Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.
Bottom Line: The presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics.Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design.
The presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics. Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design.
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Mentions: Patients from the UK-based TRACERx multi-region sequencing longitudinal observational study of NSCLC who relapse with locally advanced or metastatic disease will be eligible for the Deciphering Anti-tumor Response and evolution With INtratumour heterogeneity (DARWIN) clinical trials program (Figure 4). Patients will be allocated into molecularly stratified subgroups at the time of relapse with the a priori knowledge of the clonal frequency of the driver event at the time of surgery and at relapse, the latter being provided by analysis of a repeat biopsy of the metastatic site and by cfDNA and CTC analysis. These analyses will help to determine whether targeting clonally dominant drivers improves progression-free survival and how subclonal driver events impact upon disease progression and drug resistance. In the future, knowledge of dominant and subclonal drivers and resistance mechanisms may allow more optimal treatment allocation. WES will also allow assessment of the protein-coding mutational burden and the potential neo-antigenic repertoire of each tumor. This information can then be correlated to the response to immunotherapy of those without an actionable mutation for which there is an approved precision medicine.Figure 4