Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Area of Science:

• Oncology
• Cancer Research
• Biomarker Discovery

Background:

• Tumour mutational burden (TMB) is a validated biomarker for predicting immunotherapy response across various cancers.
• The source of tissue used for TMB measurement (primary vs. metastatic) is often overlooked and can introduce systematic bias.
• Primary tumors exhibit greater heterogeneity and longer evolutionary history, while metastases often display a more monoclonal structure.

Purpose of the Study:

• To investigate the systematic differences in TMB measurements between primary and metastatic tumour tissues.
• To evaluate the concordance of TMB from different tissue sources in predicting patient outcomes during immune checkpoint inhibitor therapy.
• To highlight the clinical implications of tissue source selection for TMB-based treatment stratification.

Main Methods:

• Comparative analysis of TMB values derived from paired primary and metastatic tumour samples.
• Statistical evaluation using the paired Wilcoxon test to assess differences in TMB.
• Assessment of the predictive performance of primary and metastatic TMB for overall survival in patients receiving immune checkpoint inhibitors.

Main Results:

• A systematic bias was observed, with metastatic TMB being significantly higher than primary TMB (36% higher, P = 0.0008).
• Despite the difference in TMB values, both primary and metastatic TMB demonstrated equivalent effectiveness in predicting overall survival.
• Borderline primary TMB values may lead to different treatment stratification if metastatic TMB is considered.

Conclusions:

• The source of tissue significantly impacts TMB measurements, with metastases yielding higher values.
• TMB from both primary and metastatic sites are equally effective predictors of overall survival in immunotherapy.
• Standardized tissue annotation or paired tissue analysis is crucial for accurate TMB interpretation and clinical implementation.