Dr. Yang is a community oncologist who sees patients with a range of cancer types and indications. She often recommends tumor biomarker testing, or genomic tumor testing, for patients with advanced cancer in order to identify targeted treatment options. She orders the same test for these patients, a broad panel including several hundred genes from a lab she likes, and is comfortable with the ordering and counseling process.
What should Dr. Yang know about the strengths and limitations of this testing approach for different kinds of patients and cancer indications? 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. The three lessons below can help you optimize your biomarker testing practices to ensure you are ordering the best test for a particular patient, and interpreting results with an awareness of the test’s capabilities.
1. Specific biomarkers of interest sometimes require a different or additional test.
Sensitivity for specific biomarkers may vary. For example, tests that assess more genomic variants may be less sensitive for particular variants, especially those that are present at low levels. Structural variants, such as some gene fusions, may be better detected with methods other than DNA sequencing, such as RNA analysis, FISH (Fluorescence In Situ Hybridization) or IHC (immunohistochemistry).
Immune checkpoint inhibition biomarkers can help identify patients who may benefit from immunotherapy. These immunotherapy biomarkers, including PD-L1, tumor mutation burden (TMB) and microsatellite instability (MSI) often need to be ordered separately. PD-L1 testing uses a different test method - immunohistochemistry - from gene sequencing panels. For clinicians who frequently order a smaller gene panel, such as a hotspot panel, TMB may not be an option. This is because TMB calculations require sequencing a relatively large amount of genomic material, beyond what is assessed in some smaller panels or hotspot panels.
Given this variability in sensitivity for different types of biomarkers, if there is a particular biomarker that you want to assess, contact the laboratory. The lab will know for which biomarkers detection may be a challenge and can help determine the most appropriate test.
2. For difficult to biopsy cancers, the tumor genome can be assessed through a blood test.
Oncologists are well versed in the challenges with obtaining sufficient tumor tissue for genomic testing. For certain cancers, such as lung cancer, biopsies only provide a small amount of tissue, which may not be enough for genomic testing. In other cases, such as bone or brain metastasis, the tumor may be difficult to biopsy. Additionally, metastasis sites may have different genomic profiles, which creates a complicated decision-making path for biopsy, genomic testing, and analysis.
Liquid biopsy is a helpful tool in such situations, allowing for biomarker analysis of circulating tumor DNA obtained through a simple blood draw. Clinicians may also consider liquid biopsy to monitor disease progression and treatment resistance in some patients.
Biomarker testing done through liquid biopsy has benefits and limitations compared to that from solid tumor biopsy, and it can be useful to weigh these pros and cons in the context of the specific patient.
3. Genomic tumor tests may or may not report germline variants.
Clinicians and patients alike have questions about whether a genomic variant detected through tumor testing is present in the germline. Indeed, this is a critical distinction as germline variants have implications for future cancer risk and management options for the patient as well as family members. As previously discussed, biomarker tests vary in their methods and scope, and this variability also impacts how potential germline results should be interpreted.
Most biomarker testing assesses only tumor tissue. When a variant in a cancer susceptibility gene is reported, clinicians often consider the patient’s family history, the frequency of the variant in the sample (variant allele frequency) and association of the involved gene and cancer type in hereditary cancer to estimate the likelihood that the variant is germline. However, tumor only tests cannot definitively determine germline status. When the goals of testing require the assessment of the presence or absence of germline variants, ordering germline testing on a peripheral blood sample will provide the most accurate and complete information.
Paired tumor-germline testing (often called “tumor-normal” testing) is another testing approach. This testing approach requires the clinician to submit a peripheral blood sample in addition to the tumor sample. Here, the lab often filters out germline variants to report on those variants present uniquely in the tumor, which are assumed to be most relevant for treatment. Tumor-normal tests may also provide a germline report, or may not.
Choosing the best biomarker test can be complex, as there are many technical and patient factors to consider. While there are many similarities between available biomarker tests, sometimes a particular patient’s diagnosis and clinical context warrant further personalization of test selection.
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Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 2019; 20: 71–88.
Li MM, Chao E, Esplin ED, et al. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG) . Genet Med. 2020;22(7):1142-1148.
Meléndez B, Van Campenhout C, Rorive S et al. Methods of measurement for tumor mutational burden in tumor tissue. Transl Lung Cancer Res 2018;7(6):661-667.
Saarenheimo J, Eigeliene N, Andersen H, Tiirola M, Jekunen A. The Value of Liquid Biopsies for Guiding Therapy Decisions in Non-small Cell Lung Cancer . Front Oncol. 2019;9:129.
Tray N, Weber JS, and Adams S. Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application . Cancer Immunol Res. 2018; 6(1):1122-1128.
Walk EE, Yohe SL, Beckman A, et al. The Cancer Immunotherapy Biomarker Testing Landscape. Arch Pathol Lab Med. 2020; 144(6), 706–724.