With Melissa Frey, MD, Assistant Professor in the Division of Gynecologic Oncology at Weill Cornell Medicine
By Sarah DiGiulio
Knowing that some cancers are linked to pathogenic variants means that relatives of gene carriers are also at risk of having those genetic variants and developing those cancers. But the benefit of knowing that risk ceases if relatives are not informed.
That's why Melissa Frey, MD, Assistant Professor in the Division of Gynecologic Oncology at Weill Cornell Medicine, and her colleagues developed a streamlined model of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing to notify relatives of patients who had been found to have cancer-associated pathogeneic variants and to help facilitate genetic testing for the relatives.
Frey's team recently published results of a study testing the model, showing that it resulted in more at-risk relatives getting tested and utilization of genetically targeted primary disease prevention, as evaluated after a short-term follow-up (J Clin Oncol 2020; doi: 10.1200/JCO.19.02005). In an interview with Oncology Times, Frey explained more about how the team's cascade genetic testing model worked and what the new data show.
1. How does cascade genetic testing work?
"When a person is found on genetic testing to have a germline pathogenic variant (for example BRCA1/2 pathogenic variant), his/her relatives are also at risk of carrying this pathogenic variant. First-degree relatives (parents, siblings, children) will have a 50 percent risk of sharing the same pathogenic variant, second-degree relatives (uncles, aunts, nieces, nephews, grandparents, grandchildren) will have a 25 percent risk and so forth. Cascade testing is the process of starting with the patient who has been diagnosed with a germline pathogenic variant (passed from parent to child) and extending genetic testing to that patient's at-risk relatives.
For cancer-associated pathogenic variants, informing relatives is critical. Informed relatives have the opportunity to undergo genetic testing to determine if they carry the same cancer-associated variant. Most importantly, if relatives are found to carry the same cancer-associated pathogenic variant, they can benefit from cancer screening and prevention.
"Currently, oncologic genetic testing is often ordered at the time of a cancer diagnosis. The goal of cascade genetic testing is to identify 'previvors' or individuals who are survivors of the predisposition to cancer, but who have not had a cancer diagnosis. With cascade testing there is the ability to identify individuals with cancer-associated pathogenic variants and offer them risk-reducing surgery and/or cancer screening that can prevent cancer or allow for early diagnosis and treatment, reducing morbidity and mortality.
"Currently, the process of cascade testing relies on the patient. The patient is encouraged to inform his/her relatives about the result and encourage his/her relatives to get genetic testing. We believe that this burden should not be placed on patients (who are often simultaneously dealing with a new cancer diagnosis), but instead there should be a paradigm shift whereby the medical system takes on this role. We developed a system for cascade testing that is facilitated by the medical team, taking the burden off of the patient with the goal of improving testing completion among at-risk relatives and hopefully reducing cancer morbidity and mortality in families with hereditary cancer syndromes."
2. The results of your study evaluating the model of cascade genetic testing that you developed were encouraging. Is it feasible that such a system might be rolled out?
"The key finding was that, when the medical team facilitates cascade testing, approximately 60 percent of at-risk relatives complete genetic testing. This is significantly higher than rates reported in the literature for cascade testing that is mediated by the patient. Furthermore, after just 6 months, we found that results of this testing led relatives to pursue cancer screening and risk-reducing surgery. This intervention is effective and has the potential to improve cancer morbidity and mortality for families with hereditary cancer syndromes.
"There have been studies in the oncology literature and other diseases (e.g., hypercholesterolemia) demonstrating that cascade genetic testing is most effective when facilitated by the medical team and when relative convenience is prioritized (e.g., offering testing in the relative's home without additional physician visits). We created our facilitated cascade testing strategy with this literature in mind with the goal to maximize our success, defined by relatives undergoing genetic testing to evaluate for the familial pathogenic variant.
"A major limitation of this study is that we did not address the cost associated with cascade testing (all testing was covered as part of participation). However, many genetic testing laboratories offer free testing for relatives of an affected individual and cascade testing is often covered by insurance. However, to demonstrate sustainability, future work is needed to evaluate the cost-effectiveness associated with genetic counseling, sequencing, and cancer preventative services per additional quality-adjusted life year.
"We are currently planning a prospective randomized controlled trial at multiple institutions to demonstrate the efficacy of this strategy compared to standard of care and in diverse medical settings."
3. Are there any privacy concerns about the family members of the patient being contacted with this information, but not necessarily consenting to receiving it?
"We only contacted relatives with the consent (written) of the patient after thorough counseling. We encouraged patients to contact their relatives to inform them about the familial pathogenic variant prior to our contact with the relative.
"When we contacted the relatives, we used a script to describe the study, but did not share any information about specific genetic findings in the family until the relative stated that she/he wanted to move forward and participate and learn about the familial findings."