ctc tumor heterogeneity

Quantifying tumor heterogeneity can elucidate resistance to targeted therapy despite markers of sensitivity. 

 

The heterogeneity of cancer has long been recognized by differences in cell morphology in a tumor and that the disease is rarely completely eliminated with any systemic therapy.  Observations on the differences in cell morphology and now further understanding of single cell genomic profiling has identified that spatial heterogeneity exists at three levels.

  • Level 1- Inter-tumor heterogeneity: Different tumors in a patient unique genomic, protein and morphologic profiles
  • Level 2- Intra-tumor heterogeneity: A branched evolution can occur within the same tumor, where on part of the tumor may have an evolved and unique genomic, protein and morphologic profiles
  • Level 3- Inter cellular heterogeneity: Single tumor cells adjacent to each other in a tumor lesion can harbor unique genomic, protein and morphologic profiles

Given the complexity of heterogeneity, the least common denominator to understanding tumor heterogeneity is the single tumor cell.

 

 

METHODOLOGY:

Profile single circulating tumor cells with PhenoGenomic™ profiling:

  • CTC genomics
    • Clonality assessment
    • Genomic Instability measures
    • Oncogenes & Tumor Suppressors
  • CTC protein profiling:
    • Driver proteins (hormone receptors)
    • Epitheial proteins (Cytokeratins)
  • CTC morphologic profiling
    • Size, shape, texture measures

 

 

tUMOR HETEROGENEITY APPLIED:

CTC heterogeneity was hypothesized as a resistance measure to AR Signaling inhibitors (ARSi) and an assumption that patients with high CTC heterogeneity would have improved outcomes utilizing broad based taxane chemotherapies.  Indeed CTC heterogeneity demonstrated a therapy interaction as a continuous biomarker of differential therapeutic response in clinical decision making in metastatic prostate cancer.  With increasing CTC heterogeneity providing increasing risk of shorten OS with patients treated by ARSi relative to taxane chemotherapy. 

Full publication here

Additionally, single CTC subytpes with unique genomic profiles have been identified providing insights into potential resistance mechanism and signaling within phenogenomic profiling

See the poster here

 

 

IMPLICATION:

CTC heterogeneity now is a vital tool to assess in a clinical trial setting to understand why some patients may not respond to a targeted therapy which targets a driver alteration within a patients tumor.  Questions to understanding CTC heterogeneity longitudinally to understand how tumors evolve during therapy.  Additionally, understanding specific cell type sensitivity to therapies in context to single or combination clinical trials.