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. 2019 Nov 18;11(11):1809. doi: 10.3390/cancers11111809

Table 4.

Dynamic emergence of tumor heterogeneity and metastasis: clinical implication of intra-patient heterogeneity.

Patients (Samples) Technology Findings and Potential Clinical Implications Ref.
100 (Matched PT and plasma samples after anti-EGFR) BEAMing, tNGS Resistant circulating mutations were detected (KRAS, NRAS, MET, ERBB2, FLT3, EGFR, MAP2K1), while treatment cessation led to re-emergence of sensitivity [78]
83 diverse advanced cancers (14 CRC, Static PT and ctDNA) tNGS, ctDNA-tNGS 30% of pts achieved disease control and targeting of more drug targets correlated with significantly favorable clinical outcomes, supporting individualized drug combinations NCT02534675
[20]
47 (archived PT, double MT samples at baseline, PR and progression and serial plasma samples) tNGS, cfDNA-tNGS

  • 50% of tumor RAS-WT patients harbor RAS mutations in baseline cfDNA

  • Dynamic tissue and liquid biopsies could predict primary and acquired cetuximab resistance and progression

 NCT02994888
[17]
33 (Serial liquid biopsies over HER2 blockade and diverse PT and MT samples) WES, ctDNA-tNGS ERBB2, RAS and PIK3CA mutations correlated to HER2-targeted therapy resistance and liquid biopsies identified primary resistance with >85% sensitivity, suggesting utility for decision-making [79]
22 (archived and post-progression tissue after anti-EGFR and static ctDNA) tNGS RAS mutations and HER2/MET amplification were the most prominent mechanisms of resistance in both tissue and ctDNA, suggesting utility for decision-making [80]
12 (Matched PT, MT and plasma samples) tNGS Limited concordance between ctDNA and PT/MT was identified, suggesting the need for refinement [81]
7 (diverse tumor samples over anti-EGFR, matched ctDNA, mouse xenografts) WES, WGS, CNA, BEAMing MET amplifications within rare pre-existing subclones confer resistance in KRAS-WT tumors during anti-EGFR therapy [82]

Abbreviations: beads-emulsion-amplification-magnetics (BEAMing), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), colorectal cancer (CRC), copy-number alteration (CNA), metastatic tumor (MT), next-generation sequencing (NGS), partial response (PR), patients (pts), primary tumor (PT), targeted NGS (tNGS), whole-exome sequencing (WES), whole-genome sequencing (WGS), wild-type (WT).