Background

WISDOM (Women Informed to Screen Depending on Measures of Risk) is a randomized trial to assess whether personalized breast cancer screening-where women are screened biannually, annually, biennially, or not at all depending on risk and age-can prevent as many advanced (stage IIB or higher) cancers as annual screening in women ages 40-74 years across 5 years of trial time. The short study time in combination with design choices of not requiring study entry and exit mammograms for all participants may introduce different sources of bias in favor of either the personalized or the annual arm.

Methods

We designed a simulation model and performed 5000 virtual WISDOM trials to assess potential biases. Each virtual trial simulated 65 000 randomly assigned participants who were each assigned a risk stratum and a time to stage of at least IIB cancer sampled from an exponential distribution with the hazard rate based on the risk stratum. Results from the virtual trials were used to evaluate two candidate analysis strategies with respect to susceptibility for introducing bias: 1) difference between arms in total number of events over total trial time, and 2) difference in number of events within complete screening cycles.

Results

Based on the simulations, about 86 stage IIB or higher cancers will be detected within the trial and the total exposure time will be about 74 000 years in each arm. Potential ascertainment bias is introduced at study entry and exit. Analysis strategy 1 works better for the nonscreened stratum, whereas method 2 is considerably more unbiased for the strata of women screened biennially or every 6 months.

Conclusion

Combining the two candidate analysis approaches gives a reasonably unbiased analysis based on the simulations and is the method we will use for the primary analysis in WISDOM. Publishing the WISDOM analysis approach provides transparency and can aid the design and analysis of other individualized screening trials.

Breast cancer risk reduction has been validated by large-scale clinical trials, but uptake remains low. A risk communication tool could provide personalized risk-reduction information for high-risk women. A low-literacy-friendly, visual, and personalized tool was designed as part of the Women Informed to Screen Depending On Measures of risk (WISDOM) study. The tool integrates genetic, polygenic, and lifestyle factors, and quantifies the risk-reduction from undertaking medication and lifestyle interventions. The development and design process utilized feedback from clinicians, decision-making scientists, software engineers, and patient advocates. We piloted the tool with 17 study participants, collecting quantitative and qualitative feedback. Overall, participants felt they better understood their personalized breast cancer risk, were motivated to reduce their risk, and considered lifestyle interventions. The tool will be used to evaluate whether risk-based screening leads to more informed decisions and higher uptake of risk-reduction interventions among those most likely to benefit.

Risk-reducing endocrine therapy use, though the benefit is validated, is extremely low. The FDA has approved tamoxifen and raloxifene for a 5-year Breast Cancer Risk Assessment Tool (BCRAT) risk ≥ 1.67%. We examined the threshold at which high-risk women are likely to be using endocrine risk-reducing therapies among Athena Breast Health Network participants from 2011-2018. We identified high-risk women by a 5-year BCRAT risk ≥ 1.67% and those in the top 10% and 2.5% risk thresholds by age. We estimated the odds ratio (OR) of current medication use based on these thresholds using logistic regression. One thousand two hundred and one (1.2%) of 104,223 total participants used medication. Of the 33,082 participants with 5-year BCRAT risk ≥ 1.67%, 772 (2.3%) used medication. Of 2445 in the top 2.5% threshold, 209 (8.6%) used medication. Participants whose 5-year risk exceeded 1.67% were more likely to use medication than those whose risk was below this threshold, OR 3.94 (95% CI = 3.50-4.43). The top 2.5% was most strongly associated with medication usage, OR 9.50 (8.13-11.09) compared to the bottom 97.5%. Women exceeding a 5-year BCRAT ≥ 1.67% had modest medication use. We demonstrate that women in the top 2.5% have higher odds of medication use than those in the bottom 97.5% and compared to a risk of 1.67%. The top 2.5% threshold would more effectively target medication use and is being tested prospectively in a randomized control clinical trial.