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Expert Discusses the Selection of Individuals for Germline Testing Based on Breast Cancer Risk

Nichole Tucker
Published Online:9:59 PM, Thu October 24, 2019
Susan Domchek, MD
Susan Domchek, MD
Over the past 10 years, gene testing panels have become more efficient and now allow physicians to send genetic testing for multiple genes at one time, said Susan Domchek, MD. Physicians are now challenged with fully understanding what it means for individuals to have mutations in certain genes and what to do once these mutations are identified.

One way of deciding what to do about the presence of gene mutations is categorizing them as either low-penetrance genes, or having a 2% to 4% risk of causing breast cancer, or high-penetrance genes. BRCA1, BRCA2, and TP53 are considered high-penetrance genes and finding mutations in these genes may either lead physicians to advise patients on taking preventative measures like mastectomies or lumpectomies. However, for low-penetrance genes like CHEK2, ATM, NBNs, BARD, BRIP, RAD51C, and RAD1D, physicians likely won’t recommend taking action and only address these mutations through targeted therapy once a patient develops breast cancer.

There is ongoing uncertainty about when to order genetic testing for patients, and when not to, said Domchek, director of the MacDonald Women’s Cancer Risk Evaluation Center, and executive director of the Basser Center for BRCA, Abramson Cancer Center, Penn Medicine. The National Comprehensive Cancer Network (NCCN) has guidelines that specifically explain when to test patients for BRCA1/2. However, these guidelines exclude the other genes, like CHEK2 and ATM. Additionally, the American Association for Cancer Education (ACCE) Framework suggests that genetic testing should have clinical validity and clinical utility.  

In an interview with Targeted Oncology, at the Lynn Sage Breast Cancer Symposium, Domchek explained the meaning of low to moderate penetrance genes and how they are indicative of breast cancer risk. She also explained the importance of germline and genetic testing to reveal mutations in these genes. 

TARGETED ONCOLOGY: Can you discuss what low to moderate penetrance gene are and how they can impact patients with breast cancer?

Domchek: In the past, we focused on genetic testing for inherited susceptibility to breast cancer on BRCA1 and BRCA2. If you have a mutation in one of these genes, you have a very high risk of developing breast cancer, ovarian, cancer, and other cancers. What has happened in the past 5 to 10 years is that we can now test quickly and efficiently for many different genes at once. This means we can now send genetic testing for 80 genes at the same time.

What we need to do now is understand what it means to have a mutation in these other genes and what to do about them. Many of these genes are what we call moderate penetrance genes and that means that the relative risk of cancer is in the 2% to 4% range rather than the much higher range associated with BRCA1/2 mutations.

TARGETED ONCOLOGY: What is the role of genetic testing in breast cancer?

Domchek: There is a lot of debate right now about what the threshold should be for genetic testing in individuals with breast cancer. There are NCCN guidelines that talk about this and are focused on things like age, family history, and the type of breast cancer. With triple-negative breast cancer, for example, it is much more likely to have a mutation in a high penetrance gene. It's worth stating that the NCCN guidelines were created to identify individuals at risk of having these high penetrance gene mutations. They weren't developed to detect mutation in other genes, such as CHEK2 or ATM, where the information related to that is less clear on how much we are adding clinical utility to patient care.

There are other guidelines including those from the American Breast Surgeons, suggesting that everyone with a new diagnosis of cancer gets genetic testing. The challenge is how we think about that. I would argue that it remains true that BRCA1/2 and PALB2 are the genes that are most clinically useful at this time, in terms of improving patient care. It is clear that some women and all men are at a much higher risk of having these mutations than others, and so we should make sure not to miss anybody in that category.

TARGETED ONCOLOGY: How can these mutations impact treatment options for patients?

Domchek: BRCA1 and BRCA2 mutations have a clear role in consideration of surgical approaches. For example, if someone has a BRCA1/2 mutation, and depending on their age, we can estimate the risk of developing a second primary cancer. Some women choose to have a bilateral mastectomy rather than lumpectomy and radiation. Because of the increased risk of ovarian cancer with BRCA1/2 mutations, women at some point will require a preventative oophorectomy. Finally, in patients with advanced breast cancer, there are specific drugs called PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), which are approved to treat metastatic BRCA1/2-related breast cancer.

Currently, there's no PARP inhibitor approved for patients with early-stage breast cancer. If that approval comes then we'll have to re-assess things. For mutation in these other genes, that direct impact is less clear at this time. There are no known therapeutic differences meaning we don't give specific drugs to patients who have CHEK2 or ATM mutation at this time. A lot of the guidelines focus on enhanced breast screening with breast MRI which is probably more relevant for someone who hasn't yet had their breast cancer. We have to figure out how to best use this information.

TARGETED ONCOLOGY: What are the key points from your presentation at the Lynn Sage meeting?

Domchek: We currently miss people who at the highest risk for having BRCA1/2 mutations. There are socioeconomic and racial disparities. We need to make sure that we're testing those who are the highest risk.

If you choose to send a multi-gene panel test, just make sure you know what genes are on the panel and make sure you understand what you might do with that information. I think it's important that we know what we're getting into before we do it and that our patients understand the pros and cons of expanded panel testing.

TARGETED ONCOLOGY: What is your advice for making sure high-risk patients are not overlooked?

Domchek: I think that in the past there have been a number of barriers to genetic testing. We might have made it too hard for individuals to access such testing. The cost was perceived to be too high. We need to make sure that patients know that if they meet the criteria for testing, the vast majority of the time, insurance covers the cost of the test. There are also low-cost options available. We need to meet patients where they are and make sure that it's easy for patients to get access to genetic testing information.

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