After being diagnosed with rectal and thyroid cancer at age 42, a woman received genetic testing for hereditary mutations at a community hospital. Her test revealed a mutation in one of her CHEK2 genes. The mutation was classified as “expected pathogenic” according to her testing report, meaning that it was expected to increase cancer risk. She had a double mastectomy to reduce her breast cancer risk.

Then she enrolled in the Ohio Colorectal Cancer Prevention Initiative, a statewide genetic testing study for people with colorectal cancer. Her second genetic testing report, from another lab, told a different story than her first. This second report said that she had a variant of uncertain significance that may or may not increase cancer risk.

Heather Hampel, a cancer genetic counselor at the Ohio State University Comprehensive Cancer Center in Columbus who leads the Ohio genetic testing program, told the story to illustrate the complexities of testing for hereditary mutations as part of a session held online May 19 at the American Association for Cancer Research (AACR) Annual Meeting 2021. (The AACR publishes Cancer Today.)

Hampel and her team set out to further investigate the woman’s variant, finding a meta-analysis indicating that the mutation does increase breast cancer risk but less so than other CHEK2 mutations, which are lower risk than certain other breast cancer-related mutations to begin with. They also reached out to the lab that did the second test and were told that they had seen the variant at equal frequencies in people with and without breast and colon cancer, indicating that it might not increase risk. The Ohio State team had to explain to the woman that even if her variant did confer some risk, it did not warrant risk-reducing surgery. The woman reported that she did not regret her mastectomy, but this and other incidents raise concerns that the rise of genetic testing can have risks as well as benefits.

Introducing Uncertainty

Hampel kicked off the session by explaining the difference between testing for mutations that are inherited and mutations that arise in a person’s body during the course of their life, called somatic mutations. All of us accumulate somatic mutations, and these mutations can lead our cells to become malignant. A person who inherits a mutation that increases cancer susceptibility starts life with a mutation in every cell in their body, often in a gene that, when working properly, prevents cells from becoming cancerous. People start out with just one copy of an inherited mutation, called a germline mutation, in each of their cells, but over time by random chance, a somatic mutation in the second, working copy of the gene can arise, starting a chain of events that can end in cancer. “Essentially, people with an inherited cancer susceptibility syndrome are born one step closer to developing a cancer,” she said.

People may get tumor testing, in which a sample of a tumor, or DNA circulating in their blood that has been shed from a tumor, is tested for somatic mutations. The goal of this testing is to guide treatment. People with a personal health history or family history that is concerning may also get germline testing, in which skin, saliva or a skin punch biopsy are tested for genetic changes that were inherited from a parent. People with certain germline mutations may benefit from added cancer screening or preventive surgeries. Their family members are often offered germline testing in hopes of identifying increased risk and preventing cancers. And these germline mutations, in some cases, can also guide treatment.

As next-generation sequencing has become cheaper and more available, patients are increasingly getting tested using multigene panels that look for a long list of mutations, including those whose importance is not yet understood. Hampel explained that with a large multigene panel, 40% to 50% of people tested may learn they have a variant of uncertain significance. Over the course of a decade, she said, around 25% of variants of uncertain significance are reclassified, and 90% to 95% of the time, they are reclassified as not harmful. Hampel said that someone whose test reveals a variant of uncertain significance should be interpreted as having tested negative for a hereditary cancer predisposition mutation.

Adding to the uncertainty, it is possible for different labs to classify the same variant differently, as happened in the case of the rectal and thyroid cancer patient Hampel described. “This can cause a lot of confusion within families when testing results are disparate,” Hampel said.

Testing Disparities

Allison Kurian, an oncologist and director of the Stanford Women’s Clinical Cancer Genetics Program in Palo Alto, California, also noted the benefits of germline testing while raising concerns about how it is being implemented. Almost all women diagnosed with ovarian cancer are recommended to receive germline testing. Recommendations on testing vary for people with breast cancer, with the American Society of Breast Surgeons recommending some germline testing for all people with breast cancer and the National Comprehensive Cancer Network recommending testing depending on various factors related to personal and family history.

Kurian’s research shows that not everyone who is recommended to get germline testing or who wants to be tested gets it. In a 2017 study published in JAMA based on a survey of more than 2,500 women, Kurian and her colleagues found that while two-thirds of women with early-stage breast cancer reported wanting genetic testing, just 29% reported actually getting a test. The patients were identified using the Surveillance, Epidemiology, and End Results (SEER) registries in Los Angeles County and Georgia, which systematically collect data on everyone diagnosed with cancer. Around 81% of high-risk patients wanted testing, but just over half these patients got a test. When asked why they didn’t get a test, around 56% of high-risk women said that their doctor didn’t recommend it, while around 14% said the testing was too expensive. Looking at the same group of patients for another paper, published in 2018 in the Journal of Clinical Oncology, Kurian and her colleagues found that just around two-thirds of people who tested positive for germline variants received genetic counseling to help them interpret their results.

New data from Kurian and her colleagues, published in the May 20, 2021, issue of the Journal of Clinical Oncology, indicate that testing uptake has not increased much as time has passed. The researchers looked at data from the SEER Program covering women diagnosed with breast or ovarian cancer between 2013 and 2017 in California or Georgia. They were able to determine whether these women got germline testing up through 2019. About a quarter of women with breast cancer and a third of women with ovarian cancer received germline testing over the study period, with the percentage of women tested increasing just 2% per year during this time. Meanwhile, the percentage of people receiving multigene panel testing, rather than just testing for BRCA1 and BRCA2 mutations, grew rapidly. About 25% and 40% of tested breast and ovarian cancer patients who were diagnosed in early 2013 received multigene panel testing, respectively. For patients diagnosed in late 2017, these proportions grew to more than 80% and more than 90%. The proportion of women learning they had variants of uncertain significance also grew from 11% of those diagnosed in 2013 to 27% of those diagnosed in 2017.

Significantly more Asian and Black women learned they had variants of uncertain significance compared to white women. Kurian called this disparity between different racial groups “a widening gap that could be potentially concerning if patients and clinicians don’t understand that variants of uncertain significance usually get reclassified to being harmless.” She emphasized the importance of communicating widely that a variant of uncertain significance should not motivate a risk-reducing surgery.

Putting Universal Testing in Practice

Even as research shows gaps in implementation of genetic testing, some research indicates that testing even more people with cancer for germline mutations could ensure that people with significant mutations are not missed.

At Memorial Sloan Kettering Cancer Center, based in New York City, all patients are able to receive sequencing via the MSK-IMPACT platform, which tests for a wide variety of mutations as part of a research study, explained Zsofia Stadler, a medical oncologist at the institution who also spoke at the AACR session. The researchers compare tumor DNA to DNA in the other cells in the body and inform patients of mutations that arose in their tumors that could impact their treatment. Since 2015, patients have also been given the option to learn about germline mutations.

Stadler discussed data she had presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, held virtually in May and June, on nearly 12,000 patients who received germline testing between 2015 and 2019. Germline cancer-related mutations are classified by their penetrance, or their likelihood of resulting in a cancer. High-penetrance mutations, such as certain BRCA mutations, are most likely to lead to cancers. The researchers found that 17% of patients had a pathogenic or likely pathogenic germline mutation, and 11% of patients had mutations with high or moderate penetrance.

The researchers also set out to determine how often these genetic mutations would impact treatment, learning that 9% of patients had mutations with potentially significant treatment implications and 4% had mutations that guided treatment with therapies approved by the Food and Drug Administration (FDA) for their cancer type. Overall, 61% of advanced cancer patients with these hereditary mutations targeted by FDA-approved therapies for their cancer type received a targeted therapy.

During a panel discussion at the end of the session, Hampel noted that Stadler’s presentation gave hints into a future where all patients might be given the option to have genetic testing. But to make sure this testing benefits patients evenly will require improvements in how testing is implemented, according to Hampel. “I’m afraid that even if we get patients tested, that the disparities will creep in in terms of management. Do they have access to the high-risk management that they need? Do they have access to risk-reducing surgeries? Do we do as well at cascade testing in their family members? We have systemic problems, as we’ve all become aware, that need tackled at every level to help with the disparities that we see in genetics,” she said.

Stadler shared that she will be presenting data at the 2021 ASCO Annual Meeting, to be held virtually in June, demonstrating that even at Memorial Sloan Kettering, where germline testing is paid for via research funding, disparities arise. “Patients across our institution within our little framework have the same access to the test, but with the positive results, what we found is that follow-through with an appointment in clinical genetics is not uniform across different ethnicities and across different races,” she said. All patients who tested positive for a pathogenic or likely pathogenic germline variant were referred to the clinical genetics service for genetic counseling. Around 74% of white patients and 79% of Ashkenazi Jewish patients completed these visits, compared to 68% of nonwhite patients, according to the abstract​ associated with the ASCO presentation.

Wenora Johnson, a patient advocate from Joliet, Illinois, who has an inherited cancer predisposition syndrome called Lynch syndrome and has had three cancers, closed out the session by emphasizing the value of germline testing and accurate information for patients. “As a patient and as a patient advocate, what immediately comes to mind is don’t underestimate the patient,” Johnson said. “We’re probably a lot more intelligent than you think. For us, knowledge is power. … That genetic report gave me the power to do something preventive,” she said.​

Kate Yandell is a writer and editor and was formerly the digital editor of Cancer Today.