This scenario is more complicated than it may seem. With genomic tumor testing, a negative result is not always definitive. In some cases a genomic variant can be present but not detected by the specific testing platform. Tests vary significantly and have different limitations, which impacts how results can and should be used for making treatment decisions. In this case, when trying to determine whether a patient is an appropriate candidate for treatment with a PARP inhibitor, the clinician needs to determine whether the test ordered assessed everything needed to answer that question. For example, consider the following:
- PARP inhibitor treatment is an option for breast cancer patients with either a germline or somatic pathogenic variant in BRCA1 or BRCA2. Determine if the test assessed genomic variants in normal cells (germline variants) as well as in tumor cells. If not, further germline testing might be appropriate as some germline variants can be missed in tumor-only testing.
- Low tumor content may affect the lab’s ability to detect variants in certain genes. Check if there were concerns with the sample.
As with any complex process, it helps to have a person with expertise in the subject responsible for facilitating these steps. The clinical navigator is an integral part of the oncology team in many practices, assisting with care coordination and patient education. Now, as large-scale genomic tumor testing has become more common, a new clinical role has emerged – the genomic navigator. Currently, the tasks related to genomic tumor testing are being accomplished by any number of existing clinical staff, including oncology nurses and nurse navigators, who may be learning these new skills on the job. To better understand the tasks and challenges in the role, I talked with Lindsey Kelley, a genomic navigator recently hired by the Maine Genomics Cancer Initiative, an initiative at The Jackson Laboratory to help make precision medicine available and relevant for cancer patients throughout Maine.
The role of a genomics navigator
Lindsey comes to this role from the MaineHealth healthcare system where she was a cancer genetic counselor, helping patients understand and navigate risk and genetic testing for hereditary cancer syndromes. While the roles and responsibilities of a genomic navigator are evolving, Lindsey describes the big picture.
“The ultimate goal of genomic tumor testing is to connect patients with the best therapies for their particular cancer, based on the genomic makeup of the cancer. This can sometimes be straight-forward, but often it is not.”
As a genomic navigator, she hopes to help “facilitate the process of ordering genomic tumor tests, interpreting the results of those tests, and then connecting patients to genomic-informed therapies.” Lindsey will be working closely with oncology practices in the state of Maine, providing support and/or resources they might need in this process.
Choosing the “best” test
Lindsey and I discussed a part of the process that may be often overlooked, identifying the most appropriate test to order for a patient’s situation. As Lindsey explained, “Genomic testing labs may use a number of different technologies and methods to collect, analyze and interpret tumor biomarkers. Like all tests, each approach has certain strengths and limitations.”
Going back to the initial scenario, the oncologist ordered genomic tumor testing to assess whether Jemma might benefit from a PARP inhibitor. The results did not clearly answer her question. Let’s take a minute to discuss the impact of the initial test choice on the next steps and the opportunity for a genomic navigator to facilitate that process.
For background, PARP inhibition therapy (PARPi) targets tumors that have a DNA repair deficiency (e.g., pathogenic variant in BRCA1/2). By disabling the PARP mechanism for DNA repair, treatment further compromises the cell and leads to increased cell death. In advanced breast cancer, certain PARP inhibitors are approved for use when there is a germline or somatic change in the BRCA1 or BRCA2 genes. The use of PARPi treatments in cancers with other DNA repair deficiencies (e.g., pathogenic variants in ATM or CHEK2) are currently under investigation. In Jemma’s case, since the oncologist’s primary question was whether she might benefit from PARPi, testing that assesses for both somatic and germline variants in all of the DNA repair genes would be the best option.
Determining when additional testing is needed or, ideally, the most appropriate test to order initially is one of the areas where a genomic navigator can help. The genomic tumor testing landscape is diverse and dynamic, and it is difficult to keep up. Available tests differ in terms of the type of cells they assess (i.e., cancer, non-cancer), which genes they test, and the type of genomic variants they can detect (e.g., single nucleotide variants, large deletions, fusions). In discussing how to navigate the different testing options, Lindsey put it this way: “The ‘best test’ for a patient will vary based on the pathology of their cancer, the availability of tissue-based tumor sample, their insurance coverage, and their ability to participate in clinical trials.”
More often than not, which test is ordered is determined by the provider’s familiarity with a particular lab and their process, as opposed to assessing the many testing options available for each patient. This means that the oncologist needs to understand the limitations of the test under consideration for a particular clinical question and be able to determine whether a different or additional test is needed. Lindsey spoke to this saying that “knowing a test’s limitations is the best way to ensure a test result has truly covered the possible genomic variants for a particular cancer.”
Testing limitations oncologists should recognize
Lindsey went on to highlight some of the limitations that are most important for oncology providers to recognize. The first is detection of germline variants, which can impact treatment options, such as in Jemma’s case, as well as risk for future cancers and cancer risk for close relatives. Not all tests are designed to differentiate between germline and somatic variants (i.e., tumor only testing). Tests that assess both tumor and non-tumor samples (tumor-normal or paired somatic-germline testing) are not all are the same. “[Even] if a provider orders a test that states it will report on germline findings, germline testing may still be indicated when there is a negative result. Some tests have the ability to report on germline findings but may not assess all relevant germline genes or variants.”
The second scenario Lindsey discussed was the detection of fusions, some of which have associated targeted treatments. Because fusions are more readily detected by assessing RNA and not DNA, “if the test is DNA-based, it is possible it will miss fusions that would have been identified using an RNA-based test.” Given that there are a number of targeted treatments associated with fusions, knowing whether or not the test ordered can detect fusions is important.
Finally, Lindsey brought up the use of liquid biopsy, where tumor cells are isolated and assessed from a blood sample. While liquid biopsy has some advantages over tumor-based testing, including its non-invasive nature, interpreting a negative result can be challenging. “If a provider receives a negative test result on a liquid biopsy, they should know that it is possible there was not sufficient tumor DNA in the sample, and it should be followed up with a tissue-based tumor test if possible.” Fortunately, Lindsey and other genomics navigators have the training to understand how tests differ and, importantly, the impact of those differences on the interpretation of results which ultimately affect decisions about treatment options.
Navigating options for obtaining genome-informed treatments
Of course, choosing the best test and recognizing limitations of the test for a specific patient is just one of the steps involved in providing genome-informed cancer care. The main goal of genomic tumor testing is to determine whether a patient is eligible for a targeted treatment. If more than one targeted treatment is identified, then the oncologist has to determine which option to prioritize. In some places, including Maine, clinicians have access to genomic (or molecular) tumor boards, during which experts discuss results from genomic tumor tests and provide their thoughts about the state of the evidence and expert opinion about how to sequence treatment options.
Obtaining targeted treatment, though, can also be complicated. Most targeted treatments are still being studied to determine effectiveness in different cancer types. They may only be accessible to patients through off-label use or clinical trials. As Lindsey described it, “the process of connecting patients to therapies through clinical trials or ‘expanded access’ programs can often be daunting and time-consuming for clinicians, and this is where a genomic navigator can provide support to facilitate this process.”
In Maine, Lindsey will be working with cancer practices to determine how she can best support their processes of accessing treatments. We look forward to speaking with her again to see how her role develops and the opportunities and challenges navigating genome-informed treatments brings.
“Precision cancer care is an evolving science, and I anticipate that my role will have to grow as the field does. There may be new opportunities for this technology, or new research and new types of therapies that may develop over time, and I will have to stay up to date with all of the new changes in the field so that I can best support oncology practices in Maine.” Lindsey’s experiences in Maine are likely to parallel other clinicians navigating these processes. Hopefully together the collective experience can help inform practices in ways to provide the best genomic care to cancer patients.
- Three things to know about genomic tumor test selection (JAX blog)
- Choosing the best genomic tumor test (JAX online module – free CME/CNE)
- Precision oncology resources (JAX resources)
- Chen HZ, Bonneville R, Roychowdhury S. Implementing precision cancer medicine in the genomic era. Semin Cancer Biol. 2019 Apr;55:16-27.
- Fountzilas E, Tsimberidou AM. Overview of precision oncology trials: challenges and opportunities. Expert Rev Clin Pharmacol. 2018;11(8):797–804.
- Reed EK, Steinmark L, Seibert DC, Edelman E. Somatic Testing: Implications for Targeted Treatment. Semin Oncol Nurs. 2019; 35(1):22-33.