rates of 6647, 3207, 1173, and 981 biopsies per 100,000 person–years, Esserman et al observe.

The researchers also report that the risk-based group had a lower rate of mammograms than the annual screening group (43,084 vs 46,920 per 100,000 person–years), but that this “varied significantly” between the risk subgroups, with the lowest rate as expected found for women in their 40s.

“The overall reduction in mammograms in the risk-based group was less than anticipated because those randomized to the risk-based group and assigned to the average (biennial screening) and lowest risk categories (no screening) screened more often than recommended,” the investigators admit.

Greater use of MRI in women with an elevated risk was also observed, despite no recommendation for this modality, perhaps due to current guidelines for MRI use in women with a family history denoting a 20% lifetime risk of breast cancer, they write.

Baxter and Phillips say that the difference between mammogram use in the risk-based and annual screening groups was “small,” at a rate of 4.3 versus 4.7 per 10 observed patient–years and suggest that “[t]his similarity in screening behavior between groups may mask any potential benefit or harm of risk-based screening.”

While emphasizing that the WISDOM study’s use of risk-based screening as a “platform for personalized primary prevention” is “[a]n important strength”, the editorialists note that just 4% of women with an elevated risk for breast cancer in the risk-based screening group made use of chemoprevention, as per guidelines.

They therefore conclude that “to fully realize the potential for breast cancer control through risk-based screening, purposeful integration with prevention is needed.”

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JAMA 2025; doi:10.1001.jama.2025.24784
JAMA 2025; doi:10.1001/jama.2025.24817