Blurred Line Between Germline and Somatic Testing for Precision Medicine

June 2022 Vol 13, No 6

Categories:

Precision Medicine

The line drawn between germline and somatic testing has grown very blurry, according to Leigha Senter-Jamieson, MS, CGC, cancer genetic counselor at The Ohio State University (OSU) in Columbus. Although similarities between the 2 types of testing do exist, it is important for navigators to be clear on the differences when it comes to educating patients and empowering them to be engaged in conversations about their own findings.

“Tumor genomic testing is becoming important for more patients with cancer,” Ms Senter-Jamieson said at the AONN+ 12th Annual Navigation & Survivorship Conference in 2021. “But we need to be able to help patients understand the implications.”

Precision/personalized medicine can hold different meanings for different people, but the Precision Medicine Initiative defines it as “…an approach for treatment and prevention that takes into account individual variability in genes, environment, and lifestyle....”

“These terms get a lot of press, even from the mainstream media outlets,” she added. “And sometimes the headlines are pretty splashy.”

According to Ms Senter-Jamieson, these sensational headlines can run the gamut; some stories spin it negatively (ie, precision medicine is financially toxic), while others can instill false hope in patients, touting it as a revolutionary cancer cure (but only citing very specific cases).

“As the people who are helping patients navigate their cancer treatment journey, we need to be able to counsel them about the use of precision medicine in the context of their specific disease, and maybe even the stage of their specific disease,” she advised. “And this means that we have to understand the applicability and the nuance of precision medicine, not just the headlines.”

Quick Review: Germline versus Somatic

A germline mutation (or variant) is a mutation in a reproductive cell (egg or sperm) that is transmitted to every cell in the offspring. These are referred to as “hereditary” or “inherited” variants and are usually detected in a blood or saliva sample. Importantly, these can be detected in healthy people who have not developed cancer.

“Those variants actually equate to having a cancer predisposition,” she said. Somatic mutations occur after conception. In cancers, these usually occur in the tumor cells, and any cells that are derived from those mutated cells will have the same mutation.

Germline Cancer Genetic Testing

This type of testing involves an analysis of a set of genes that can inform the likelihood of developing cancer. Or, in someone who has already been diagnosed, this type of testing can sometimes shed some light on where that cancer may have originated from a molecular standpoint.

This is recommended for a growing number of patients with cancer (even those without a family history of cancer), and it is often performed in the context of genetic counseling. The results can have therapeutic implications, as well as implications for a patient’s family members.

Ms Senter-Jamieson noted that while at-home testing kits analyze genes in the germline, they often are not comprehensive enough for cancer risk-management purposes. “With rare exception, those at-home tests are usually not the same kind of test that we would order in a clinical setting,” she explained. “So take a close look at what they’ve actually had done.”

Tumor Genomic Testing

In contrast, tumor genomic testing usually involves testing on archived tumor tissue. Generally, this tissue is kept for a minimum of 10 years, but if those specimens are not available, tumor genomic testing can be conducted through a liquid (blood) biopsy.

“Liquid biopsy is another one of those buzzword terms that patients have often heard in the media, but there’s not really a good understanding of what it means,” she said. “Essentially what the test does is analyze DNA from a blood sample, but this DNA is different from germline DNA in the sense that it’s been generated and sloughed off by a tumor. So it represents the tumor’s DNA.”

Results of a germline genetic test—whether conducted on a person who is 10 years old or 100 years old—should generally stay the same. However, results of tumor genomic testing can change over time (ie, at diagnosis, after treatment, disease progression, etc).

Tumor genomic tests are often ordered at the point of care in oncology and are recommended for a growing number of patients with cancer. As opposed to germline test results, these results do not typically have implications for family members.

The Blurred Line = “Incidental Findings”

Since a germline mutation is present in every single cell of the body, it is also present in a person’s cancer cells.

“So when you have a tumor genomic test result that’s positive for a pathogenic mutation, do you explain that to a patient as a germline mutation or a somatic mutation?” asked Ms Senter-Jamieson. “The truth is, it’s probably actually both. The trouble is that you typically can’t distinguish between the two.”

But the distinction is important. While the therapeutic implications may be the same, 1 distinct difference between germline and somatic testing lies in the implications for future cancer risk in family members, depending on the origin of the mutation identified.

The National Comprehensive Cancer Network guidelines state that if a mutation with clinical implications is identified on tumor genomic testing and is also identified in the germline, follow-up germline testing should be conducted because, according to Ms Senter-Jamieson, “those implications could be great.”

What If a Tumor Shows a Potential Germline Mutation?

If a patient’s tumor result shows what could be a germline mutation, a few steps should be taken. First, check to see if there’s a mutation in a gene that is important in the germline (because some of the many genes seen in a tumor genomic test are not relevant to the germline). Molecular tumor boards, genetic counselors, and Precision Working Group Recommendations from the European Society for Medical Oncology are good sources of information, she advised.

Next, if a gene that might be important to the germline is identified, germline testing should be conducted to confirm or rule out germline origin.

Preparing Patients

“We want to avoid shocking results, and help patients to anticipate what can happen when we’re doing tumor genomic testing,” she said.

According to the American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility, oncology providers should communicate the potential for incidental and secondary germline information to patients before conducting somatic mutation profiling, and should review the potential benefits, limitations, and risks before testing.

Additionally, providers should carefully ascertain patient preferences regarding the receipt of germline information, and should allow patients to decline receipt of germline information.

She also noted that although a general consensus exists about pretest germline genetic counseling, there is generally more variation in opinion about pretumor genomic testing.

Ms Senter-Jamieson and her colleagues at OSU wondered how realistic these guidelines are, and whether oncology providers at their institution were doing things like ordering tumor genomic tests, discussing the limitations of tumor testing or the possibility of incidental findings with patients.

Surveys revealed that more than half of respondents did not feel they had enough time during a routine visit to discuss tumor genomic testing with patients.

“Almost all of the oncologists who responded to the surveys said they counsel patients on the benefits of tumor genomic testing before doing it, while slightly more than half said they counsel patients on the limitations,” she reported. “But less than 20% discussed potential incidental germline findings with patients.”

Managing Expectations

The problem is, many patients are still reluctant to undergo testing. This can typically be attributed to the fear of incidental findings, information overload (as they’re often having these discussions at the time of diagnosis or recurrence), or lack of a clear benefit to testing. Also, patients whose treatment does not change based on the results of their tumor test feel less confident that their treatment will work.

“Patients tend to be overly optimistic,” she noted. “Almost half believe that tumor genomic testing will guide their therapy, when in reality, it’s closer to 10%.”

It has been established that a stronger patient–provider therapeutic alliance results in improved adherence to therapy, improved caregiver coping, and improved cancer outcomes, but for some patients, having tumor genomic testing and not seeing their treatment course change is “a big letdown,” only compounded by the fact that a higher percentage of oncologists talk about the benefits of testing, as opposed to the limitations.

“So we have a real need to manage expectations here,” she said.

Genetic counseling can help to manage those expectations, but according to Ms Senter-Jamieson, more needs to be done.

“We’re working on this now with a new project using video aids; it helps us to deliver consistent messaging that’s less affected by the oncologist’s enthusiasm,” she said. “But we need other ideas, because our ability to scale this information and make it accessible to more patients is of utmost importance at this time.”

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Last modified: August 10, 2023

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