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On September 13, 2018, Friends of Cancer Research (Friends) reconvened the TMB Harmonization Working Group, which consists of several stakeholders across all health sectors. Building from previous workshops hosted by Friends in the Fall of 2017 and the Spring of 2018, working group members:
- Reviewed the findings of the first phase of the TMB Harmonization Project, which assessed variability in TMB estimates in-silico using publicly available data from The Cancer Genome Atlas (TCGA), and;
- Formally launched the second phase of the Project, which seeks to promote the alignment of TMB estimates through the creation of a universal reference standard using human tumor cell lines.
Project Background
The TMB Harmonization Project focuses on three components that would benefit from standardization: defining TMB, establishing an analytical validation approach, and ensuring optimal clinical implementation. It was agreed that to achieve these goals a multi-step approach was necessary, where diagnostic companies would seek agreement on analytical and clinical validation studies to support a standardized method of TMB measurement and reporting. The three phases consist of an in silico TMB analysis using publicly available data from TCGA, an empirical TMB analysis using publicly available human tumor cell lines, and a clinical analysis using clinical samples.
Meeting Summary
Eleven diagnostic partners (ACT Genomics Co., Ltd, AstraZeneca, Caris Life Sciences, Foundation Medicine, Inc., Guardant Health, Inc., Illumina, Inc., Memorial Sloan Kettering Cancer Center [MSKCC], NeoGenomics Laboratories, Inc., Personal Genome Diagnostics [PGDx], QIAGEN, Inc., Thermo Fisher Scientific) analyzed in silico data to assess the correlation between TMB calculated using whole exome sequencing (WES) and a uniform analytical method agreed upon the diagnostic participants, and TMB calculated using their own gene panels and methodologies. All participants used the same data for this analysis (the Multi-Center Mutation Calling Multi-tumor Completion effort, or MC3 TCGA data), which consisted of thousands of samples from various cancer types. The goal of this initial step of the project was, for the first time, to compare how the bioinformatic approaches impact TMB calculations and how closely the different tests relates to one another.
The results showed that TMB determined by the different tests is relatively consistent across a range of mutational burden, and that despite the various methods employed to analyze and count mutations, the in silico analysis results demonstrated that TMB as evaluated by the eleven diagnostic partners is in a close enough range that further alignment is achievable. Moreover, TMB by cancer type was also analyzed, and differences were observed in the distribution of TMB values by cancer type. It was suggested that some of these differences may be attributed to biology, however, other factors such as batch effects needed to be explored in more detail.
Based on this initial analysis, several suggestions were proposed that would improve the analytical validation of this novel biomarker. The final in silico TMB data will be used for the development of a manuscript to be submitted for publication at a peer-reviewed journal and a late-breaking abstract oral presentation to take place at the Society for Immunotherapies in Cancer (SITC) Annual Meeting in November of 2018.
Launch of Phase Two of the TMB Harmonization Project
In the second phase of the project cell line samples will be used with the aims of finding agreement upon the creation of a universal TMB reference standard based on WES and assessing the correlation between panel-derived TMB score and the universal reference standard. From these initial analyses, a set of cell lines with high concordance across panels can be selected to serve as future reference materials.
An initial group of 14 matched tumor/normal cancer cell line samples that harbor a range of TMB values will be evaluated to define a universal reference standard. The team has selected commercially available matched lung and breast cancer cell lines for which preliminary analysis reveals a broad range of TMB values. The TMB values of these cancer cell lines will be calculated using WES and a uniform analytical method as agreed upon by the diagnostic partners. The growth and maintenance of these cell lines, as well as the isolation of DNA will be performed by our collaborators at SeraCare Life Sciences. Inc. The Molecular Characterization (MoCha) Laboratories at the Frederick National Laboratories who will serve as the neutral, credentialed, and validated central laboratory that will conduct the WES of the cell lines and calculate TMB using a uniform method previously agreed by the partners. Panel developers will also calculate TMB using their own panels and bioinformatic methods.
The WES-derived TMB values will be optimized as a reference standard. The reference standard will be used as an alignment tool to make TMB values calculated using different gene panels comparable to one another, thus providing consistency during TMB reporting.
Next Steps
Data from phase 2 is expected to be generated and analyzed during winter 2018-2019. PrecisionFDA, a cloud-based next-generation DNA sequencing data platform that allows researchers to upload and compare data against reference genomes, will be utilized to store the data generated from phase 2 and will streamline the analyses.
Working group members discussed the need to validate the utility of cell lines serving as a reference standard and the desire to analyze a representative number of clinical samples to verify that results from the cell lines correlated with the cell line samples. Additionally, the clinical implications of the TMB harmonization effort were further assessed and the implications of clinical cut-off values and patient outcomes to explore in phase 3.
For more information on our the project itself, please click HERE.
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