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

Abstract

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. Results In 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. Conclusions PM-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.

Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin

“…In terms of survival, median overall survival was 33 months (95% CI 28–38 months) for colorectal cancer and 130 months (95% CI 98–162 months) for pseudomyxoma patients [ 122 , 123 ]. Current nationwide Norwegian data report a median survival of 49 months from the time of CRS HIPEC and a 5-year overall survival of 40.1% for colorectal cancer [ 103 ], in concordance with results from British and French tertiary referral centers [ 22 , 95 ]. These outcomes are realistic figures that have been met and exceeded by specialized Swiss centers [ 104 , 105 ].…”

“…However, a national prospective cohort of Norvegian patients treated with CRS HIPEC between 2005 and 2015 did not see any differences in survival according to KRAS of BRAF mutations. Interestingly, patients who presented with a BRAF mutation and microsatellite instability had significantly better survival [ 103 ]. In a further analysis of 505 patients who underwent CRS HIPEC at 4 European centres, KRAS mutations and to a lesser extent positive nodal stage were independent predictors of peritoneal recurrence following CRS HIPEC [ 104 ].…”

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

“…Some studies have identified RASmt as a negative prognostic marker after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasectomy [38], but a recent Norwegian study found a similar OS of around 49 months after cytoreductive surgery with HIPEC irrespective of RAS and BRAF status [39]. In the latter study a BRAFmt subgroup with dMMR had superior survival among the patients with BRAFmt and this has also been reported in an unselected CRC cohort [40].…”

Mutational profiles and prognostic impact in colorectal and high‐grade appendiceal adenocarcinoma with peritoneal metastases

“…Previous studies have shown that patients with CRC and peritoneal metastases may have worse prognoses with RAS mutations, though these data are mixed, and we did not observe any notable trend for KRAS mutations in this study. [17][18][19] mutations have also been associated with poor OS in earlier-stage colon cancers, although their impact on metastatic disease has not been fully characterized. 20 Patients with metastatic CRC have more consistently demonstrated poor survival with BRAF mutations, although the incidence of these mutations is low at 0%-9%.…”