ideasIdea
A single calibrated tumour mutational burden across all sequencing panels
Tumour mutational burden decides who gets immunotherapy in some settings, but every sequencing panel calculates it differently. A shared calibration would make the number mean the same thing everywhere.
The Friends of Cancer Research TMB Harmonization Project showed that panel-derived TMB values can be aligned to whole-exome TMB with panel-specific calibration and reference samples. Yet the pembrolizumab approval for TMB above 10 mutations per megabase was tied to a single assay. Requiring each panel to report a calibrated TMB traceable to a common reference set, with published calibration curves, would make the biomarker portable across assays.
Hypothesis
Calibrated TMB reporting will reduce the inter-assay disagreement in classifying tumours as TMB-high from around 20 to 30% to under 10%.
Rationale
The harmonisation project has already provided the method and reference cell lines; adoption, not science, is the gap.
What would test it
Have ten commercial panels report calibrated TMB on a shared 100-sample set; measure classification agreement before and after calibration.
Maturity
early clinical
Who has to act
industry
Cost to try
Small (under $1M)
Years to first evidence
2
Bottlenecks it attacks
- Biomarkers are not validated or standardised · Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.
- No one can predict who responds to immunotherapy · Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.