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Circulating tumor DNA driving anti-EGFR rechallenge therapy in metastatic colorectal cancer: the RASINTRO prospective
Aziz Zaanan1,2, Elisabeth Sophie Bergen1,3, Ludovic Evesque4
1Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris (APHP), University of Paris Cité, Paris, France.
Background:
In RAS wild-type (WT) metastatic colorectal cancer (mCRC), preliminary data have suggested that circulating tumor DNA (ctDNA) may select patients for anti-EGFR rechallenge therapy.
Methods:
RASINTRO is a prospective nonrandomized study evaluating anti-EGFR rechallenge strategy in third and later line treatment in RAS/BRAF WT mCRC. Liquid biopsies for ctDNA analysis were collected before the first (C1) and second (C2) cycles of anti-EGFR rechallenge therapy. The primary endpoint was the progression-free survival (PFS) according to RAS/BRAF mutational status on ctDNA at C1.
Results:
Among 74 patients screened between November 2017 and March 2020, 62 were enrolled: median age, 66.1 years; median number of previous lines of therapy, 3; panitumumab or cetuximab rechallenge alone (66.2%) or with chemotherapy (33.8%); ctDNA RAS/BRAF status at C1, 42 WT (67.7%) and 20 mutated (32.3%). Median PFS (3.3 vs 1.9 months: hazard ratio (HR) = 0.43; P <.01) and overall survival (OS) (7.9 vs 4.9 months; HR = 0.46; P =.01) were significantly longer for patients with ctDNA RAS/BRAF WT vs mutated at C1. Among the 32 patients with ctDNA RAS/BRAF WT at C1 and available blood samples at C2, those who have experienced an early decrease of >50% in ctDNA concentration (n = 15) had a significantly longer median PFS (4.2 vs 2.8 months; HR = 0.39; P =.01) and OS (10.2 vs 4.2 months; HR = 0.39; P =.02).
Conclusion:
This study showed that anti-EGFR rechallenge therapy in refractory disease is more effective in patients with RAS/BRAF WT on ctDNA, and in those who experienced an early decrease of >50% in ctDNA concentration.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03259009.
Insights
Circulating tumor DNA (ctDNA) RAS/BRAF wild-type status predicts better outcomes for anti-EGFR rechallenge therapy in metastatic colorectal cancer. Early ctDNA concentration decrease further improves progression-free and overall survival.
Area of Science:
- Oncology
- Molecular Diagnostics
- Cancer Therapeutics
Background:
- Metastatic colorectal cancer (mCRC) treatment often involves anti-EGFR therapy.
- RAS/BRAF wild-type (WT) status is crucial for anti-EGFR efficacy.
- Circulating tumor DNA (ctDNA) analysis shows potential for patient selection in anti-EGFR rechallenge therapy.
Purpose of the Study:
- To evaluate the efficacy of anti-EGFR rechallenge therapy based on ctDNA RAS/BRAF mutational status.
- To assess the impact of early ctDNA concentration changes on treatment outcomes in mCRC patients.
Main Methods:
- Prospective nonrandomized RASINTRO study in third/later-line mCRC.
- ctDNA analysis from liquid biopsies at cycles 1 (C1) and 2 (C2) of anti-EGFR rechallenge.
- Primary endpoint: Progression-free survival (PFS) based on ctDNA RAS/BRAF status at C1.
Main Results:
- 62 patients enrolled; 67.7% had ctDNA RAS/BRAF WT at C1.
- ctDNA RAS/BRAF WT at C1 correlated with significantly longer PFS (3.3 vs 1.9 months) and OS (7.9 vs 4.9 months).
- Patients with >50% ctDNA decrease by C2 showed improved PFS (4.2 vs 2.8 months) and OS (10.2 vs 4.2 months).
Conclusions:
- Anti-EGFR rechallenge is more effective in refractory mCRC patients with RAS/BRAF WT ctDNA.
- An early decrease (>50%) in ctDNA concentration is associated with superior PFS and OS.
- ctDNA analysis is a valuable tool for guiding anti-EGFR rechallenge therapy decisions.
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