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Updated: May 1, 2026
Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
Published on: August 24, 2017
Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing
Sumitra Mohan1, Ellen Heitzer1, Peter Ulz1
1Institute of Human Genetics, Medical University of Graz, Graz, Austria.
Abstract:
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as KRAS, BRAF, PIK3CA, and EGFR. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of KRAS in four patients (40%), which occurred either as novel focal amplifications (n = 3) or as high level polysomy of 12p (n = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as MET (n = 2) and ERBB2 (n = 1). Overrepresentation of the EGFR gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of KRAS, BRAF, PIK3CA, and EGFR did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
Insights
Acquired KRAS gene gains, not mutations, drive resistance to Epidermal Growth Factor Receptor (EGFR) therapies in metastatic colorectal cancer (CRC). Plasma sequencing (plasma-Seq) detects these changes, aiding early therapy adjustments to prevent disease progression.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are crucial for metastatic colorectal cancer (CRC) treatment.
- Resistance to anti-EGFR therapies is common, yet mechanisms and timing remain poorly understood.
Purpose of the Study:
- To investigate the mechanisms and timing of resistance evolution in patients with metastatic colorectal cancer treated with anti-EGFR therapy.
- To identify novel biomarkers predictive of anti-EGFR therapy efficacy and resistance.
Main Methods:
- Whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of resistance-associated genes (KRAS, BRAF, PIK3CA, EGFR) were performed on plasma DNA from ten CRC patients.
- Analysis focused on identifying genetic alterations associated with acquired resistance to anti-EGFR therapies.
Main Results:
- Acquired KRAS gains (focal amplifications or 12p polysomy) were observed in 40% of patients, associated with resistance.
- Focal amplifications of MET (2 patients) and ERBB2 (1 patient) were also identified as resistance mechanisms.
- EGFR gene overrepresentation correlated with initial treatment efficacy, and predictive biomarkers were identified in 70% of patients.
- No novel acquired mutations in KRAS, BRAF, PIK3CA, or EGFR were detected by deep sequencing.
Conclusions:
- Acquired KRAS gains, rather than mutations, are a significant mechanism of resistance to anti-EGFR therapy in CRC.
- Plasma-Seq is a powerful tool for detecting novel resistance mechanisms and identifying predictive biomarkers.
- Early detection of resistance mechanisms via plasma-Seq can facilitate timely therapeutic adjustments to improve patient outcomes.
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