Discussing PRS With Patients - A Genetic Counselor (GC) Perspective

Ask a GC - Implementing Polygenic Risk Scores
Chapter 3 - Discussing PRS With Patients - A Genetic Counselor (GC) Perspective

Hello, and welcome to the latest edition of Ask a GC! This series (and, more specifically, our next few clinically-focused posts) will likely be most helpful for genetic counselors and other clinicians looking to hone their polygenic testing knowledge. However, please feel free to read on if you’re interested in learning more about Polygenic Risk Scores (PRS), no matter your experience, background, or goals! 

PRS determination contributes to both personalized risk assessment and population health screening. Guidelines on managing patients with increased-risk PRS results have not been finalized; nonetheless, healthcare providers can use their established arsenals of clinical management approaches to use polygenic risk score assessment in the clinic. While this series is not intended to serve as a fully comprehensive or official guide to PRS clinical implementation, we will share some tips in this blog post about how we-as GCs-navigate educating patients about their PRS results.

Initiating the discussion

I like to start off genetic test results disclosure visits by making sure the patient knows exactly which test results are the focus of the discussion. I’ll ask questions such as, “What’s your recollection of the test we’re here to discuss today, and do you remember what it tests for?” This gives me an idea of how closely aligned the patient and I are regarding their genetic testing. Interestingly, patient responses can run the gamut here. You will probably have some patients who know exactly what testing you will review with them, those at the other end of the spectrum who will express no memory of providing a sample (nor what the test is for), and many somewhere in between. This is why it is important to establish upfront how much the patient understands, so you know how much time to dedicate to refresh their memory of the test before discussing the actual results.

Once the patient and I are on the same page regarding the test’s purpose, the next step is to evaluate the patient’s impression of the possible implications of the results. For example, I might ask the patient what it would mean if they were to have a “negative” vs. a “positive” result (when referencing monogenic testing) or an “average risk” vs. “increased risk” result (when referencing PRS testing). This question allows me to better understand my patient’s grasp of the potential implications of different results. This is a great time to clarify misconceptions about what a given test’s results might mean. For example, I’ve had patients undergoing monogenic hereditary cancer testing express that they think the test result demonstrates that they currently have cancer (incorrect), allowing me to correct these misunderstandings before reviewing the actual test results. When dealing with PRS results, a patient may believe that a PRS will inform whether they will or will not ever develop certain diseases (like diabetes, heart disease, or cancer). This is an opportunity to clarify that PRS cannot tell us whether they will or will not develop disease, only whether they have average risk versus increased risk for developing such diseases at some point in their lifetime.

Reviewing what PRS can (and can’t) tell us

Ideally, patients should have pre-test counseling before undergoing a polygenic risk assessment – or any type of genetic testing/screening – to include a conversation about (at a minimum):

• What the testing can tell us: Whether their risk of developing a given disease is similar to or increased from the average person’s risk.
  
  
• What it cannot tell us: Whether the patient will certainly be diagnosed with a given disease; the age at which they might be diagnosed with a given disease; how severely they will be affected by a given disease; whether their relatives will develop a given disease; or whether they have a given disease currently.
  • Ensure the patient understands that a PRS only informs one component of disease risk and that other genetic and non-genetic factors may contribute to that risk. This includes but is not limited to other monogenic/mendelian genetic and environmental factors (e.g., lifestyle, behaviors, personal and family health history, etc.)
    
    
• Potential implications of possible results: 
  • An “average-risk” result does not mean the patient will not develop a given disease at some point in their lifetime.
  • An “increased-risk” result does not mean the patient will definitely develop a given disease. 
  • An “increased-risk” result does not indicate whether or not the patient currently has a given disease.

Regardless of a patient’s initial ability to recall pre-test counseling points, I always like to refresh their understanding once testing is complete. For example, I might start with something like: “Unlike other types of genetic testing, which typically look for single gene mutations that are rare in the population and can inform us of increased risk levels for certain diseases, polygenic risk scoring looks at tens to hundreds of thousands of more common, small variations in your genetic code that, combined together, can result in your being at either increased or average risk for certain complex but well-known conditions like diabetes, cancer, or heart disease.” 

Other phrases I might use to ensure the patient understands what a PRS reveals (and, just as importantly, what it cannot reveal) include:

“This test does not, and cannot, tell us if you currently have [disease name] or will certainly develop [disease name] in the future. It only tells us whether your personal risk for developing the disease is similar to or higher than the average population risk.”

“It is important to note that there are other risk factors, both genetic and non-genetic, for [disease name] that are NOT assessed for with this type of test. Based on your personal and/or family history, additional genetic (or other) testing may be indicated further to clarify your risk for [disease name].”

Disclosing an increased-risk PRS result

• Reducing patient anxiety: Some patients will feel natural anxiety upon being informed of a “positive” or “increased-risk” result. 
  • To allay any potentially disproportionate fear about the initial disclosure, I focus on keeping my voice calm and matter-of-fact and ending the disclosure statement with a discussion of what to do next. 
    • For example, I may say: “Your polygenic testing shows that you have increased risk for [disease name]. I will talk you through what that means and how you can work with your doctor to take steps to mitigate that risk and/or ensure you receive proper screening for this disease/condition.”

• CONTEXT is a big deal! Many patients (and some providers!) assume that “increased risk” equates to an extremely high or almost 100% likelihood of developing the disease or condition. This is a common and natural response without proper context. While this may (or may not) be true for diseases with an already high baseline prevalence (such as coronary artery disease affecting 1 in 2 individuals assigned male at birth (AMAB) and 1 in 3 individuals assigned female at birth (AFAB) on average), in other cases, an increased risk identified on PRS still equates to a relatively low actual risk. Helping the patient understand the context associated with a relative risk score (and how it compares to the baseline population risk for that disease) helps clarify their understanding of the results. This context also acts as a reference point for healthcare providers when considering the best next steps for the patient. 

Here are a couple of examples of how I might provide context for a patient with an increased risk result:

• “Your PRS for Type 1 Diabetes is increased at 2x, meaning that you are approximately twice as likely as the average person to develop the disease. The average lifetime risk for an individual assigned female at birth to develop Type 1 Diabetes is 0.45%. So, with your doubled risk of 2 x 0.45%, you have an approximate 0.9% likelihood of developing this in your lifetime. As you can see, though your PRS is increased, your total risk for developing this disease is still <1%. However, now that we know it is slightly increased, your doctor may want to do additional tests to screen you for diabetes at your next visit, and/or they may suggest some lifestyle modifications to help modify your risk.”

• “Your PRS for prostate cancer is increased, meaning you are approximately 1.5 times as likely as the average individual assigned male at birth to develop the disease. The average lifetime risk is 12.5%. So, with your 1.5 x 12.5% risk, you have an approximate 18% likelihood of developing this in your lifetime. This may warrant a discussion with your healthcare team about consideration of a more individualized screening protocol.”
• You could go on to offer more context, if desired, such as: “While your risk identified by your PRS is higher than average, it is not as high as if, say, you carried a mutation in a very high-risk gene such as BRCA2. Individuals assigned male at birth with mutations in this gene have up to a 61% lifetime risk for prostate cancer” [per Version 2.2024 of the National Comprehensive Cancer Network Genetic High-Risk Assessment Guidelines]. 

• “Your PRS for CAD is increased, meaning you are approximately twice as likely as the average Assigned Female At Birth (AFAB) individual to develop the disease. The average lifetime risk for an AFAB individual to develop CAD is 33%. So, with your doubled risk of 2 x 33%, you have an approximate 66% lifetime risk. You could consult a Cardiologist to discuss this risk and screening recommendations. Additionally, given this increased baseline genetic risk, it will be especially important for you to work hard on decreasing other risk factors which you can control, like maintaining a healthy diet, not smoking, engaging in regular physical exercise, etc.”

Discussing next steps: What kinds of recommendations might a clinician make for a patient who has received an increased-risk PRS? To help a patient conceptualize their result, an increased-risk PRS can be compared to increased risk due to other common and well-known risk factors, such as a family history of disease or certain behavioral risk factors. Let’s review some examples: 

• Example 1: A 35-year-old patient who identifies as male has an increased-risk PRS result for Type 2 Diabetes (T2D). This means he has at least a two-fold risk compared to the average 1 in 11 (9%) lifetime risk for T2D in his sex cohort. This is comparable to the commonly seen risk factors of being overweight or having a close relative with T2D. One could consider managing this patient using similar protocols as would be followed by the average overweight patient with close relatives who have T2D. 

• Example 2: A 46-year-old patient who identifies as female has an increased-risk PRS result for Coronary Artery Disease (CAD). This means she has at least a two-fold risk compared to the average 1 in 3 (~33%) lifetime risk^(1-3) for CAD. This is comparable to common risk factors like hyperlipidemia and/or having a family history of CAD. Therefore, one could consider managing this patient using similar protocols as are used with an average patient with high cholesterol and a family history of CAD.

Disclosing an average-risk PRS result

• Clarifying that “average risk” does NOT equal “no risk”: It is well-understood by healthcare professionals that having an average risk for a given disease does not mean a person has no risk for developing that disease. However, I’ve found that patients don’t always understand this nuance, especially when dealing with genetic test results. As was introduced in the Recounting what a PRS can (and can’t) tell us section above, it’s important to stress to patients that genetic risk is only one contributor to overall disease risk. 
  • For example, I have seen many patients for post-test counseling after they have undergone Mendelian genetic breast cancer testing (think BRCA1/2 genes) who express that they are relieved to have a negative result because “now they do not have to worry about ever getting breast cancer.” Much of my post-test counseling for patients with negative results focuses on hammering home the point that their test results simply suggest they do not have a higher-than-average risk but that they still have risk! This is where explaining the relevance of the average population risk comes in.
    • Using breast cancer as an example: The average person AFAB has a 1 in 8 (12.5%) chance of developing this disease in their lifetime. This means that having a negative genetic test result for BRCA1/2 gene mutations still means that the patient has a baseline 1 in 8 (12.5%) chance of developing breast cancer in their lifetime, not to mention additional factors that may further modify that risk. Negative BRCA1/2 gene mutation results simply tell us that they do not have the increased (>60%) risk for lifetime development of breast cancer that is seen in individuals AFAB with a mutation in one of those genes.
  • This logic also applies to patients who have undergone PRS testing. A patient with an average-risk result for Type 2 Diabetes needs to understand they still have an approximate 1 in 11 (for individuals Assigned Male At Birth [AMAB]) or 1 in 12 (for individuals AFAB) risk for developing the disease even with an average-risk result.  Furthermore, they need to understand that proper diet and adequate levels of exercise, etc. are still very important for mitigating risk and that an average-risk result does not mean they “do not have to worry” about developing diabetes or that they can “eat whatever they want,” and so forth. It is important that patients with average risk results have a full understanding of the difference between the type of risk being assessed on their test report and how that relates to their total risk of developing a particular disease. 

• Discussing next steps: When patients have average-risk PRS results, this information can be added to an overall risk assessment for the patient for the applicable disease(s). Just as a healthcare provider would not necessarily use a single lab test or a single piece of any subjective or objective data to determine a healthcare plan for a patient, we similarly would not want to use a PRS as a single reference point for developing a healthcare plan for a patient. Let’s review some examples of how to discuss next steps with ‘average risk’ patients.
  • Example 1: A 25-year-old patient has an average-risk PRS result for obesity. However, the clinician notes that the patient has a higher than average BMI, that her spouse, who accompanies her to the visit, is clinically obese, and that the patient and spouse are actively eating Cheetos during the visit and discussing the movie marathon they are planning for the weekend. While the patient’s PRS result is reassuring in terms of not identifying increased polygenic risk for obesity, the clinician would likely still want to counsel the patient on healthy dietary and lifestyle habits to ensure they understand their PRS result does not indicate an absence of risk.

• • Example 2: A 46-year-old patient has an average-risk PRS result for Atrial Fibrillation (AFib). However, this patient also has high blood pressure and admits to moderate-to-heavy alcohol use. The clinician could reassure the patient that the polygenic analysis did not identify an increased genetic risk. Still, they would likely also want to encourage the patient to be compliant with taking his blood pressure medicine as prescribed and to work on decreasing alcohol intake.

• • Example 3: A 49-year-old patient has an average-risk PRS result for prostate cancer. However, this patient also has an enlarged prostate on a digital rectal exam and a strong family history of the disease (brother diagnosed at 45, father deceased from the disease at 59, and paternal grandfather deceased from the disease at an unknown age). Though the patient’s PRS for prostate cancer is average, the clinician will likely still want to consider additional screening such as PSA, and/or referring the patient to Genetics for evaluation for additional Mendelian prostate cancer genetic testing.

Discussion 

Polygenic risk assessment is becoming a more accepted method of accurately and successfully identifying a person’s individual risks for certain common diseases. Its use is becoming more widespread in various clinical areas (including the fields of primary care, cardiology, oncology, metabolic medicine, and more), and studies have shown that it is capable of improving healthcare outcomes both in individuals and in the healthcare system as a whole (stay tuned for more specifics on this in upcoming blog posts!). Because this form of testing is ‘new’ to many clinicians, it’s important to ensure that pre- and post-test discussions leave patients with a satisfactory understanding of their personal polygenic risk and how that relates to other risk factors like average population risk, total risk, environmental risk, and additional monogenic or Mendelian risks. 

While becoming familiar with a new type of risk analysis may take some time and a little practice, it can be worth it for both patients and their providers. Whether increased or average results, either scenario can potentially impact patient adherence and comprehension of the different factors that play a role in disease development. Personalized genomic medicine is becoming increasingly common across our ever-evolving healthcare landscape. Whether you actively pursue ordering PRSs or not, chances are high that you’ll see these sorts of reports trickle into your practice sooner or later. Familiarizing yourself with their methodology and clinical utilization will ensure you are well-educated and prepared when that day comes! 

Disclaimer 

This blog post is provided by GenomicMD’s certified genetic counselors to serve as a helpful resource and tool for genetic counselors and other clinicians. GenomicMD’s blog posts do not (and are not intended to) dictate an exclusive course of management nor guarantee a particular outcome. They are also not intended to replace discussion with a qualified specialist.

Blog/Abbreviation Glossary:

• AFAB - Assigned Female At Birth
• AFib - Atrial Fibrillation (often called A-Fib or AF) is a medical condition that causes an irregular and often very rapid heart rhythm (arrhythmia) that can lead to severe complications such as blood clots in the heart.
• AMAB - Assigned Male At Birth
• CAD—Coronary Artery Disease is a medical condition in which plaque builds up in a person’s coronary artery, the main supplier of blood to the heart muscle. When this happens, the heart muscle does not receive adequate blood, oxygen, and nutrients.
• Increased-risk PRS result - A polygenic risk score that is at least twice as high as the average population risk for the said disease (or at least 1.5x as high for prostate cancer specifically). Please note that this level of risk may change over time as we learn more! 
• Mendelian/monogenic genetic testing—Tests that analyze for mutations/variants in consecutive sequences of nucleotides within a gene. A mutation impacts the gene’s function with sufficient magnitude to result in a significant risk for disease.
• Polygenic Risk Assessment (PRA)— The analysis of the presence of many genetic variants (SNPs) across the genome that, combined, impact a person’s risk for developing certain common conditions or traits. The results of a PRA are presented as a single or group of PRS (typically one per disease).
• Polygenic Risk Score (PRS) - A single value that represents a person’s relative risk for developing a condition compared to the risk for that condition in an average individual within the population. Note that, depending on the context, PRS can also mean polygenic risk scores (plural).
• Relative Risk - The likelihood the person will develop a given disease compared with (or relative to) the average individual. Some testing methodologies will compare results to a more specific subset of people, like those of a particular ancestry or background. 
• T2D - Type 2 Diabetes is a chronic condition that affects the body’s ability to regulate a hormone called insulin, resulting in elevated blood sugar levels.

References

1. Brown JC, Gerhardt TE, Kwon E. Risk Factors for Coronary Artery Disease. [Updated 2023 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554410/ 
2. Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999 Jan 9;353(9147):89-92. doi: 10.1016/S0140-6736(98)10279-9. PMID: 10023892.
3. Lloyd-Jones, D. M., Leip, E. P., Larson, M. G., D’Agostino, R. B., Beiser, A., Wilson, P. W. F., Wolf, P. A., & Levy, D. (2006). Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation, 113(6), 791–798. https://doi.org/10.1161/circulationaha.105.548206