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

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

abstract

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.
   
citation Schneider M A, Eden J, Pache B, Laminger F, Lopez-Lopez V, Steffen T, Hübner M, Kober F, Roka S, Campos P C, Roth L, Gupta A, Siebenhüner A, Kepenekian V, Passot G, Gertsch P, Glehen O, Lehmann K. Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin. Ann Surg 2018; 268:845-853.
   
type journal paper/review (English)
date of publishing 7-11-2018
journal title Ann Surg (268/5)
ISSN electronic 1528-1140
pages 845-853
PubMed 30303876
DOI 10.1097/SLA.0000000000002899
contact Ulrich Beutner