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Tumor Mutational Burden: A Valuable Addition to the Pathologist's Toolbox

We picture pathologists behind the scenes, facing a microscope in a lab rather than a patient in a clinic. Although most patients may never even meet one, there may be no specialist more important to ensuring that the cancer treatment team delivers an effective regimen.

For generations, pathologists’ keen eyes and deep knowledge have been valuable sources of information for understanding a tumor. And today, pathologists have access to genomic information as well, making their role more up-front than ever. As we gain insight into how certain genomic alterations relate to treatment response, pathologists have had to become just as adept at interpreting genomic mutations as they are at identifying rare types of cancer.

Discovering More

Now, with innovations like targeted therapies and immunotherapies, genomics has become more vital than ever to understanding cancer. This topic will be front and center at this year’s College of American Pathologists (CAP) annual meeting, particularly as it relates to the immune checkpoint revolution in cancer treatment.

Certain markers have been identified which may correlate to treatment response. For example, PD-L1 expression level is currently being tested in a number of clinical trials as a marker to help predict responses to checkpoint inhibitor cancer immunotherapies.1 But just how useful this marker is still remains unclear. Several different assay types exist, and each has its own definition of PD-L1 positivity.2 Indeed, pathologists may disagree on which test is more accurate. Furthermore, PD-L1 is dynamically expressed on multiple types of cells, including immune cells as well as tumor cells.3 Together, these factors make it complicated to rely on PD-L1 as a predictive biomarker.

Predictability Quantified

Tumor mutational burden (TMB) has emerged more recently as a quantitative marker that can help predict potential responses to immunotherapies across different cancers, including melanoma, lung cancer and bladder cancer.4,5,6 TMB is defined as the total number of mutations per coding area of a tumor genome. Importantly, TMB is consistently reproducible. It provides a quantitative measure that can be used to better inform treatment decisions, such as selection of targeted or immunotherapies or enrollment in clinical trials. You can learn more about TMB in our infographic here.

TMB is now included in the FoundationOne® comprehensive genomic profiling (CGP) test. Unlike hotspot testing, the FoundationOne® test uses massively parallel DNA sequencing to probe the entire coding sequence of the 300+ genes currently known to be altered in solid tumors. The comprehensive nature of this test also offers a practical option for molecular testing. It requires only a small tissue sample (8-10 slides) that can be taken from a previous biopsy while still providing results across a wide spectrum of genomic cancer drivers.

The addition of TMB to the FoundationOne® test represents a unique and important advance in our ability to navigate the emerging science of cancer immunotherapy. By adding this clinical marker that has a well-established relationship to treatment response.4,5,6 FoundationOne® can help pathologists unlock the full potential of precision medicine for cancer treatment.

Notes
  1. Rebelatto M, Mistry A, Sabalos C, et al. Development of a PD-L1 companion diagnostic assay for treatment with MEDI4736 in NSCLC and SCCHN patients [ASCO abstract 8033]. J Clin Oncol. 2015;33(suppl).
  2. Kerr et al. Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art? Journal of Thoracic Oncology. 2015;10(7):985-989.
  3. Hansen AR and Siu L. PD-L1 testing in cancer. JAMA Oncology. 2016;2(1):15-16.
  4. Rizvi et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
  5. Rosenberg et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
  6. Snyder et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. New England Journal of Medicine. 2014;371:2189-2199.
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