BRAF V600E Mutation, Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer, mCRC, BRAF V600E, Targeted therapy resistance, Encorafenib, Cetuximab, EGFR inhibition, BRAF inhibition, Liquid biopsy, Precision oncology, Patient-derived organoids, Circulating tumor DNA, ctDNA, Microbiome, Comprehensive genomic profiling, SCI/SAKK
Brief summary
This study prospectively investigates the molecular mechanisms of primary and acquired resistance to standard-of-care BRAF V600E-directed therapy in patients with metastatic colorectal cancer and aims to pre-clinically develop novel strategies to reverse therapy resistance. Clinically approved combination treatment with cetuximab, encorafenib and chemotherapy improves patient outcomes, yet patients eventually experience disease progression. In this prospective multicenter study, tumor tissue, blood, and stool samples will be collected before treatment and at progression, to identify genetic and non-genetic mechanisms of resistance. Additionally, tumor tissue-based in vitro models (patient-derived organoids, PDOs) will be generated and exploited for functional in vitro testing, including genomic and pharmacologic perturbation studies. The overarching goal is to generate knowledge that can help develop new and more effective treatment strategies for future patients.
Detailed description
BRAF V600E-mutated metastatic colorectal cancer accounts for about 8-10% of cases and is an aggressive disease with poor prognosis and limited treatment options. The current standard treatment for patients is the combination of the BRAF inhibitor encorafenib and the anti-EGFR antibody cetuximab, together with FOLFOX or FOLFIRI chemotherapy in 1st line systemic treatment, which improves survival and response rates compared to chemotherapy alone. However, nearly all patients eventually develop resistance to this treatment, and there are no well-established therapies after progression. Resistance develops through complex and often multiple mechanisms, including genetic changes in signaling pathways such as MAPK and receptor tyrosine kinases, as well as non-genomic factors such as changes in gene expression, the tumor microenvironment, and potentially the microbiome. These mechanisms are not yet fully understood, especially in combination and over time during treatment. This study, PARTACER-Suisse, is a prospective multicenter investigator-initiated study in patients with BRAF V600E-mutated metastatic colorectal cancer receiving standard treatment with encorafenib and cetuximab, with or without concomitant chemotherapy. The study is conducted across a federated network of Swiss oncology centers organized under the Swiss Cancer Center/Swiss Group for Clinical Cancer Research (SCI/SAKK), with a central translational research backbone at the University Hospital Zurich. The aim is to better understand how resistance develops by analyzing tumor samples, blood samples, and stool samples collected before treatment and at disease progression. Blood samples will be used to study circulating tumor DNA over time, and stool samples will allow analysis of the microbiome. Tumor tissue will undergo detailed molecular analyses to identify genetic and non-genetic changes associated with resistance. In addition, tumor samples will be used to generate patient-derived organoids, which are laboratory models that allow functional testing of tumor behavior and response to treatment. By combining molecular analyses with functional experiments, the study aims to identify key resistance mechanisms and explore new treatment strategies that could prevent or overcome resistance. Overall, this study is expected to provide a more complete understanding of resistance to combined BRAF and EGFR inhibition in this patient population and to support the development of improved and more personalized treatment approaches for the future.
Interventions
OTHERLongitudinal translational sampling
Longitudinal translational sampling (tumor tissue, plasma ctDNA, stool, PBMCs).
Sponsors
Swiss Cancer Institute
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of unresectable or metastatic BRAF V600E-mutated colorectal cancer * Planned initiation of treatment with combined anti-EGFR antibody and BRAF inhibitor * Patients receiving treatment in any line, with or without chemotherapy * At least one tumor lesion accessible for biopsy * ECOG performance status 0-2 * Life expectancy of at least 3 months * Age ≥18 years * Ability to provide written informed consent
Exclusion criteria
* Medical or surgical contraindication for tumor biopsy * Active second malignancy (except non-melanoma skin cancer) * Inability to comply with study procedures (e.g., due to language barriers or cognitive impairment) * Pregnancy or breastfeeding * Previous treatment with a BRAF inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Detection rate of molecular alterations associated with acquired resistance | from baseline (pre-treatment) to disease progression (approximately 12 months) | Proportion of patients with detectable molecular alterations associated with acquired resistance to combined BRAF and EGFR inhibition, identified in tumor tissue collected before treatment and at disease progression using molecular profiling. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Detection rate of targetable resistance alterations | Baseline to disease progression (approximately 12 months) | Proportion of patients with acquired resistance alterations that are potentially targetable by available or investigational therapies, identified through molecular profiling of tissue and liquid biopsy samples. |
| Detection rate of non-genomic resistance mechanisms | Baseline to disease progression (approximately 12 months) | Proportion of patients with non-genomic mechanisms of resistance, including transcriptomic changes and tumor microenvironment alterations, identified through molecular analyses. |
| Comparison of resistance alterations in tissue versus liquid biopsies | Baseline to disease progression (approximately 12 months) | Concordance and detection rates of resistance-associated molecular alterations in matched tumor tissue and circulating tumor DNA samples. |
| Establishment rate of patient-derived organoids (PDOs) | From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample) | Proportion of collected tumor biopsies (baseline and progression) from which patient-derived organoid cultures are successfully established for downstream functional analyses. |
| Longitudinal dynamics of circulating tumor DNA (ctDNA) | Baseline, every 8 to 12 weeks during treatment, and at disease progression (up to approximately 24 months) | Quantitative changes in plasma ctDNA tumor fraction and variant allele frequencies of mutations from baseline through on-treatment time points to progression, and their association with radiological response and resistance evolution. |
| Compositional characterization of the gut microbiome | Baseline and at disease progression (approximately 12 months) | Compositional and functional features of the gut microbiome at baseline and at disease progression, and their association with treatment response and resistance. |
Countries
Switzerland
Contacts
CONTACTKrista Zackel
STUDY_CHAIRRalph Fritsch, MD
University of Zurich
Outcome results
None listed