Need for Germline Testing Becomes Increasingly Pronounced in Oncology

Mark E. Robson, MD

A strong cognizance of germline testing is becoming increasingly important in the field of oncology, across an array of tumor types, according to Mark E. Robson, MD, who also emphasized the critical role of genetic professionals in terms of interpreting assay results during the 38th Annual CFS® virtual conference.

“Importantly, germline predisposition is more common than we once believed, and it can't always be identified through traditional criteria. In fact, about 50% of women with BRCA-mutated triple-negative breast or ovarian cancers do not appear to have a family history that would have triggered testing before they were diagnosed themselves,” Robson explained. “This must be kept in mind. This is particularly the case now that PARP inhibitors have become such an integral part of the care pathway for patients with these diseases. This is now expanding, with the evidence that PARP inhibitors are active in prostate and pancreatic cancers, and they may be beneficial in other tumor types and other genes, as well.”

In an interview with OncLive, Robson, who is the chief of Breast Medicine Service at Memorial Sloan Kettering Cancer Center, discusses the critical importance of germline testing and genetic counselors in the field of oncology.

OncLive: What are some of the limitations with germline testing? What research efforts are needed to address these challenges?

Robson: Understanding of the germline landscape in patients who have cancer is becoming increasingly important. One of the challenges is establishing a distinction between testing for therapeutic decision making, which should be quite broad, and testing for the purposes of risk assessment in unaffected individuals, which perhaps could be narrower.

The reason that the distinction is important is because the way that providers should go about obtaining consent, is different. People who need the information for treatment decision making, may need a different level of decision making for assistance. This is the same for men if they’re trying to establish their own personal risk level. So, the traditional counseling models that are focused on risk assessments remain highly appropriate for that setting; however, it might not be efficient enough to test people for therapeutic decision making.

Furthermore, interpreting test results remains difficult and, in some ways, it's becoming more difficult as more genes are incorporated into multi-gene panel testing.

It’s very important, on the back end, to ensure that the input from informed genetics professionals is being interpreted and acted upon correctly. Unfortunately, this is not always happening. People are defaulting to how they would manage a [patient with a] BRCA mutation, even if the individual has another alteration.

Could you further expand on these reports and how they are evaluated? 

The report is just like any other laboratory report, it tells us whether there is a finding. However, moving from the finding to an action requires education. The provider has to understand what the appropriate recommendations are. If they're not entirely clear about what the recommendations are, they need to ensure that there’s access to more specialized information and they should refer the patient to a genetic counseling group.

How do liquid and tissue biopsies compare?

Germline testing is usually conducted by using blood and normal cells that are circulating in the blood; however, oftentimes, saliva could also be used. When you start talking about tissue or liquid biopsies, it’s true that germline abnormalities can be reflected in those samples. However, in theory, they could also just be abnormalities that arose in the tumor itself.

There are patients who have mutations, such as BRCA1/2, which are only present in tumors and not in the blood. As such, if you're using circulating tumor DNA from the tumor or blood as a way of identifying mutations in these genes, then you must reflect on the blood test to evaluate whether it’s inherited and potentially shareable with other members of the family.

How could we augment the utility of germline testing in this space?

We need to develop 2 different pathways. We need to develop a clear-cut pathway for providing individuals with the information they need to essentially ask or agree to germline testing in the setting of therapeutic decision making. It’s particularly important for them to understand that these results do potentially have family implications and, therefore, they need to be prepared to share that information with family members.

Efficient pathways are critical, especially when providing information to people who do not have cancer and are seeking risk assessment. We must leverage new technologies such as telehealth and centralized testing.

Moreover, we need to have satisfactory follow-up pathways established for individuals who are undergoing therapeutic decision making, along with those who are undergoing a risk assessment test, without the involvement of a genetic counselor. I believe that there's a number of places where those handoffs are not as robust as they could be.

As we continue to discover more actionable alterations, do you see the field of oncology broadening multi-gene panels or creating more tumor-specific assays?

It’s probably going to be broad because it’s more efficient that way. The incremental cost of adding additional genes onto a multi-gene panel is relatively limited. There are technological limits to what one can do but, pragmatically, making tumor-specific decisions is just going to become increasingly challenging.

If you're doing this in the germline setting, it becomes complicated because you have several different kinds of information that you can get from a tumor agnostic panel. Some of that is not relevant at all. For instance, if you conduct a broad multi-gene panel, you may find an alteration in a gene that causes Lynch syndrome in someone who has breast cancer, which is probably not a Lynch syndrome-associated cancer. While you're looking for a therapeutic target, you’re also simultaneously screening the population, which is complicated.

People have to understand that, even with the different types of information that flows out of a multi-gene panel, it doesn't necessarily mean that they need to choose.

Is there anything that you would like to add?

Genetics professionals continue to play a critical role in variant interpretation [and in making] recommendations for non-therapy–related actions, such as screening and prevention-related actions. With cascade testing, we could maximize the benefits for the family as a whole. The models that do not fully incorporate genetics professionals into this process are unwise and are certainly not taking full advantage of the information that can be provided.