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

Hiley C, de Bruin EC, McGranahan N, Swanton C - Genome Biol. (2014)

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.

View Article: PubMed Central - PubMed

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.

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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.
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Fig4: 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.

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 (FigureĀ 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


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

Hiley C, de Bruin EC, McGranahan N, Swanton C - Genome Biol. (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4281956&req=5

Fig4: 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.
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 (FigureĀ 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

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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus