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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients
Stefano Mariani1, Marco Puzzoni1, Riccardo Giampieri2
1Azienda Ospedaliera Universitaria (AOU) Cagliari, University Hospital and University of Cagliari, Cagliari, Italy.
Background:
Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population.
Methods:
CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status.
Results:
A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, p = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, p = 0.013 and not reached vs. 3.0 months, HR: 0.20, p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, p = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, p = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, p = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS.
Conclusions:
Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.
Insights
Rechallenging colorectal cancer (CRC) patients with cetuximab, selected using liquid biopsy for RAS wild type (WT) status, shows effectiveness. A longer interval without prior anti-EGFR therapy is a key predictor of improved survival outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Rechallenge with epidermal growth factor receptor (EGFR) inhibitors offers a potential strategy for patients with RAS wild type (WT) colorectal cancer (CRC).
- RAS WT status determined via circulating tumor DNA (ct-DNA) is emerging as a critical selection criterion for this approach.
- This study investigates the efficacy of a liquid biopsy-guided cetuximab rechallenge in a carefully selected population of RAS and BRAF WT CRC patients.
Purpose of the Study:
- To evaluate the effectiveness of cetuximab rechallenge in colorectal cancer (CRC) patients selected using circulating tumor DNA (ct-DNA) for RAS and BRAF wild-type (WT) status.
- To identify predictive factors for improved outcomes in patients undergoing cetuximab rechallenge.
- To explore the role of liquid biopsy in guiding therapeutic decisions for CRC treatment.
Main Methods:
- Analysis of 26 colorectal cancer (CRC) patients with RAS and BRAF WT status in both tumor tissue and ct-DNA at baseline, who received cetuximab rechallenge.
- Utilized pyro-sequencing and nucleotide sequencing assays for ct-DNA analysis of RAS-BRAF mutations.
- Employed real-time PCR and droplet digital PCR to confirm RAS-BRAF mutational status.
Main Results:
- The overall response rate (RR) was 25.0%, with a median overall survival (mOS) of 5.0 months and a median progression-free survival (mPFS) of 3.5 months.
- A longer anti-EGFR free interval (>14 or >16 months) was significantly associated with improved mPFS and mOS.
- Previous response to anti-EGFR therapy and receiving more than two prior lines of treatment also correlated with improved survival outcomes.
Conclusions:
- Liquid biopsy-guided cetuximab rechallenge is an effective strategy for selected RAS WT colorectal cancer (CRC) patients.
- The duration of the anti-EGFR free interval is a significant predictive factor for patient outcomes.
- Combining ct-DNA analysis for RAS mutations with a prolonged anti-EGFR free interval can optimize patient selection for cetuximab rechallenge.
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