Tumor mutational burden
Also known as TMB
Tumor mutational burden (TMB) is a biomarker that measures the total number of mutations that a patient has across their tumor's genome. When a patient has their tumor sequenced, their TMB value can typically be calculated from their sequencing results. Metastatic prostate cancer patients who have a high TMB value may be eligible to take immune checkpoint inhibitors, such as Pembrolizumab.
How is TMB measured?
TMB is an estimate of the number of mutations that a tumor has in each "megabase" (Mb) of the tumor's genome. A "Megabase" is a distance of 100,000 bases (the letters A, C, G, T) in a genome. As a reference, the human genome has approximately 3 billion bases, or 3,000Mb (Sergey Aganezov et al, 2022).
To do a "gold standard" measurement of TMB, we take both "normal" (non-cancerous tissue, typically blood) and tumor tissue from a patient, and perform exome sequencing. Exome sequencing includes all of the genes in a human that are used to create proteins. We then count the mutations that are present only in the tumor (and not in the patient's "normal" sample).
Interpreting TMB measurements requires care. The Friend's of Cancer Research created a TMB harmonization project to understand why TMB results are different across clinical tests (D M Vega et al, 2021). The TMB harmonization project identified several reasons that TMB measurements varied:
- How many genes were included? Many clinical sequencing tests cover a limited number of genes, instead of covering all of the genes in the human exome. Some "liquid biopsy" tests cover fewer than 100 genes, while tests that use tumor tissue from a surgical biopsy typically include 400-700 genes. In general, panels that cover more genes will be more accurate.
- Did all providers count variants the same way? Clinical testing providers use different definitions of which variants to count. In their study of 16 clinical tests, they found that 7 of 16 (44%) of clinical tests did not count "synonymous" mutations. The remaining 9 of 16 (56%) of clinical tests did include "synonymous" mutations in their TMB measurement. A "synonymous" mutation is a mutation that changes the DNA for a gene, but not the protein.
- Did the test include a "normal" sample? Some clinical sequencing tests do not have a "normal" sample. To calculate TMB, these tests will typically remove mutations that have been seen in genomic databases that do not study cancer. Since all humans have some genomic variants that are unique to them (All of Us Research Program Genomics Investigators, 2024), tests that lack a "normal" sample will overestimate TMB. This problem particularly impacts non-White patients, as many historical genomic databases underrepresent non-White individuals.
Once a TMB number has been calculated, TMB is typically divided into "low" and "high" categories. When approving TMB as a biomarker for Pembrolizumab, the FDA set the TMB-high threshold at >10 mutations per megabase (mut/Mb). This threshold was set assuming that patients received the FoundationOneCDx test. Because clinical tests can vary, if you are using your TMB measurement to make a treatment decision, you should work with your oncologist to make sure you are using the right TMB values.
What are typical TMB values for prostate cancer patients?
The majority of prostate cancer patients have a low TMB value. Numerous real world studies have estimated that 5-10% of prostate cancer patients will have high TMB.
| When was the study published? | What data did it use? | How many patients were included? | What % of patients were TMB-H? | What % of TMB-H patients were MSI-H? | References |
|---|---|---|---|---|---|
| 2019 | FoundationOne | 3,476 advanced prostate cancer patients | 3.3% | 71.2% | Jon H. Chung et al, 2019 |
| 2022 | FoundationOne | 741 mCRPC patients, who took a checkpoint inhibitor or taxane chemotherapy and had measured TMB | 44 of 741 (5.9%) | 20 of 44 (45%) | Ryon P. Graf et al, 2022 |
| 2022 | Exome sequencing | 100 mCRPC patients in an English cancer center | 14% | MSI status was not measured | María Dolores Fenor de la Maza et al, 2022 |
How does TMB impact my treatment options?
For a patient with metastatic castration resistant prostate cancer, getting your TMB tested may give you additional treatment options. Patients who are TMB-high may be eligible to take Pembrolizumab.
References
- Sergey Aganezov, Stephanie M. Yan, Daniela C. Soto, Melanie Kirsche, Samantha Zarate, Pavel Avdeyev, Dylan J. Taylor, Kishwar Shafin, Alaina Shumate, Chunlin Xiao, Justin Wagner, Jennifer McDaniel, Nathan D. Olson, Michael E. G. Sauria, Mitchell R. Vollger, Arang Rhie, Melissa Meredith, Skylar Martin, Joyce Lee, Sergey Koren, Jeffrey A. Rosenfeld, Benedict Paten, Ryan Layer, Chen-Shan Chin, Fritz J. Sedlazeck, Nancy F. Hansen, Danny E. Miller, Adam M. Phillippy, Karen H. Miga, Rajiv C. McCoy, Megan Y. Dennis, Justin M. Zook, Michael C. Schatz. (2022) 'A complete reference genome improves analysis of human genetic variation', Science.
See article at PubMed Central See article at publisher's site - D M Vega, L M Yee, L M McShane, P M Williams, L Chen, T Vilimas, D Fabrizio, V Funari, J Newberg, L K Bruce, S-J Chen 6, J Baden, J Carl Barrett, P Beer, M Butler, J-H Cheng, J Conroy, D Cyanam, K Eyring, E Garcia, G Green, V R Gregersen, M D Hellmann, L A Keefer, L Lasiter, A J Lazar, M-C Li, L E MacConaill, K Meier, H Mellert, S Pabla, A Pallavajjalla, G Pestano, R Salgado, R Samara, E S Sokol, P Stafford, J Budczies, A Stenzinger, W Tom, K C Valkenburg, X Z Wang, V Weigman, M Xie, Q Xie, A Zehir, C Zhao, Y Zhao, M D Stewart, J Allen, TMB Consortium. (2021) 'Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project', Annals of Oncology.
See abstract at PubMed Central See article at publisher's site - All of Us Research Program Genomics Investigators. (2024) 'Genomic data in the All of Us Research Program', Nature.
See article at PubMed Central See article at publisher's site - Jon H. Chung, Ninad Dewal, Ethan Sokol, Paul Mathew, Robert Whitehead, Sherri Z. Millis, Garrett M. Frampton, Gennady Bratslavsky, Sumanta K. Pal, Richard J. Lee, Andrea Necchi, Jeffrey P. Gregg, Primo Lara, Emmanuel S. Antonarakis, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Neeraj Agarwal. (2019) 'Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors', JCO Precision Oncology.
See article at PubMed Central See article at publisher's site - Ryon P. Graf, Virginia Fisher, Janick Weberpals, Ole Gjoerup, Marni B. Tierno, Richard S. P. Huang, Nicolas Sayegh, Douglas I. Lin, Kira Raskina, Alexa B. Schrock, Eric Severson, James F. Haberberger, Jeffrey S. Ross, James Creeden, Mia A. Levy, Brian M. Alexander, Geoffrey R. Oxnard, Neeraj Agarwal. (2022) 'Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer', JAMA Network Open.
See article at PubMed Central See article at publisher's site - María Dolores Fenor de la Maza, Khobe Chandran, Jan Rekowski, Irene M Shui, Bora Gurel, Emily Cross, Suzanne Carreira, Wei Yuan, Daniel Westaby, Susana Miranda, Ana Ferreira, George Seed, Mateus Crespo, Ines Figueiredo, Claudia Bertan, Veronica Gil, Ruth Riisnaes, Adam Sharp, Daniel Nava Rodrigues, Pasquale Rescigno, Nina Tunariu, Xiao Qiao Liu, Razvan Cristescu, Charles Schloss, Christina Yap, Johann S de Bono. (2022) 'Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer', European Urology Oncology.
See abstract at PubMed Central See article at publisher's site