Family History Plays Key Role in Germline Testing for Hereditary Breast and Ovarian Cancers


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Sofia D. Merajver, MD, PhD, discusses the importance of germline testing in patients with breast and ovarian cancer along with how this testing is being used to personalize treatment.

Sofia D. Merajver, MD, PhD

Understanding family history is needed to inform which panel of genes should be tested for in an individual who may be at increased risk for breast or ovarian cancers, according to Sofia D. Merajver, MD, PhD, who added that new technology that could allow patients to more easily compile these data is a necessary focus of ongoing research efforts.

“A patient’s life is lived outside of the doctor's office. Thus, when they go to see their healthcare provider, doctor, nurse, or counselor, they need a better understanding of this. Part of this understanding comes from the health of other family members, but the other part pertains to each individual patient,” Merajver explained. “The healthcare providers must understand information such as alcohol consumption, if patients smoke, their height and weight, the amount of physical activity they get each day, as well as what their diet look like. Genes do not act in isolation; they act as a whole. Ultimately, the story a patient tells in the doctor's office is the compilation of everything else that happens.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Precision Medicine, Merajver, professor of epidemiology and internal medicine who is also the director of the Breast and Ovarian Cancer Risk and Evaluation Program at the University of Michigan, discussed the importance of germline testing in patients with breast and ovarian cancer along with how this testing is being used to personalize treatment.

OncLive®: What is the prevalence of hereditary disease in breast and ovarian cancers and how can germline testing potentially lower these numbers?

Merajver: About 10% to 15% of all [patients with] breast cancer, along with about 15% to 20% of all [patients with] ovarian cancer, have a hereditary basis. This means that these individuals were born with an alteration or mutation in major genes that participate in the development of breast or ovarian cancer.

Over their lifetime, as their exposures, habits, and their overall state of health progresses, these mutations are present in every cell of their body. There is only 1 copy that is functional for the particular gene that they have inherited. As a result, these individuals are really much more prone to cancers than an average person who does not harbor a mutation.

In March 2020, Mayo Clinic stated that the National Comprehensive Cancer Network guidelines for germline genetic testing in breast cancer should be expanded to include women aged 65 and under. What is your viewpoint on this?

I believe there are ways to tailor that. One of the dangers of putting out very broad guidelines is that you are setting the stage for a discordance between the quality of the testing and the quality of the counseling. The problem with testing more broadly comes down to what we are doing with that information.

Many years ago, when we began screening for breast cancer, we realized that even if we pass laws and we had guidelines that everyone needed a mammogram, we needed companion guidelines and resources to ensure that those who don't have the means also have access to the care that came after the mammogram.

Now, fast forwarding 40 years, we are in a similar situation with genetic testing. I'm all for the public and individuals being informed of their own genetic makeup, but in the context of understanding the real health implications for them, the choices they have to make to manage the risk, they have to understand that just knowing the risk doesn't automatically manage the risk. You can only prevent a bad outcome if you appropriately manage the risk.

As such, I believe it’s important to manage the guidelines rather than having a blanket statement, like testing all patients who are under 65 years of age. We are testing some people who are over 70 years of age and it’s appropriate to test them. We are discovering mutations in patients and hoping to save the lives of their cousins, children, nieces, and nephews. I believe the age limit is not nearly as important as figuring out how to integrate risk assessment with risk management.

What is your advice for implementing some of the testing guidelines that are issued to practice? What are some of the challenges faced?

It is a huge challenge for primary care physicians to integrate guidelines. I’ve been a part of the committee that writes these guidelines for a very long time, and I am honored. Notably, the guidelines are very useful but incredibly hard to implement with the way they are written. The evidence is what backs up the guidelines and we are trying our best to ensure that we prioritize testing and risk assessment in the workforce, to test those who have at least a 5% chance of testing positive under the current technologies and the current state of knowledge.

Once you set that level to try to test patients who are at greater than 5% risk of testing positive for [cancer], the question is how to get there. This is super complicated because there are many different models, all of which have now been broadly validated in diverse populations. We are really looking for innovative ways to do this.

There is a great need to deploy in primary care, throughout the country and the world, a way to enter the data in a manner that makes it easy to implement guidelines. It's nice to write guidelines, but if they're not used effectively, they don't really realize their full potential.

One way of doing that is to provide the patient with the ability to take his or her time to provide that information. As they do that, they gather information from the rest of the family. To have some kind of an online tool, where they can save their work and return to it later on as they gather more information, would allow for accurate data to be compiled. This type of technology would be very beneficial. One company that has this type of technology right now is InheRET LLC; others are currently under development, as well.

Could you expand on how germline testing is assisting in personalizing treatment in ovarian and breast cancer?

Beyond prevention, germline testing has different opportunities to impact treatment and outcomes in patients with cancer. Ovarian cancer is a salient example; in this disease, mutations in BRCA1/2 will mark the tumors that are more sensitive to PARP inhibitors.

This allows us to take advantage of the fact that the DNA repair machinery of the cancer cells is already defective in one branch. The PARP inhibitors come in and inhibit another branch, which prevents the cell’s ability to repair; they are then much more destined to go into cell death. Interestingly, there may be other genes as well that will, in time, qualify patients to receive PARP inhibitors, if they have ovarian cancer. That research is currently under development.

Shifting into the breast cancer space, there is a possibility of patients with triple-negative breast cancer who harbor a BRCA1/2 mutation; however, in this space, it will most likely be a BRCA1 mutation. In a clinical trial or metastatic setting, PARP inhibitors can be administered in combination with other drugs or alone, depending on the situation.

What role does family history play in testing selection?

Sometimes we have families that, for 3 or 4 generations, breast cancer has been observed in women; we might also see an occasional case of prostate cancer in a male family member on the same side of the family. For those patients, it's very appropriate to do a breast panel, a more limited panel, of either 8, 12, or 15 genes. The opportunities vary with different testing companies. It’s paramount that we emphasize genes that are definitely linked to familial hereditary breast cancer.

On the other hand, some patients have a family history that is very heterogeneous or diverse. That means there are family members who may have breast, colon, prostate, bladder, stomach, and ovarian cancers. These mixed patterns on the same side of the family will prompt us to expand the panel, to include genes that may not be linked necessarily to breast cancer primarily. We mostly make these decisions based on family history.

Sometimes, due to life or world events, individuals don’t have a great understanding of their family history. For example, Holocaust survivors or those who were adopted may not be able to reconstruct their family history. For those individuals, we tend to use larger panels.

What barriers are associated with germline testing and how has the coronavirus disease 2019 pandemic enhanced these challenges?

If you look at the statistics over the whole country, there are tremendous barriers of access to genetic risk evaluation. When you interview doctors, nurses, health care providers, primary care physicians, and primary care specialties such as family medicine, OBGYN, and pediatrics, they will tell you that one of the biggest barriers is their inability to collect a good family history.

Nowadays, with telemedicine, this is even more important. People are no longer in waiting rooms, filling out very detailed paperwork that helps us to make these decisions. The right technology could make this process of conveyance of family history incredibly easy for the patients, allowing them to submit the information to their doctors, and ensuring that their records are available. This allows for decisions to be made equally, regardless of race, financial situation, and geographic location. Patients will all receive the same link to enter their family history on a chosen device. Once that information is in there, it takes very little time to act on it because you have a basis that you can trust. That is one of many ways that could help eliminate disparities.

The more morbidities a patient has, such as type 2 diabetes, a heart arrythmia, or arthritis, when they go to the doctor, there's hardly enough time in the visit to adequately cover family history. A patient must decide on what insulin dose or pill to take for their diabetes and what physical therapy to undergo for their arthritis; there are too many issues to cover. Family history and testing for risk of breast cancer, ovarian cancer, or colorectal cancer takes a backseat.

However, 3 years later, that very same person may have skipped getting a mammogram or may have skipped getting a colonoscopy and is then diagnosed with stage III colorectal cancer. The actor Chadwick Boseman, for example, died from colorectal cancer that he was diagnosed with 4 years ago. I don't know any details about his family history but it’s possible that he had a family history or there were other risk factors that might have been considered.

What I often think about is, when someone is 45 or 50 years of age and they get cancer, there was a time when they were 23 years of age, they did not have cancer. The question is, “What could have been done differently then, earlier on, to prevent cancer from developing later on?” How do we ascertain those who need to take action? Several actions can be taken, all of which are tailored to the preferences of each individual patient.

In the breast and ovarian cancer space, why must we keep a close eye on medium-risk genes?

The big revolution came after the Supreme Court of the United States rejected the notion that people could patent genomic DNA; that's a natural product and is not patentable. After that happened in June 2013, it opened the door for competition among genetic testing companies to offer different types of services; that was the birth of panel testing.

Once we opened that up, we realized that we have very strong cancer genes including BRCA1/2, p53, along with others, but we also have a large number of not-so-strong cancer genes that are a little more common in the population. If patients carry mutation in those genes, their risk of breast or ovarian cancer is not 80% or 50%; it may be 30%. However, that's still more than double the average risk of a person who doesn't have it. Some actions can be taken to help manage those risks.

That's the situation we're in right now, where we are testing for panels and we are finding out that people carrying mutations in what we refer to as medium-risk genes. This is to help them decide what to do to manage their risk in a manner that preserves their quality of life and allows them to fulfill their aspirations, such as having children.

Most importantly, at the population level, we live in the era of a pandemic where there is tension between medicine and public health. What we do for individuals and what we do for populations must merge, so that we can help everyone. The real litmus test of whether what we are doing is right, will be the resulting better outcomes if people get cancer or decreasing the incidence of cancer by true prevention; those are the long-term goals of this work.

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