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. 2025 Jul 24;11(9):1072-1082.
doi: 10.1001/jamaoncol.2025.2203. Online ahead of print.

Defining Lifetime Risk Thresholds for Breast Cancer Surgical Prevention

Xia Wei  1   2 , Lea Mansour  2 , Samuel Oxley  2   3 , Caitlin T Fierheller  2 , Ashwin Kalra  2   3 , Jacqueline Sia  2   3 , Subhasheenee Ganesan  2   3 , Michail Sideris  2   3 , Li Sun  1   2 , Adam Brentnall  2 , Stephen Duffy  2 , D Gareth Evans  4 , Li Yang  5 , Rosa Legood  1   2 , Ranjit Manchanda  1   2   3
Affiliations

Defining Lifetime Risk Thresholds for Breast Cancer Surgical Prevention

Xia Wei et al. JAMA Oncol. .

Abstract

Importance: Expanding access to genetic testing and availability of validated breast cancer (BC) risk prediction models are increasingly identifying women at elevated BC risk who do not carry high-penetrance BRCA1/BRCA2/PALB2 pathogenic variants. The precise BC risk threshold for offering risk-reducing mastectomy (RRM) for BC prevention is unknown.

Objective: To define the lifetime BC risk thresholds for RRM to be cost-effective compared with nonsurgical alternatives for BC prevention.

Design, setting, and participants: This economic evaluation used a decision-analytic Markov model to compare the cost-effectiveness of RRM with BC screening and medical prevention in a simulated cohort. Extensive sensitivity analyses were performed. The study setting was from a UK payer perspective over a lifetime horizon until age 80 years. The simulated cohort included women aged 30 to 60 years at varying lifetime BC risks from 17% to 50%. The study was conducted between September 2022 and September 2024.

Exposures: Undergoing RRM or receiving risk-stratified BC screening with medical prevention (tamoxifen or anastrozole).

Main outcomes and measures: The incremental cost-effectiveness ratio was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with the UK willingness-to-pay (WTP) threshold of £20 000 (US $27 037) to £30 000 (US $40 555) per QALY. BC cases prevented were estimated at the population level.

Results: In the simulated cohort of 100 000 thirty-year-old women in the UK, undergoing RRM became cost-effective at a 34% lifetime BC risk using the £30 000 (US $40 555) per QALY WTP threshold. This increased to a 42% lifetime BC risk using the £20 000 (US $27 037) per QALY WTP threshold. The identified lifetime BC risk thresholds for RRM to be cost-effective among women aged 35, 40, 45, 50, 55, and 60 years were 31%, 29%, 29%, 32%, 36%, and 42%, respectively, using the £30 000 (US $40 555) per QALY WTP threshold. Overall, undergoing RRM was deemed cost-effective for women aged 30 to 55 years with a lifetime BC risk of at least 35%, with more than 50% of simulations being cost-effective in probabilistic sensitivity analysis. Offering RRM for women with a lifetime BC risk of 35% or higher could potentially prevent approximately 6538 (95% CI, 4454-7041), or approximately 11% (95% CI, 8%-12%), of the 58 756 BC cases occurring annually in women in the UK. In the probabilistic sensitivity analysis, 20.71% to 59.96%, 44.04% to 81.29%, and 97.26% to 99.35% of simulations were cost-effective for women with 35%, 40%, and 50% lifetime BC-risk undergoing RRM at age 30 under the £20 000 to £30 000 per QALY WTP threshold, respectively.

Conclusions and relevance: In this economic evaluation, undergoing RRM appears cost-effective for women aged 30 to 55 years with a lifetime BC risk of 35% or higher. These results could have significant clinical implications to expand access to RRM beyond BRCA1/BRCA2/PALB2 pathogenic variant carriers. Future studies evaluating the acceptability, uptake, and long-term outcomes of RRM among these women are warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Oxley reported grants from Rosetrees Trust during the conduct of the study. Dr Fierheller reported grants from Wellbeing of Women–Peaches Womb Cancer Trust Postdoctoral Research Fellowship outside the submitted work. Dr Kalra reported grants from Barts Charity during the conduct of the study. Dr Brentnall reported personal fees from Cancer Research UK outside the submitted work. Dr Yang reported grants from China Medical Board (19-336), National Natural Science Foundation of China (71673004 and 72174010), and National Key R&D Program of China (2021YFC2500400 and 2021YFC2500405) during the conduct of the study and grants from Beijing Natural Science Foundation (M22033) and Beijing Emergency Management Bureau (11000024210200093866-XM001) outside the submitted work. Dr Manchanda reported grants to Queen Mary University of London from Rosetrees Trust, Barts Charity, and China Medical Board during the conduct of the study; grants from Yorkshire Cancer Research, GSK, NHS England, and North East London Cancer Alliance Research outside the submitted work; and personal fees for serving on the advisory boards for EGL, MSD, GSK, and AstraZeneca outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Model Overview
The upper part of the diagram shows the decision tree pathway for choosing risk-reducing mastectomy (RRM) or breast cancer (BC) screening. The lower part of the diagram is a schematic illustration of the health states and key transitions for the Markov model. DCIS indicates ductal carcinoma in situ.
Figure 2.
Figure 2.. Tornado Diagrams of 1-Way Sensitivity Analyses
A, Risk-reducing mastectomy (RRM) vs breast cancer (BC) screening for women aged 30 years with a 34% lifetime risk. B, RRM vs BC screening for women aged 30 years with a 42% lifetime risk. ICER indicates incremental cost-effectiveness ratio; QALY, quality-adjusted life years.
Figure 3.
Figure 3.. Cost-Effectiveness Acceptability Curves for Risk-Reducing Mastectomy in Women Aged 30 Years
BC indicates breast cancer; QALY, quality-adjusted life-years.
See this image and copyright information in PMC

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