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Germline Testing in Oncology

Nov 16, 2020

ORION by VieCure

Volume 1, Issue 10

Interview with Lisa Madlensky, PhD, CGC

About 25 years ago, BRCA1 and 2 were identified as breast cancer susceptibility genes and testing formally began for these genes in 1996. Since that time, genetic testing within oncology has accelerated. Clinician's and researcher's understanding of the importance and science of germline genetic testing and the associated benefits it brings to patients and their families has increased substantially since that time. We interviewed VieCure Clinical Advisory Council Member, Lisa Madlensky, PhD, CGC, Professor of Medicine at the University of California, San Diego and a certified Genetic Counsellor, to learn more about germline genetic testing and the opportunity it presents for cancer patients.

Under what circumstances is germline genetic testing important in the oncology setting?

There are two main circumstances where germline testing should be considered. First, patients who have a personal and/or family history that is suggestive of an inherited cancer predisposition. Second, patients who might benefit from a targeted therapy if they are shown to have a mutation in a particular gene or pathway. In both cases, the NCCN guidelines are helpful in determining which specific patients are appropriate for germline testing.

What are the benefits of genetic testing?

There are several benefits to genetic testing for cancer patients. For those who test positive and are found to have a mutation, they have the opportunity to understand their risk of future additional primary cancers, and what they can do to mitigate that risk. Importantly, family members can find out who also has the mutation (and who does not) so that those at elevated risk can avail themselves of cancer prevention and early detection. With respect to treatment options and benefits, there may be targeted therapies or clinical trials available for patients who have a germline mutation. And for those who test negative it often provides some reassurance to patients who are worried about the risk of cancer in their children.

There are a lot of labs that offer genetic testing. What are the key issues I should consider when selecting a lab?

Sometimes, the patient's insurance will make that decision for you if they are contracted with a specific germline laboratory. If you do have a choice, I like to use labs that a) are experienced with germline cancer genetic tests; b) have committed to re-issuing test reports when a "variant of unknown significance (VUS)" gets reclassified; c) have committed to depositing data in the ClinVar database so that their variant calls can be reviewed and compared to that of other labs; d) offer a menu of tests (and ideally the ability to customize my order with the genes that I want to test, eliminating genes from the panel that really aren't indicated); and e) offer ease of ordering and reporting with good customer service. If you work with a genetic counselor, they can be a great resource in helping decide which lab might be the best choice for a particular patient.

Next generation sequencing results based on a patient’s tumor tissue revealed a BRCA2 aberration. Following my consultation with a genetic counselor, it was determined that the mutation was benign. How often does this happen?

This scenario does happen quite frequently; germline labs follow a very strict set of rules in reporting whether a variant is classified as pathogenic (a positive test), benign (a negative test), or having uncertain significance (a VUS). Tumor profiling labs sometimes report out variants that are not considered to be pathogenic by the germline labs. We always recommend having a genetics professional review a tumor profile to help determine if follow-up germline testing is appropriate.

Some patients have a great deal of anxiety concerning genetic testing and counseling What can I do to mitigate that anxiety?

It's certainly distressing for a newly diagnosed cancer patient to think that their family members might also be at risk of developing cancer. I generally emphasize that the primary goal of germline testing is cancer prevention and early detection- whether it be for the patient or for their family members. It's also worth noting that many patients overestimate their risk of having a mutation-- highly penetrant cancer syndromes are actually relatively uncommon. Genetic counselors are trained to walk patients through the testing process and explain every step, as well as offer support and navigation to patient's family members. We absolutely understand how difficult it can be to consider an increased cancer risk. But if a patient is willing to be proactive and can agree that the information can be important for their own cancer care (as well as for their relatives) then often they will move ahead with genetic counseling and/or testing.

Lisa Madlensky, PhD, CGC

Professor, Molecular Genetics

University of California San Diego

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