Germline testing for cancer management: BRCA and beyond

“Angelina Jolie takes the biggest credit for raising awareness of inherited cancer and the possibility of preventing it through genetic testing,” says Leonard Gomella, a urologist at Thomas Jefferson University Hospital’s Sidney Kimmel Cancer Center, in Philadelphia.

In 2013, the American actress was featured on the cover of Time magazine for undergoing a prophylactic double mastectomy after learning that she was at high risk of developing breast cancer due to a mutation in her BRCA1 gene. The ‘Angelina-effect’ has led to a sustained increase in the rates of risk-reducing surgery¹.

While the majority of cancers are ‘sporadic’, caused by damage to genes in an individual cell during a person's life — also known as somatic or acquired genetic variants — up to 10% of cancers are caused by pathogenic germline variants such as BRCA1 in a sperm or egg cell. These variants are passed directly to offspring at conception and are found in every cell in their body. Because the variants are transferred from generation to generation, they are key indicators of hereditary cancer risk.

In the United States today, women with a personal or family history of breast, ovarian, fallopian tube or peritoneal cancer are offered genetic testing and counselling. The results are used to guide treatment decisions and take preventive measures in unaffected women, such as annual screening and risk-reducing surgery.

Since the discovery of the association of BRCA1/2 variants with hereditary breast and ovarian cancer almost 30 years ago, these and other pathogenic germline variants have been linked to inherited forms of pancreatic, colorectal and prostate cancer, prompting changes to genetic testing and screening guidelines.

The cost of genetic testing has plummeted due to advances in sequencing technologies, making it feasible to test for many genes at the same time. “We are finding a growing list of variants because of the expanded scale at which we can now carry out genetic testing,” says Tuya Pal, Associate Director of Cancer Health Disparities and a Clinical Geneticist, based at the Vanderbilt-Ingram Cancer Center at the Vanderbilt University Medical Center in Nashville. “Back in 2013, the cost of testing just BRCA1 and BRCA2 would have been over $4,000, whereas today you can test for many cancer risk genes at the same time for a self-pay cost of $250.”

Yet, as germline testing has expanded beyond BRCA1/2, Pal warns that “testing itself does not improve outcomes; it is acting on the results of testing through follow-up care that has the potential to lead to better outcomes”. To realise the promise of gene testing for cancer risk, researchers need to learn more about the role of pathogenic variants in disease and develop more targeted strategies.

Identifying new inherited genomic predictors

Saud H. AlDubayan is a clinical geneticist and computational biologist at the Dana-Farber Cancer Institute in Boston. He splits his time between seeing patients who have a familial tendency to develop cancer, and doing research focused on identifying germline genetic determinants of cancer risk, response to treatment and disease progression.

Using computational and machine-learning approaches, AlDubayan’s team has been comparing whole exome sequencing data from a large number of patients who have cancer, with data from cancer-free individuals. They are finding gene variants that increase cancer risk or are associated with other attributes of clinical interest such as early onset or the development of multiple cancers. The presence of these variants can also influence the response to treatment.

“Pathogenic germline variants in certain DNA repair genes put individuals at a much higher risk of developing a whole array of cancers,” he says. “The silver lining, however, is that these patients may be more responsive to targeted therapies with fewer side effects, such as PARP inhibitors.”

In 2016, AlDubayan was part of a multicentre study demonstrating that the incidence of germline pathogenic variants in genes mediating DNA-repair processes among men with metastatic prostate cancer was significantly higher than the incidence among men with localized prostate cancer². “We found that germline pathogenic variants in BRCA2 conferred a 25-times higher risk of developing clinically and histologically aggressive disease,” he explains.

Based on these and other similar findings, a group including Gomella and Veda Giri, now at Yale Cancer Center, created the first multidisciplinary, consensus-driven guidelines regarding the evaluation, management and implementation of prostate cancer genetic testing⁵. Key recommendations, which have now been added to the National Comprehensive Cancer Network (NCNN) guidelines, include germline genetic testing all men with metastatic prostate cancer regardless of age of presentation and family history, as well as cascade testing to first- and second-degree relatives.

AlDubayan and colleagues have also identified germline ATM and CHEK2 variants that confer 3-5 times higher risk of developing colorectal cancer or testicular cancer, respectively^3,4. Interestingly, he adds, these variants have previously been associated with breast and pancreatic cancer risk, providing further evidence that germline pathogenic variants can increase the risk of multiple types of cancer, and supporting the use of pan-cancer profiling with NGS panels.

This is likely just the start. “We are far from done identifying genes associated with cancer,” AlDubayan says. To detect more pathogenic germline variants, he is developing and evaluating machine-learning approaches. A 2020 analysis of 2,367 germline exomes of patients with cancer consistently showed a higher molecular diagnostic yield for deep learning-based germline pathogenic variant analysis compared with standard genetic analysis methods⁶. “The higher sensitivity of the deep learning-based method will improve our ability to uncover novel gene–disease associations and likely shape multi-gene panel testing for hereditary cancer.”

Unlike the BRCA genes, which have very large effect sizes and a cumulative lifetime risk of breast cancer at age 70 of around 70%, many of the recently discovered genomic predictors of cancer risk have moderate effect sizes. “These variants are harder to find, yet they are clinically relevant and may lead to changes in care,” says AlDubayan.

The prospect of germline testing for all

As the cost of sequencing decreases and knowledge advances, there is an ongoing debate about whether multi-gene cancer panels should be used on broader populations, and what those populations might look like.

Gomella argues that genetic testing should only be performed when the result can inform treatment decisions or clinical trial eligibility. “There is a misunderstanding that all prostate cancer patients should be germline tested, but it is important to remember that 70-80% cases are sporadic, there is not necessarily an inherited component.”

Gomella is concerned about the rise of ‘self-service’ health care, whereby people use direct-to-consumer tests that focus on looking for a single pathogenic variant to self-assess their risk of cancer⁷. “Testing for just one particular mutation in the HOXB13 gene, one of several prostate cancer susceptibility genes, is unlikely to be helpful for most as it is extremely rare; this approach is no substitute for properly conducted evaluation and screening,” he says.

There is also the matter of resources and potential for overtreatment. “At present, it makes sense to focus on high-risk populations, given that three decades following the discovery of the BRCA genes, only a small fraction of the adult population that carries a BRCA mutation know about it,” says Pal. She emphasizes the need to ensure that resources are available to provide accurate interpretation of results and implement care according to current guidelines. “It is not appropriate to apply BRCA recommendations to carriers of moderate penetrance genes as this can lead to overtreatment and inappropriate care,” she says.

Although cascade testing of close relatives has been shown to be an efficient and cost-effective method for identifying individuals at high risk of hereditary non-polyposis colorectal cancer and hereditary breast and ovarian cancer syndrome, rates vary significantly^8,9. Uptake can be improved by addressing various ethical and social issues, such as privacy and protection of genomic data from being used against an individual’s insurance eligibility. “While the discovery of a pathogenic variant may inform screening approaches, there may also be unintended consequences in areas such as disability and life-insurance denials in the patient’s otherwise healthy relatives,” says Gomella.

Sharing positive test results with at-risk relatives is not always easy for patients. “Wanting to share, and being able to effectively communicate the information to family members so they are able to understand the importance of the results, are two different things,” says Pal. “As a health-care community, we should be developing tools to facilitate these conversations.”

Genetic counselling is one of the major tools. Since the profession was first established in the United States in 1969, the number of trained counsellors has grown to more than 7,000 worldwide¹⁰. Counsellors have a crucial role in supporting families with genetic conditions: they help patients understand the implications of their test results, and discuss options with them for cascade testing or additional testing¹¹. As advances in molecular medicine drive changes in testing guidelines to include more cancer patients in whom germline testing can be informative, AlDubayan suspects that the field is moving towards universal testing. “Testing all cancer patients could soon be justified as a cost-effective approach to improve cancer management,” he says.

More than a decade ago, Pal set up ICARE, a research registry for individuals interested in participating in studies focused on inherited cancer. Through this registry, research and clinical advances are regularly communicated to participants and providers. “As guidelines are updated, we inform our participants about changes that may be relevant to them or their family. We also contribute to the larger research mission through our own studies, and through collaborations with researchers worldwide — all with the goal of improving care and outcomes among individuals with inherited cancer predisposition,” she explains.

As inherited cancer risk calculations become more refined, reflecting the contribution of multiple genes and lifestyle risk factors, doctors will be able to implement more personalized preventive measures. Gomella reflects on the path ahead: “Our ability to potentially change the course of a disease that has not manifested, or that has no effective treatment, is a challenge that medicine and society will have to address as the technology evolves.”