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Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin

Schneider, Marcel André, MD*; Eden, Janina, MD; Pache, Basile, MD; Laminger, Felix, MD§; Lopez-Lopez, Victor, MD, PhD||; Steffen, Thomas, MD; Hübner, Martin, MD; Kober, Friedrich, MD§; Roka, Sebastian, MD§; Campos, Pedro Cascales, MD, PhD||; Roth, Lilian, MD*; Gupta, Anurag, PhD*; Siebenhüner, Alexander, MD; Kepenekian, Vahan, MD#; Passot, Guillaume, MD, PhD#; Gertsch, Philippe, MD*; Glehen, Olivier, MD, PhD#; Lehmann, Kuno, MD, PhD*

doi: 10.1097/SLA.0000000000002899
ESA PAPERS

Background: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear.

Methods: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction.

Results: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3–12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes.

Conclusion: RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.

*Department of Surgery and Transplantation, University Hospital of Zurich, Zurich, Switzerland

Department of Surgery, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland

Department of Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland

§Department of Surgery, Center for Peritoneal Carcinomatosis, Hanusch-Krankenhaus, Vienna, Austria

||Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

Department of Medical Oncology, University Hospital of Zurich, Zurich, Switzerland

#Department of Digestive Surgery and Surgical Oncology, Université Hospital Lyon, Lyon, France.

Reprints: Kuno Lehmann, MD, PhD, Department of Surgery and Transplantation, UniversityHospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail: Kuno.Lehmann@usz.ch.

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).

Thomas Steffen, Martin Hübner, Philippe Gertsch and Kuno Lehmann: For the Swiss Peritoneal Cancer Group of the Swiss Society for Visceral Surgery, Switzerland.

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