Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients

S G Larsen,E Hofsli,K Flatmark,S Dueland,S E Steigen,H Sorbye,V J Dagenborg,M A Goscinski,A Torgunrud,M Lund-Iversen

doi:10.1038/s41416-021-01620-6

Abstract

BackgroundPatients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated.MethodsIn total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC.ResultsIn total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis.ConclusionsPM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the world [1]
Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has shown promising results in patients with limited and resectable peritoneal metastasis (PM)-CRC
A recent Swiss study found that both RAS and BRAF mutations were negative prognostic factors after HIPEC [22] and a Swedish study suggested that metastatic colorectal cancer (mCRC) patients with mutBRAF and isolated PM should rather be considered for alternative treatment customised molecular microsatellite instability (MSI) panels with the following markers: (BAT 26 (HMSH2 intron), BAT25 (c-KIT intron), NR24 (Zinc finger 2, 3’UTR), NR21 (SLC7A8, 5’UTR), TGF-Beta-RII (c.374-3c383), BAT 40 (1p13.1), CAT25 (CASP2,3’UTR), RCC2 (5’UTR)

Summary

BACKGROUND

Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS: In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival.

INTRODUCTION

METHODS

RESULTS

DISCUSSION

Limitations

ETHICS APPROVAL AND CONSENT TO PARTICIPATE