Polygenic risk scores for breast cancer prevention: a guide for physicians
George Busby, Allelica CSO & Co-Founder
Breast cancer remains a major health challenge for women worldwide. While traditional risk factors — such as family history, age, and lifestyle — are well-established components of risk assessment, advances in genomics have introduced a transformative tool: Polygenic Risk Scores (PRS). PRSs quantify the combined effect of numerous genetic variants on an individual’s risk of developing breast cancer, enabling a more refined and personalized risk prediction model. PRS have been integrated into clinical risk assessments globally. This guide aims to provide physicians with a deeper understanding of PRS in breast cancer, their integration into clinical practice, and the substantial benefits they offer for patient care.
Why do we need PRSs?
Breast cancer risk arises from a combination of environmental, physiological, lifestyle, and genetic factors. Genetic risks can be divided into rare pathogenic variants in high-penetrance genes (e.g. BRCA1/2, PALB2) and common genetic variants captured by PRS. While pathogenic variants are rare (found in fewer than 5% of women), they account for only about 10% of breast cancer cases. Conversely, PRS can identify a significant proportion (10–20%) of women at increased genetic risk.
Unlike high-penetrance mutations, PRS are not diagnostic of disease but provide a valuable extension to traditional risk assessments by identifying additional women who might otherwise be overlooked. When combined with other risk factors, PRS significantly enhance the accuracy of breast cancer risk prediction. Crucially, they capture genetic risks not accounted for by other methods, making them essential for comprehensive risk assessment.
Guidelines and Recommendations
Integrating PRS in breast cancer prevention aligns with national and international guidelines that promote personalized risk assessment approaches. For instance, both the American Cancer Society and the National Comprehensive Cancer Network (NCCN) emphasize individualized risk assessment in developing screening strategies. PRS can improve adherence to these guidelines by providing precise risk assessments that inform decisions about screening initiation and frequency. High-risk women, based on PRS, may start mammography earlier or receive additional imaging, such as MRI, while those with lower PRS may follow less intensive screening schedules.
Incorporating PRS into clinical practice supports the broader shift toward precision medicine, where healthcare is increasingly tailored to individual characteristics, including genetic makeup. By integrating PRS into risk assessment protocols, physicians can offer care that better aligns with each patient’s unique risk profile, thereby enhancing outcomes.
The Scientific Basis for PRS in Breast Cancer
PRSs are calculated using multiple single nucleotide polymorphisms (SNPs), each contributing minimally to overall risk. While a single SNP’s effect is negligible, collectively they can considerably influence a patient’s risk profile. The development of PRS is grounded in genome-wide association studies (GWAS) that have identified numerous loci associated with breast cancer. Recent studies have shown that PRS can predict breast cancer risk with much greater precision than models relying solely on traditional risk factors. For example, a PRS using hundreds of SNPs can stratify women into different risk categories, with those in the highest risk decile facing up to a threefold increased risk compared to the general population.
The utility of PRS extends beyond identifying high-risk individuals; it also provides insights into how genetic predisposition interacts with environmental and lifestyle factors, enhancing risk prediction accuracy. This detailed level of risk assessment is particularly valuable in populations where conventional risk factors are less informative or where adherence to breast cancer screening is low.
Clinical Implementation of PRS
Incorporating PRS into clinical practice requires strategic consideration. PRS are particularly valuable for:
- Women undergoing risk assessments using models like Tyrer-Cuzick or BOADICEA. Those identified as high-risk may benefit from earlier mammography or MRI screening.
- Individuals with a family history of breast cancer who lack high-penetrance mutations (e.g. BRCA1/2). PRS can clarify risk levels in these “gray area” cases.
- Women previously diagnosed with breast cancer who want to understand if a high PRS contributed to their disease, facilitating cascade testing for relatives.
The implementation process involves collecting a saliva or blood sample to analyze relevant SNPs. The resulting PRS is combined with clinical data to create a comprehensive risk assessment, guiding decisions on screening frequency, preventive measures, and potential lifestyle changes.
Risk Stratification and Prevention
A key advantage of PRS is its potential to enhance risk stratification and allow for more targeted breast cancer prevention strategies. High-risk women, based on PRS, may start screening earlier and more frequently, using mammography or MRI. In contrast, those with a low PRS could avoid the risks of over-screening, such as false positives and unnecessary biopsies.
Moreover, PRS can help determine the optimal timing for preventive interventions. Research indicates that genetic risk factors for breast cancer can manifest earlier for some women; identifying these individuals allows for early and potentially more effective interventions, such as lifestyle changes or enhanced surveillance.
PRS also enables personalized medicine approaches. For instance, lifestyle interventions like weight management, physical activity, and dietary adjustments can be more effectively tailored to a patient’s genetic risk profile, maximizing their preventive potential.
Integrating PRS into Clinical Practice
To effectively use PRS in clinical settings, physicians must be adept at interpreting PRS results and communicating their implications to patients. This involves understanding not only the genetic basis of PRS but also their limitations — PRS are not standalone diagnostic tools but are valuable risk factors that enhance overall risk assessments.
Patient education is crucial for successful PRS implementation. Patients should be well-informed about what their PRS means, its implications for their health, and how it fits into their overall health context, including family history. Genetic counseling plays a vital role in helping patients understand their results and make informed decisions.
Conclusion
Polygenic Risk Scores represent a significant advancement in the field of breast cancer prevention, offering a more personalized and precise approach to risk assessment. As the scientific evidence supporting PRS has matured, it has become clear that these scores are ready for clinical implementation. By incorporating PRS into clinical practice, physicians can enhance risk stratification, personalize preventive strategies, and ultimately improve patient outcomes.
