The Polygenic Risk Score – What is it and what does it mean for breast cancer?

The Polygenic Risk Score – What is it and what does it mean for breast cancer? The Polygenic Risk Score – What is it and what does it mean for breast cancer?

By: Fawad Khan, MDHolly Pederson, MD • Posted on October 19, 2021

How Polygenic Risk Score Helps Breast Cancer Risk Assessment

Scientists are busy working on improving risk prediction for breast cancer using genetic data. Aside from genes like BRCA1 and BRCA2 that strongly predispose a woman to getting breast cancer, there are now over 300 SNPs (Single Nucleotide Polymorphisms) linked to breast cancer. These gene changes individually confer little risk, but in combination called the Polygenic Risk Score (PRS) they may affect risk quite significantly. As the PRS evolves, it may have the potential to improve and personalize breast cancer risk assessment - both for gene carriers and those without genetic mutations.

Breast cancer affects 1 out of every 8 women in the United States1, with hereditary breast cancer accounting for approximately 10-15% of diagnoses2. Multigene panel tests look for high and moderate risk gene mutations. However, medical research shows that other common genetic variants called SNPs may explain an additional 14-20% of breast cancers.3 The PRS has the potential to improve and personalize breast cancer risk assessment and help women make decisions using their own genetic information as an additional piece of risk information4.

History of PRS

The first seven breast cancer SNPs were discovered by Dr. Easton in 20075. The researchers used genetic data from Genome Wide Association Studies (GWAS) where people with a disease are compared to women without the disease to assess for differences between the groups. This was first done with large groups of Caucasian European women.

In 2015, the first large study was published in Europe showing that a PRS made up of multiple SNPs could sub-stratify risk in women with and without family history6. There have been various studies done to validate the PRS since then and ensure that it is generalizable and calibrated for non-European populations7, and to assess whether it does help high risk women make decisions8,9,10,11. Early identification, detection and preventive strategies for high risk patients saves lives.

Use of PRS in Risk Models

Currently, in women without genetic mutations, risk is estimated using mathematical models that incorporate traditional risk factors such as age at first period, age at first live birth, family history, etc. The two models most commonly used are the:

  1. Modified Gail model (BCRAT)12
  2. Tyrer-Cuzick model13

It has been shown that combining the PRS with these risk model estimates makes them more accurate. One risk model out of Europe, the CanRisk model14, can incorporate traditional risk factors with the PRS both in gene carriers as well as in those without mutations to further refine risk.

Can PRS Help Gene Carriers?

Individuals who carry certain gene mutations are at higher risk of breast cancer compared to the average population. These changes are present in every cell in one’s body, and can be passed on to children. The “highly penetrant” or very high risk genes such as BRCA1, BRCA2, PTEN, TP53, CDH1 and PALB2 are associated with high levels of risk that the patient is more likely than not to get breast cancer over the course of her lifetime15,16.

“Moderately penetrant” genes confer risks of ~30% over the course of one’s life15,16, but it has been found that the risk in both of these groups can be sub-stratified by the PRS17. Though risks remain high (or higher) with the highly penetrant genes, with the moderate risk gene carriers and with noncarriers, the spread is wide. For example, with CHEK2, the risk can range from 6.6% to 71% depending on the PRS17. Women might make different risk management decisions, particularly about taking risk-reducing medications, by knowing this information.

What about Breast Cancer patients?

Patients with breast cancer are faced with the surgical options of lumpectomy, mastectomy or bilateral mastectomy. Patients with BRCA mutations have been shown to have reduced mortality by choosing bilateral mastectomy,18 but in the US about 20% of all breast cancer patients choose bilateral mastectomy despite a relatively low estimated risk of developing breast cancer on the unaffected side19. The PRS has been shown in two studies to help predict “contralateral” breast cancer risk20,21. By having a better risk estimate of cancer on the other side patients can make a more informed choice for bilateral mastectomy.

PRS: Role in Screening

Guidelines for screening mammography in average risk women are currently a topic of significant debate.

  • The United States Preventive Services Task Force (USPSTF) recommends biennial screening from age 50-7422
  • The American College of Radiology and the National Comprehensive Cancer Network (NCCN) recommend annual screening starting at age 4023,24. .

Shared decision-making with one’s healthcare provider is recommended to personalize these decisions. Improved risk stratification using the PRS may ultimately aid in this process by providing an objective estimate of a woman’s risk to help her and her healthcare provider make more informed choices. The PRS (and a baseline assessment of breast density which also affects risk25) may further improve risk estimation and influence decision-making for the individual and potentially for health policy and guidelines.

    Interpretation of PRS

    With liberal use of multigene panel testing, it is critical that patients and their health care providers understand the results.

    • Women found to carry genetic mutations are more prone to cancer but will not necessarily get cancer, and patients with negative results may still be at risk.
    • “Uncertain results” or Variants of Uncertain Significance (VUS) are considered clinically as negative and most of these changes are reclassified as being benign.

    If all of this weren’t hard enough to explain well, adding the polygenic risk score and its influence on risk will make the conversation even more complex. More training for primary care providers and more access to genetic specialists will be necessary to make sure that results are communicated accurately and do not result in unnecessary anxiety or overtreatment26.


      • The PRS has the potential to further refine the estimated risk for developing breast cancer in both the average population as well as in high risk individuals. It may be helpful in estimating the risk of contralateral breast cancer in cancer patients.
      • Objective and enhanced risk stratification is critical for optimizing personalized discussions and decision-making for patients at all levels of risk. However, accurate interpretation of results and counseling is required from subject matter experts. The PRS in combination with traditional risk factors (using risk models), is thought to provide an additional layer of risk stratification, helping women make decisions about preventive strategies.
      • More data is needed in women of color in genetic research, but a framework for the PRS has been created that is more appropriately calibrated for women of non-European ancestry with improved ability to separate high risk from low risk women.
      • We eagerly anticipate results of studies identifying the benefits of personalized screening based on the PRS27,28. As the PRS continues to evolve, these studies and others will be fundamental in demonstrating its importance and potential use in clinical practice.
      • Genetic testing is becoming more common and may ultimately be available for all breast cancer patients, and possibly eventually for all women. Early identification of patients at hereditary cancer risk and further refinement of risk for all women using the polygenic risk score will ultimately reduce cancer burden and save lives.

      Be Strong, Be Healthy, Be in Charge!
      - Dr. Fawad Khan and Dr. Holly Pederson

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      About Fawad Khan, MD

      Dr. Fawad Khan is a Medical Breast Physician and Interim Chairman of Primary Care department at Cleveland Clinic Abu Dhabi. He will be leading the Medical Breast Program due to be launched later this year where his practice will be focused on breast diagnostics, breast cancer risk assessment and management of the high risk patients. Prior to joining Cleveland Clinic Abu Dhabi, Dr. Khan served as a Medical Director for ambulatory clinics at Mediclinic Hospitals Group after moving from England. His previous roles included Lead Clinician at Malling Health Group in England. He represented the company at Dartford and Gravesham Commissioning Group. Dr Khan went through family medicine residency training at Grampian University Hospitals in the UK after earning a medical degree from Allama Iqbal Medical College in Lahore, Pakistan.

      About Holly Pederson, MD
      Holly Pederson, MD is the Director of the Medical Breast Program at Cleveland Clinic and Associate Professor of Medicine at CCLCM. She completed a clinical genetics fellowship at CCF in 2008 and the City of Hope Course in 2017.

      She is actively involved in clinical research and is co-appointed in the Lerner Research Institute.She has served on the NCCN Risk Reduction and Genetic Committees and speaks nationally with a focus on management of high-risk patients. She has developed an internal fellowship for training of Medical Breast Providers, a program which she helped to create.

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