Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival

Abstract

Background: Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. Methods: Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. Results: We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. Conclusions: We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.

Significance of Tumor Mutation Burden in Immune Infiltration and Prognosis in Cutaneous Melanoma

“…Patients in the high-TMB group had significantly better survival outcomes. In previous studies, even without immunotherapy, higher TMB represented a better prognosis from adjuvant chemotherapy in patients with colorectal cancer and resected non-small-cell lung cancer (60,61), but the correlation was not significant in melanoma (62). Besides, our research found that older patients and male patients have higher TMB levels, which is consistent with the significant trend of TMB increasing with age, with a 2.4-fold difference between age 90 and age 10 years (63).…”

Is tumor mutational burden predictive of response to immunotherapy?

“…Consistent with published studies 6,20,21,24,27 , we find ( Figure 1A and Figure S1 ) that only the melanoma datasets (mel1 and mel2) and non-small cell lung cancer datasets (lung1 and lung2) yield a significant difference in TMB between responders and nonresponders (p=8.3×10 −6 and p=7.7×10 −3 for lung1 and lung2, p=2.6×10 −2 and p=4.1×10 −2 for mel1 and mel2, Mann-Whitney U test). Two of the three other cancer types analyzed – clear cell Renal Cell Carcinoma (ccRCC) and Head and Neck Squamous Cell Carcinoma (HNSCC) – showed no trend or an unexpected inverse one between TMB and response, although the association was non-significant ( Figure 1A ).…”

“…However, this paradigm is largely based on a series of early papers that examined response in melanoma and lung cancer that we show here to be potentially confounded by tumour subtype. Several recent studies have also reported poor association of TMB with response for specific cancer types, and highlighted TMB and its expression/presentation-based derivatives as problematic for clinical cohort classification 27 . In particular for melanoma, recent analyses 24 A recent ICB clinical trial that used FDA-approved TMB threshold (KEYNOTE-158) 44 has focused on rare cancers, excluding melanoma and lung cancer.…”

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

“…It is worth noting that TMB does not always correlate with ICI responsiveness and its applicability should be considered with caution due to important limitations as a predictive biomarker, especially when used in isolation. Major challenges for TMB utility and its limitations have been reported and critically discussed in excellent recent studies and review articles [ 29 , 37 , 38 , 39 , 40 ]. A composite predictor that also includes other critical variables, such as PD-L1 IHC, immune-related mutational and epigenetic landscapes as well as gene expression signatures, MHC and T cell receptor repertoire, clonality of neoantigens and tumor heterogeneity, is urgently needed [ 33 , 38 ].…”