277 Predictive genetic biomarkers for the development of peritoneal metastases in colorectal cancer INTRODUCTION Metastatic colorectal cancer (CRC) is a common cause of cancer-related mortality. At initial diagnoses, almost one-fourth of CRC patients present with metastases 1, 2. Liver metastases (LMs) occur most frequently, followed by peritoneal metastases (PMs) 2, 3. PMs are characterized by the development of solid tumor deposits on the peritoneal surface 4. It is suggested that PMs develop through the shedding of tumor cells from the primary tumor, leading to intraperitoneal seeding 1. Synchronous PMs are found in approximately 5–15% of patients with colorectal cancer at primary surgery 2-5, but PM may also develop metachronously after curative-intent treatment of the primary tumor. In clinical studies, these metachronous PMs are reported in 4–12% of patients following curative resection for colon cancer and in 2–19% of patients following curative resection for rectal cancer 5. Routine imaging techniques frequently fail to detect PMs due to their small size along with the inherently low contrast resolution of the soft tissue in which they occur, resulting in an underestimation of their true incidence 2, 5, 6. Since colorectal PMs occur less frequently than liver and lymph node metastases, they are considered less important from a prognostic perspective 7, 8. Nonetheless, the consequences of PMs are significant. Without treatment, the average life expectancy is six to twelve months after diagnosis 4, 9, 10. Currently, the only potential treatment to improve the survival of patients with colorectal PM is the surgical removal of all visible tumor deposits (cytoreductive surgery, CRS) followed by the application of heated chemotherapy, called hyperthermic intraperitoneal chemotherapy (HIPEC). Inquiries emerged concerning the requisite of adjuvant HIPEC subsequent to CRS, as CRS alone resulted in a survival advantage of over 40 months in the PRODIGE-7 trial 11. Unfortunately, only a selection of physically fit patients with limited colorectal PM (peritoneal cancer index (PCI) below 20) are eligible for this therapy 2, 9, 10, 12. With the changing perspective of this disease, many aspects of the biological and clinical understanding of this challenging disease process remain to be better understood 13. In patients with synchronous PMs, genetic alterations are interesting as a biomarker to determine prognosis or to predict response to therapy 14-16. In addition, genetic alterations in the primary tumor may also be useful for the prediction of PM occurrence. Several pathogenic mutations occur during adenoma-to-carcinoma transformation in CRC. Important oncogenes are adenomatous Polyposis Coli (APC), tumor suppressor gene TP53, KRAS, transforming growth factor beta (TGF-β), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and loss of the chromosome arm 18q 17. Additionally, some genetic alterations are described in relation to a specific metastatic site. For example, differences in APC, BRAF, KRAS, and NRAS are associated with the location of the primary tumor, whereby mutations in KRAS and BRAF seem to result in worse overall survival and the recurrence site in patients with PM 17, 18. 12
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