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December 17, 2020

Tumor Mutation Burden and Cancer Treatment

Author Affiliations
  • 1Department of Individualized Cancer Medicine, Moffitt Cancer Center, Tampa, Florida
  • 2Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
JAMA Oncol. 2021;7(2):316. doi:10.1001/jamaoncol.2020.6371

What Is Tumor Mutation Burden?

The goal of cancer treatment is to kill cancer cells while not hurting the body’s healthy cells. One way this is done is by using a drug to target a specific genetic change (also referred to as a mutation) in the cancer cells that is not seen in healthy cells. Historically, many of these mutations have been associated with an aggressive biology and sometimes resistance to cancer treatments, such as chemotherapy. But with immunotherapy, which is treatment given to stimulate or remove inhibition of the immune system to help combat a cancer, a higher number of mutations in a tumor can also be associated with a greater probability of response to treatment. This is because the immune system has a better opportunity to attack the cancer effectively if it can recognize it, and the body’s immune system may better identify cancer cells that have a higher number of mutations.

Here, the number of mutations is like lottery tickets. Although buying a large number of lottery tickets does not mean you will always have a winning ticket, it increases the chance of winning compared with only buying 1 or 2 tickets. Similarly, if a tumor has many different mutations, the odds are greater that the immune system will be able to recognize at least 1 of these mutations and kill the cancer (win the lottery). The number of mutations in a tumor cell is commonly referred to as the tumor mutation burden (TMB) of the cancer.

Measuring TMB

  • The TMB can be measured by a laboratory test that uses next-generation sequencing of tumor tissue, which looks broadly for a wide range of mutations.

  • Although not as established as measuring TMB from a biopsy sample of tumor tissue, studies are now evaluating measuring TMB from circulating tumor DNA in the plasma, making it potentially possible to test TMB from blood in the future.

  • The TMB is reported as the number of mutations seen in a section of DNA and reported as mutations per megabase (mut/Mb).

  • Cancers with a TMB of 10 mut/Mb or greater (called TMB-high) may be more likely to respond to drugs called immune checkpoint inhibitors that help activate the immune system to better recognize cancer cells.

Current Role of TMB in Cancer Therapy

The TMB can be helpful in predicting response to immune checkpoint inhibitor treatment across many cancer types. However, it may be a better predictor for some cancers and not as helpful for others. Clinical trials are being conducted now to understand which cancers with high TMB respond best to drugs that help turn on the immune system. The immune checkpoint inhibitor pembrolizumab is approved for treating both adults and children with advanced cancers that have a high TMB (defined as ≥10 mut/Mb) after other drugs have been tried.

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Article Information

Published Online: December 17, 2020. doi:10.1001/jamaoncol.2020.6371

Conflict of Interest Disclosures: Dr Walko reported serving as a molecular tumor board consultant for Intermountain Healthcare Molecular Tumor Board Consultant and Jackson Laboratories Molecular Tumor Board Consultant outside the submitted work. No other disclosures were reported.

1 Comment for this article
Problems and prospects in TMB-based cancer genomic medicine in Japan
takuma hayashi, MBBS, DMedSci., GMRC, PhD | National Hospital Organization Kyoto Medical Center
In addition to PD-L1 expression, various clinical factors are currently being investigated as predictors of the effectiveness of immune checkpoint inhibition. Tumor gene mutation burden (TMB) is the approximate amount of gene mutation that occurs in the genome of a cancer cell.
Originally, in mammalian cells including humans, a "gene repair system" that removes gene mutations is provided. However, cells with many TMBs have abnormalities in this repair system and are thought to be easily transformed into cancer cells (1,2).
In addition, cancer cells with many TMBs are thought to produce many mutant proteins that are recognized as foreign products
by the self-immune system (3). Therefore, TMB has been established as an independent predictive biomarker for immune checkpoint inhibitors.
In the cases of tumor gene mutation burden-high (TMB-High), it has been observed high anti-tumor effect by immune checkpoint inhibitors (4,5).

On June 17, 2020, the US Food and Drug Administration (FDA) approved pembrolizumab (product name: Keytruda) monotherapy for unresectable or metastatic solid tumors with tumor gene mutation burden-high (TMB-High). In addition, on June 26, 2020, the FDA approved Foundation One CDx (Foundation Medicine, Inc.) as a companion diagnostic for pembrolizumab.

According to the guidelines of the Japanese Ministry of Health, Labor and Welfare, immune checkpoint inhibitors such as Nivolumab, Atezolizumab, and Pembrolizumab are recommended for patients with TMB-High (cutoff value of 10 or higher) from the results of the cancer genome test by NCC Oncopanel or Fundation One CDx, which are covered by insurance as a cancer genome test.

In Japan, medical treatments (total 576 cases) by cancer genome test (129 cases by NCC Oncopanel, 447 cases by Fundation One CDx) were performed at a national university hospital in 2020. Six of the 129 cases by NCC Oncopanel were diagnosed with TMB-High. However, close examination of the results of the cancer genome test revealed that 3 cases were erroneously diagnosed as TMB-High due to contamination of the sample. Of the 447 cases with Fundation One CDx, 19 were diagnosed with TMB-High. Only 4 cases were diagnosed with TMB-High 20 or higher.

Japan Ministry of Health, Labor and Welfare of has stated the following points as future issues.

1. In TMB, 10/MB is the cutoff value. However, is this 10/MB appropriate as a cutoff value to judge as TMB-High?
2. As a problem of quality control of samples, there is a concern about DNA fragmentation due to long-term storage of samples. As a problem with the sample collection site, there is concern about DNA fragmentation due to radiation therapy (RT).

Many patients with advanced refractory cancer with MSI-High are given the option of being treated with immunotherapy. It is important to improve the problems that have been recognized in the conventional cancer genome testing and medical treatment. In the future, if it becomes cheaper and the need for tissue collection and pathological tissue becomes less, the cancer genome test is likely to be more accessible for many cancer patients.

Disclosure of potential conflicts of interest
The authors declare no potential conflicts of interest.

We thank all the medical staffs and co-medical staffs for providing and helping medical research at National Hospital Organization Kyoto Medical Center.

1.Genome Med. 9(1): 34, 2017. 2.Cell. 171(5): 1042-1056, 2017. 3.Cancer Cell Int. 19: 2020. 4.J Clin Oncol 36(7): 633-641, 2018. 5.N Engl J Med 378(22): 2093-2104, 2018.