In Reply We have read the comment from Wood et al about our Viewpoint,1 and we share their concern about the hurdles that tumor mutation burden (TMB) presents for standard-of-care use in the clinical setting.
Wood et al pointed out that TMB should not be considered a predictor of overall survival (OS), but rather, should be considered as an indirect measure that correlates with immunotherapy response.2 In principle, we agree that we were not looking at the prognostic value of the TMB for OS in patients with cancer. However, TMB has been perceived as a potentially helpful biomarker for OS benefit in patients who go on to receive immune checkpoint inhibitor (ICI) therapy. To date, no evidence has shown TMB to be a biomarker for OS in patients treated with ICIs. Indeed, several aspects about TMB remain undefined: cutoff values, sources (tissue or circulating tumor DNA), panel harmonization, and prospective validation of OS benefit with a well-defined TMB cutoff in clinical trials. Notably, the value of programmed cell death ligand 1 (PD-L1) as a biomarker for OS has been demonstrated in a prospective trial of patients receiving ICIs, where the patient selection was prespecified3 and PD-L1 expression was a randomizing factor. Are we ever going to see a similar trial design using high TMB instead of PD-L1? Until we see prospective data demonstrating at least equivalence in performance compared with PD-L1 in predicting OS, the use of TMB in clinical decision making is questionable.
Identify all potential conflicts of interest that might be relevant to your comment.
Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.
Err on the side of full disclosure.
If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.
Not all submitted comments are published. Please see our commenting policy for details.
Addeo A, Banna GL, Weiss GJ. Tumor Mutation Burden—From Doubts to Concerns—In Reply. JAMA Oncol. 2019;5(12):1809. doi:10.1001/jamaoncol.2019.4141
Coronavirus Resource Center
Customize your JAMA Network experience by selecting one or more topics from the list below.