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January 16, 2017

The Promise of Tumor Mutational Burden for Cancer Immunotherapy

Quantitative Biomarkers Could Be the Next Step for Precision Oncology

The Promise of Tumor Mutational Burden for Cancer Immunotherapy

Tumor mutational burden (TMB) is the total number of mutations per coding area of a tumor genome.

  • Sixty years ago, chemotherapy revolutionized cancer treatment. It gave physicians their first new weapon to treat cancer since the discovery of radiation therapy in the early 1900s, and was a tangible means to control and even stop tumor growth.

    Such transformative breakthroughs in cancer care are few and far between. But inarguably, we are finding ourselves in the midst of one now.

    The ability to use a patient’s own immune system to fight malignancy is truly the next big innovation in cancer treatment. The approach is having an impact across a range of cancers that were once considered largely untreatable. But the field of cancer immunotherapy is still relatively young, and new advances in precision medicine are poised to increase its impact even further by identifying potential biomarkers of response.

    These biomarkers can often be as important as the therapies they guide, because they can help to match patients with the right treatment. However, some biomarkers have limitations based on the way they are measured and analyzed. A new, more quantitative biomarker called tumor mutational burden (TMB) could be the answer for immunotherapies. 

  • New Questions

    Checkpoint inhibitor immunotherapies that target the PD-1 and PD-L1 proteins have undoubtedly changed the treatment paradigm for a variety of cancers, including lung cancer, melanoma, and bladder cancer. In certain studies, 20–40 % of people who receive these therapies show durable responses, often remarkable ones.1 And in some cases, immunotherapy is becoming the first-line standard of care.

    But with this landscape change comes a bevy of new questions, including whom to give these powerful new therapies in order to help ensure that these treatments deliver the most benefit to the most people— while also saving time, alleviating costs, and helping to address potential disappointment. The time to answer them is now.

  • Enter TMB

    One way to do this is with biomarkers and, for cancer immunotherapy, PD-L1 protein expression is one of the most thoroughly studied. But even from the beginning, it was clear that developing biomarkers for checkpoint inhibitor immunotherapies would be challenging.

    The challenge primarily lies in the technology used to measure the biomarker and the dynamic nature of PD-L1 protein expression levels. Detecting protein-based biomarkers, such as PD-L1, commonly requires immunohistochemistry (IHC) staining, which is by nature qualitative and can even depend on human judgment to estimate the intensity of the signal. Combined with the variability of PD-L1 protein expression levels, the differences in antibodies used to score expression levels and the slightly different methods performed by different labs, the degree of variability in using this method can be high.

    It was this inherent variability that drove the need for a more reliable, quantitative, genomic-based solution, and therefore to the discovery of TMB.

    TMB is a new clinical marker that predicts responses to immunotherapy in a range of advanced cancers.2,3,4 Unlike protein-based biomarkers, TMB is a quantitative measure of the total number of mutations per coding area of a tumor genome. Tumors that have higher levels of TMB are believed to express more neoantigens – a type of cancer-specific antigen – that may allow for a more robust immune response and therefore a more durable response to immunotherapy.2,3

    The concept of TMB was born several years ago by leading academic groups that were using whole-exome sequencing to count somatic mutations in checkpoint inhibitor clinical trial cohorts. Their goal was to see if there was a meaningful difference in the number of mutations in patients who responded to immunotherapies compared to those who didn't.2 The underlying theory motivating their research was that by giving patients a checkpoint inhibitor therapy, you’re not just treating the tumor, you’re also treating the immune system. Since the immune system relies on a sufficient number of neoantigens in order to appropriately respond, the number of somatic mutations was in effect acting as a proxy for determining the number of neoantigens per tumor.

    Comprehensive genomic profiling tests that can accurately measure TMB without the need for whole-exome sequencing are now available. There is a growing body of clinical research demonstrating the potential benefits of TMB as a diagnostic marker in terms of accuracy, sensitivity and reproducibility. Most importantly, it provides a quantitative measure that can be used to better inform treatment decisions.

  • TMB in Action

    There is an urgency to identify patients most likely to respond to checkpoint inhibitor therapies and improve access to clinical trials. In a recent case involving a young woman in her 30s with colorectal cancer, this need couldn’t have been more apparent. Although a comprehensive genomic profiling test revealed no actionable genomic alterations for targeted therapies, she did exhibit high TMB. Based on this result, her physician administered checkpoint inhibitor therapy, to which she has experienced a rapid and significant response.

    However, for each success, there may be countless patients not even considered for a potentially lifesaving immunotherapy treatment because their TMB levels are unknown. Adding TMB to oncologists’ arsenal of information could make the difference for those patients most in need of immunotherapies.

    It is important to consider that TMB is not going to be a universal solution. I believe a multi-pronged approach that combines TMB with protein or gene expression information will ultimately have improved utility over either biomarker on its own. But in the current landscape, TMB is an essential tool that can help physicians maximize the benefits of the latest innovation in cancer care.

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