Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine

Abstract

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.

Figure 1

Evolution of three tumors. The left panel shows the evolutionary history of each tumor, the middle panel represents a snapshot of the tumor at a given time, and the right panel shows the potential future development. Tumor A shows a linear evolution pattern; tumors B and C display a branched pattern. Single snapshots of Tumors B and C may suggest that they have identical evolutionary processes, but their past and future evolution actually follow different patterns.

Figure 2

Somatic aberrations in cancer cell populations. The DNA copy number and number of mutant alleles (red stars) within single cancer cells can be difficult to discern when looking at a whole population of cancer cells. Samples 1-3 on average each have three copies of a particular chromosome, and a variant allele frequency of 0.33, but the collection of cancer cells in each population are vastly different. Single-cell sequencing may be required to elucidate the underlying population structure.

Figure 3

Timing of mutations. The number of copies of a mutation can shed light on when it occurred. A mutation that is acquired before a chromosome doubling event will be present on multiple chromosome copies, whereas a mutation acquired after the doubling event will be present on only one chromosome copy.

Figure 4

Schematic overview of the Tracking Non-small Cell Lung Cancer Evolution Through Therapy (TRACERx) observational cohort study and how this is linked with the Deciphering Anti-tumour Response and evolution With INtratumour heterogeneity (DARWIN) trials program. Multi-region sampling with ultra-deep 500x coverage whole-exome sequencing (WES) will be used to characterize tumor heterogeneity. Tumor heterogeneity and clonal dynamics may affect the response to precision drugs. Only patients from the TRACERx observational study will be eligible for a DARWIN trial. Therefore, in comparison to other molecularly stratified studies TRACERx & DARWIN provide a unique opportunity to study the affect of intratumour heterogeneity and clonal architecture on patient outcome. The effect of tumor heterogeneity and mutational burden on anti-tumor immunity will also be assessed through an immunotherapy arm. Bx, biopsy; CTC, circulating tumor cell; cfDNA, cell free DNA; IMT, immunotherapy; ITH, intertumor heterogeneity; NSCLC, non-small cell lung cancer; PrM, precision medicine; SOC, standard of care.