336 Chapter 14 evaluated in metastatic tumors. Most research on BRAF mutation has been performed in case of metastatic CRC, and its therapeutic approach is complex due to their resistance to conventional therapies 81. The treatment landscape for BRAF metastatic CRC has rapidly evolved in recent years, with efforts focused on combining therapies to improve outcomes 82. Despite initial hopes based on outcomes in BRAF-mutant melanoma, monotherapy with BRAF inhibitors (iBRAF) has shown lower efficacy in metastatic CRC 81-84. While the addition of anti-vascular endothelial growth factor (anti-VEGF) therapy to standard chemotherapy has shown limited benefit, combining BRAF inhibitors with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies has emerged as a promising approach 81, 85. Ongoing research must still explore the role of triplet combinations with MEK or PIK3CA inhibitor, but also the wide variance in tumor response rates 82, 86, 87. Transcriptomic signatures suggest potential responsiveness to immune checkpoint inhibitors, leading to ongoing investigations into combination therapies 82, 88. Acquired resistance mechanisms pose challenges, with liquid biopsies offering a noninvasive means to identify and address resistance 82. Ongoing studies are exploring novel combinations with BRAF inhibitors to overcome acquired resistance, underscoring the importance of continued research into BRAF-V600E-mutant biology to enhance patient care 81, 82. With survival rates about half as long as those of BRAF wild-type patients 85, urgent exploration of new treatments is necessary to improve outcomes for BRAFmutant CRC patients. Based on the results of Chapter 11 and 12, our research teams suggests that greater attention should be given to BRAF-mutated tumors regarding the development of metachronous PM in CRC patients without metastases. Therefore, an alternative approach could be to not only focus on BRAF status as a treatment option when metastases occur, but to use the BRAF status as a part of a prediction model to identify the patients at risk for metachronous PM and invent preventive strategies for these patients. Alternatively, exploring biomarkers beyond the primary tumor focus may reveal some promising avenues. An interesting topic in this field is circulating cell-free DNA (cfDNA). Circulating tumor DNA (ctDNA) is a component of cfDNA that is shed by malignant tumors into the bloodstream and other bodily fluids, like the peritoneal cavity, and may be used as a marker for residual or recurrent disease 89. Research has indicated the feasibility of detecting peritoneal cfDNA in ascites and peritoneal lavage fluid and conclude that peritoneal cfDNA’s may be promising as a biomarker for postoperative monitoring and as an adjunctive tool for diagnostic laparoscopy in detecting peritoneal spread in high-risk CRC cases 90, 91. It is therefore interesting to further investigate cfDNA and its potential in guiding high-risk PM patient selection for targeted therapies, as biomarkers in the primary tumor may be not sensitive enough. Ideally, a minimally invasive preventive treatment option for patients at high risk to develop PM should exist. In recent years, considerable research has been dedicated to develop drug delivery systems that aim to prolong the intraperitoneal retention time of cytostatic agents without inducing systemic toxicity, and to enhance minimal invasive approaches 92. Previous
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