288 Chapter 12 Treatment Options and Future Perspectives BRAF mutations can be considered as an independent negative prognostic factor in early stage MSS tumors and as a negative predictive factor for therapeutic approaches 55. The therapeutic approach to treat BRAF-mutated tumors is not straightforward due to its resistance to standard therapies 55. Research into anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor (VEGF) antibodies has not shown statistical benefits in BRAF-mutated patients 55, 74. BRAF inhibitors (iBRAF) have revolutionized the treatment of BRAF V600E metastatic melanoma, but so far, results in CRC patients are disappointing due to resistance 40, 55, 75. Studies are currently ongoing with dual or triple drug therapy to blockade the MAPK pathway 55, 75. Until now, partial activity of different combinations has been shown, but this is far from the promising results in melanoma patients. Ongoing research will hopefully demonstrate that combination strategies with iBRAF and other drugs can overcome the lack of efficacy 55. As survival is about half as long as that of BRAF wildtype patients 74, there is an urgency to unravel new treatments that improve BRAF-mutant CRC patients’ outcomes. In current clinical practice, the classification of the MSI status is the only genetic test that is routinely performed in CRC patients to decide adjuvant therapy decisions 76. Other genetic tests, such as BRAF mutation status, are only evaluated in metastatic tumors. Based on the results of this paper, we believe greater attention should be paid to BRAF-mutated tumors in relation to the development of metachronous PM in CRC patients without metastases. Standard clinical screening for BRAF mutations might feel too early as it does not offer any new treatment options, but a stricter follow-up in this population may be clinically beneficial. Based on new international guidelines, the first follow-up CT scan is not performed until 12 months after primary surgery. However, in a BRAF-mutated population, earlier follow-up imaging and more clinical monitoring for PM development may be warranted. Of course, future prospective research (e.g., with liquid biopsies) into the validation of BRAF mutations in relation to the development of metachronous PM is needed to substantiate this proposition. Strengths and Limitations A very homogenous group of tumors was selected for genetic analysis. To our knowledge, this is the first study investigating T3 tumors in relation to metachronous CRC metastases. Previous studies focused on T4 tumors with mostly synchronous PMs and had no other metastases group (LM) as a comparator. While PMs may develop from different cancer types, we specifically examined the colorectal origin and excluded appendiceal origin as it is known that gene expression from appendiceal tumors is distinct from CRC 65. Due to refinements in DNA and RNA extraction techniques from formalin-fixed paraffin-embedded (FFPE) tissue material, the sensitivity of DNA and RNA testing has been increased. Our targeted TSO500 NGS technique accurately measures TMB, microsatellite instability, single-nucleotide variants, indels, copy-number/structural variation, and gene fusions in a single assay using relatively
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