Understanding Biomarker Testing: Types, Benefits & Limitations

Summary: This resource defines and compares benefits and limitations of types of biomarker testing including somatic testing (via tissue and liquid biopsy), paired somatic-germline testing, and genetic testing for inherited cancer risk. 

By JAX Clinical Education | October 2025 

There are different types of tests available to assess cancer biomarkers and identify potential treatment targets. It is important to understand the strengths and limitations of each test to appropriately interpret the results. Note that multiple commercial testing companies and academic laboratories offer these tests, and each may have different limitations than discussed here. 

Test Types

Somatic Testing assesses biomarkers in cancer cells, using either tumor tissue (solid tumor testing) or blood (liquid biopsy testing) to guide treatment decisions. 

• Liquid Biopsy Testing – The blood sample contains a mix of cancer cells, circulating tumor DNA, and DNA from non-cancer cells. This makes it possible to assess many but not all biomarkers. 

• Solid Tumor Testing – The tumor tissue allows for additional biomarker testing since some methods (e.g., IHC) can only be performed on tissue. 

Paired Somatic-Germline Testing (also called tumor-normal testing) assesses biomarkers in both cancer cells and non-cancer cells. This approach filters out inherited (germline) variants and focus on variants that originated in the cancer (somatic) to more accurately guide treatment decisions.  

Though germline variants are assessed, these tests are not typically clinically validated for assessing inherited cancer risk. 

Genetic Testing for Inherited Cancer Risk (also called germline testing) assesses non-cancer cells. It is optimized and clinically validated to detect germline variants associated with increased cancer risk.  

Concurrent Somatic + Germline Testing occurs when somatic testing and genetic testing for inherited cancer risk are ordered at the same time but performed as independent tests. The germline testing is performed and reported separately from the somatic testing results and are typically not used to filter the somatic results.  

Benefits and Limitations

Somatic vs. Germline Variant Assessment 

Genomic variants in cancer cells can be acquired during carcinogenesis (somatic), or they could have been present prior to carcinogenesis and seen in all body cells (germline). Knowing whether a variant is somatic or germline can impact whether a targeted treatment is suitable for a patient. Somatic variants are more likely to be driving cancer growth and, therefore, are the best targets for treatment. Less commonly, germline variants drive cancer growth and can be targeted therapeutically, such as germline variants in BRCA1/2.  

• Somatic testing generally cannot determine if a variant is somatic or germline. Somatic testing only assesses cancer cells, and cancer cells contain both germline and somatic variants. Labs use existing databases and bioinformatics to identify potential germline variants, but this is not a validated germline assay.  
• Paired somatic-germline testing can determine if a variant is somatic or germline. Non-cancer cells are analyzed to identify germline variants, and the germline results are filtered from the somatic results.  
• Concurrent somatic + germline testing includes a comprehensive and clinically validated assessment of germline variants. However, the germline testing is reported separately from the somatic testing results and is typically not used to filter the somatic results. 

Cost 

The cost of testing is affected by the amount of testing being performed. 

• Somatic testing is less expensive because it assesses a single sample. 
• Paired somatic-germline testing is more expensive because it assesses cancer cells and non-cancer cells using both tumor and blood samples.  
• Concurrent somatic + germline testing is typically the most expensive because it adds genetic testing for inherited cancer risk to the test(s) performed to assess for somatic variants. 

Most insurance companies cover biomarker testing and genetic testing for inherited cancer risk when clinical criteria are met. 

Assessment of Inherited Cancer Risk 

Identifying germline variants provides the opportunity to assess a patient’s risk for hereditary cancer, which can have implications for their treatment for current cancer, future cancer risk and their relatives’ cancer risk.  

• Somatic testing is not designed to differentiate between somatic and germline variants. As such, genetic testing for inherited cancer risk may be warranted when somatic results, personal history, or family history raise concern for an inherited predisposition, or when knowing about a germline variant could guide treatment (e.g., use of PARP inhibitors). 
• Paired somatic-germline testing uses germline testing to help identify variants unique to cancer cells. However, this should not be considered a comprehensive hereditary cancer risk assessment. Typically, fewer genes are tested, and certain variant types (e.g., large deletions and duplications) may not be detected. A negative germline result lowers the likelihood of a germline variant but does not rule it out. 
• Concurrent somatic + germline testing includes a comprehensive and clinically validated assessment of germline variants. 

Learn More

Liquid Biopsy FAQ. Describes the benefits, risks and limitations of liquid biopsy.

Comparing Cancer Biomarker Tests. Provides information about how cancer biomarker test offerings may differ among laboratories.

Indications for Genetic Testing for Inherited Cancer Risk After Biomarker Testing. Provides a quick reference about the factors to consider when determining the appropriateness of genetic testing for inherited cancer risk.

Exploring Cancer Biomarker Testing (CME|CNE). Learn about benefits, limitations, and challenges of using cancer biomarker testing.

Choosing the Best Genomic Tumor Test. Learn about the benefits and limitations of different genomic tumor test options for patients with cancer and how to determine the best test for each patient.

Interpreting Cancer Biomarker Testing – When is Additional Testing Needed? (CME|CNE). Learn when additional cancer biomarker testing is indicated for further evaluation of genome-informed therapy.

References

Clark DF, Maxwell KN, Powers J, et al. Identification and Confirmation of Potentially Actionable Germline Mutations in Tumor-Only Genomic Sequencing. JCO PrecisOncol. 2019;3:OI,19,00076.

De Mattos-Arruda L, Siravegna G. How to use liquid biopsies to treat patients with cancer. ESMO Open. 2021 Apr;6(2)

DeLeonardis K, Hogan L, Cannistra SA, Rangachari D & Tung NJ. When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing? J Oncol Pract. 2019;15(9):465-473.

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.

Mandelker D, Donoghue M, Talukdar S, et al. Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group. Ann Oncol. 2019;30(8):1221-1231.

Mandelker D, Zhang L, Kemel Y et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017;318(9):825-835.

Reed EK, Steinmark L, Seibert DC, Edelman E. Somatic Testing: Implications for Targeted Treatment. Semin Oncol Nurs. 2019; 35(1):22-33.

Disclaimer
All information in this resource is provided for educational purposes only.