Abstract
Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
Highlights
Cancer immunotherapy has revolutionized treatment across various tumor types, with its main focus on the therapy involving immune checkpoint inhibitors (ICI) such as antiPD-1, anti-PD-L1, and anti-CTLA-4
Patients with lower tumor mutation burden (TMB) had longer overall survival (OS) in some cancer types including non–small cell lung cancer (NSCLC) (P < 0.001), COAD (P 1⁄4 0.012), PRAD (P 1⁄4 0.012), and HNSC (P 1⁄4 0.006), BLCA (P 1⁄4 0.006) exhibited an association that was opposite, which indicated the existence of intertumor heterogeneity of TMB as a prognostic biomarker (Fig. 1A)
To demonstrate whether TMB and copy-number alteration (CNA) served as independent prognostic biomarkers or interacted with each other, we did multivariate analysis of clinical and genetic features associated with OS in eight cancer types of MSK pan-cancer non-ICI–treated cohort, and we found that TMB and CNA were independent as prognostic factors in the NSCLC cohort [TMB: hazard ratio (HR), 0.72; P 1⁄4 0.002 and CNA: HR, 0.78; P 1⁄4 0.034; respectively], BLCA cohort (TMB: HR, 2.16; P 1⁄4 0.002 and CNA: HR, 0.38; P 1⁄4 0.001; respectively), and prostate adenocarcinoma cohort (TMB: HR, 0.61; P 1⁄4 0.043 and CNA: HR, 0.22; P < 0.001; respectively; Supplementary Table S2)
Summary
Cancer immunotherapy has revolutionized treatment across various tumor types, with its main focus on the therapy involving immune checkpoint inhibitors (ICI) such as antiPD-1 (programmed death 1), anti-PD-L1 (the ligand of PD-1), and anti-CTLA-4 (cytotoxic T lymphocyte antigen 4; refs. 1–3). Cancer immunotherapy has revolutionized treatment across various tumor types, with its main focus on the therapy involving immune checkpoint inhibitors (ICI) such as antiPD-1 (programmed death 1), anti-PD-L1 (the ligand of PD-1), and anti-CTLA-4 Despite durable response and improved survival in a subset of patients, the objective response rate (ORR) was merely 20%–30% of the unselected patients with advanced stage diseases [4]. Substantial efforts have been put into identifying and developing effective predictive biomarkers, including IHC-based. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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