Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial

Abstract

Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.

Paradigm Shift From Halstedian Radical Mastectomy to Personalized Medicine

“…Personalized screening is difficult today due to the lack of long-term (15 to 20 years), prospective, randomized clinical trials comparing screening of low-risk women to women participating in the present screening guidelines. On the other hand, a new ongoing randomized controlled trial of annual vs. personalized screening [WISDOM (The Women Informed to Screen Depending On Measures of risk)] will study the efficacy, safety, and acceptability of riskbased screening (18). As WISDOM is one of the first trials on riskbased personalized screening, these data will be crucial in evaluating whether precision screening will improve the effectiveness of breast cancer screening, particularly whether it leads to screening algorithms that identify cancers for which treatment extends a woman's life.…”

Community education to enhance the more equitable use of precision medicine in Northern Manhattan

“…For cancer health outcomes, targeted therapy guided by molecular and histologic features of tumors has proven extremely effective for the treatment of many common cancers including breast (Krop et al, 2017; Nishihara et al, 2013; Rebbeck et al, 2002; Schwaederle et al, 2016). Cancer screening also has a long history of using approaches targeting underlying genetics and family history information in terms of age of screening initiation and frequency of screening and, more recently, targeting other factors, mainly using risk‐based methods that are not based on cancer family history (Marcus, Freedman & Khoury, 2015; Shieh et al, 2017).…”

Optical assessment of mammographic breast density by a 12‐wavelength vs a continuous‐spectrum optical spectroscopy device

“…While age is the strongest risk factor for BC, tailoring screening based on other risk factors in addition to age may allow for a more efficient use of the mammography infrastructure, particularly in economically depressed areas as well as in middle‐ and low‐income countries. Ways to personalize screening programs using additional risk information are under investigation . Risk factors used for the personalization of screening should ideally be applicable population‐wide, easy to obtain, objective and independent of age.…”