Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer

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.

• Detection rate of targetable resistance alterations [Time frame: Baseline to disease progression (approximately 12 months)]
• Detection rate of non-genomic resistance mechanisms [Time frame: Baseline to disease progression (approximately 12 months)]
• Comparison of resistance alterations in tissue versus liquid biopsies [Time frame: Baseline to disease progression (approximately 12 months)]
• Establishment rate of patient-derived organoids (PDOs) [Time frame: From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample)]
• Longitudinal dynamics of circulating tumor DNA (ctDNA) [Time frame: Baseline, every 8 to 12 weeks during treatment, and at disease progression (up to approximately 24 months)]
• Compositional characterization of the gut microbiome [Time frame: Baseline and at disease progression (approximately 12 months)]