The limitations of Polygenic Risk Scores (“PRS”) for cancer risk prediction highlight the need for alternative methods that offer higher discriminatory power, prioritize poor prognostic cancers and account for a range of risk factors. Epigenetic-based approaches, such as the WID tests, hold significant promise for developing more effective and practical cancer risk prediction tools that can ultimately help reduce cancer morbidity and mortality.

Growing Skepticism & Unfavorable Bias

In recent years, there has been significant excitement surrounding the use of Polygenic Risk Scores (PRS) for predicting cancer risk. However, a growing number of experts are now expressing skepticism about whether PRS can be effectively implemented in the clinical setting (McCarthy & Birney, 2021 Nature; Sud et al., 2023 BMJ). The discriminatory power of PRS is currently too low to be practically helpful, and the potential for improvement is limited (Zhang et al., 2020 Nat Commun).

Moreover, studies suggest that a PRS-targeted approach could overlook cancers in patients with the worst prognoses and which would benefit most from early intervention (Lopez Cardozo et al., 2023 JCO). Not only would this lead to overdiagnosis, but – most importantly – it would lead to inappropriate reduced screening for women who eventually develop poor prognostic breast cancer and who would have benefited most from early detection.

Requirements

To address these shortcomings, predictive approaches are needed to minimize false positives and negatives, flag individuals with high risk for poor prognostic cancers, and dynamically reflect how “close” an individual is to cancer development. In addition to genomic predisposition, these approaches must account for modifiable internal and external factors.

A Promising Alternative

Promising alternatives are epigenetic-based risk-predictive tests (Widschwendter et al., 2018 Nat Rev Clin Oncol),e.g., the WID-BC test for identifying poor prognostic breast cancer (Barrett et al., 2022 Nat Commun). The epigenome, which refers to chemical modifications that affect gene expression without altering the DNA sequence, can integrate both genetic and non-genetic risk factors. By analyzing epigenetic patterns in easily accessible surrogate tissues, these tests calculate WID indices, which are indicators of cancer risk. WID tests have been trained to identify individuals at the highest risk of developing cancer with poor prognoses, allowing for targeted and intensified screening efforts. This approach can help prioritize screening for individuals who need it the most, ultimately improving cancer detection and treatment outcomes.