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Updated: Jul 22, 2025
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
The emergence of RAS mutations in patients with RAS wild-type mCRC receiving cetuximab as first-line treatment: a
Hsiang-Lin Tsai1,2, Chun-Chi Lin3,4, Yung-Chung Sung5,6
1Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Absrtact:
BACKGROUND: Patients treated with anti-epidermal growth factor receptor (anti-EGFR) will ultimately develop acquired resistance promoted by clonal selection, mainly the emergence of mutations in the MAPK pathway (mostly RAS mutations). Baseline assessment of RAS mutations in the blood of patients correlates well with RAS tumour tissue testing and is currently an alternative option in routine clinical practice to guide first-line therapy. The aim of this study was the prevalence of acquired genomic alterations detected in the auxiliary tool of ctDNA testing and investigated the role of RAS ctDNA status for detecting tumour response and predicting benefit to anti-EGFR therapy.
Methods:
Only patients with concordant wild-type formalin-fixed, paraffin-embedded (FFPE) tumour tissue and baseline ctDNA RAS wild-type were included. RAS mutations in plasma were evaluated using MassARRAY platform. Blood samples were collected at baseline, every 3 months during first-line treatment, and at disease progression. The primary endpoint was the detection rate of RAS mutations during cetuximab treatment. The correlation between response and survival outcomes and the emergence of circulating RAS mutations was also analysed.
Results:
The detection rate of RAS mutations during treatment was 9.3% (10/108). RAS mutations detection occurred a median of 3 months prior to radiologic documentation. The subgroup of patients with RAS mutations exhibited significantly inferior progression-free survival and overall survival (P = 0.002 and 0.027, respectively) but the baseline characteristics, response rates, disease control rates, and metastatectomy were not significant (all P > 0.05).
Conclusions:
We demonstrated that RAS ctDNA status might be a valuable biomarker for detecting early tumour response and predicting benefit to anti-EGFR therapy.
Clinical Trial Registration:
NCT03401957 (January 17, 2018).
Insights
Acquired resistance to anti-EGFR therapy is often driven by RAS mutations. Detecting RAS mutations in circulating tumor DNA (ctDNA) can predict treatment response and survival outcomes in patients receiving anti-EGFR therapy.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anti-epidermal growth factor receptor (anti-EGFR) therapy resistance is a significant clinical challenge.
- Acquired resistance is frequently driven by mutations in the MAPK pathway, particularly RAS mutations.
- Baseline RAS mutation assessment in blood (ctDNA) is a validated alternative to tumor tissue testing for guiding therapy.
Purpose of the Study:
- To determine the prevalence of acquired genomic alterations using circulating tumor DNA (ctDNA) testing.
- To investigate the role of RAS ctDNA status in predicting tumor response and benefit from anti-EGFR therapy.
Main Methods:
- Patients with wild-type tumor tissue and baseline ctDNA RAS were included.
- RAS mutations in plasma were analyzed using the MassARRAY platform.
- Blood samples were collected serially to monitor RAS mutation emergence during treatment.
Main Results:
- RAS mutations were detected in 9.3% of patients during treatment, a median of 3 months before radiographic evidence.
- Emergence of RAS mutations was associated with significantly worse progression-free survival and overall survival.
- No significant differences were observed in baseline characteristics, response rates, or disease control rates.
Conclusions:
- RAS ctDNA status is a valuable biomarker for early detection of tumor response.
- RAS ctDNA analysis can predict patient benefit from anti-EGFR therapy.
- Monitoring ctDNA for RAS mutations offers insights into resistance mechanisms and treatment outcomes.
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