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

Abstract

Background: Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied.

Methods: This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.

Results: Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.

Conclusions: There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.

Clinical trial registration: NCT01531621/EudraCT2011-003158-24.

Conflict of interest statement

All authors report institutional research funding from Eli Lilly, Merck KGaA, Roche Oy, Sanofi and unrestricted grants from Amgen and Servier, during the conduct of the study. AU, EO, PH, RK, AÅ, TS, AL, LMS, RR, KL, HS, EH, TM, JK, AN, AO, AK, MK, JS, LN, MM, TK, AR, HI and PO report grants, personal fees or non-financial support from Abbvie, Amgen, Astra-Zeneca, Baxalta/Shire, Bayer, BMS, Celgene, Eisai/Ewopharma, Eli Lilly, Erythech Pharma, Fresenius, Incyte, Jansen-Cilag, Medicom, Merck, MSD, Nordic Drugs/Pharma, Novartis, Nutricia/Danone, Pierre-Fabre, Roche Oy, Sanofi, Servier, Sobi and/or Varian.

© 2022. The Author(s).

Figures

Fig. 1. Metastatic sites at baseline and during disease trajectory (months).

aRAS and BRAF wild-type. bRAS mutated type. cBRAF mutated type.

Fig. 2. Appearance of the metastatic sites over time for patients who were diagnosed with metastases in specified organs during trajectory.

aRAS and BRAF wild-type. bRAS mutated type. cBRAF mutated type.

Fig. 3. Resectability and resections.

a Central Resectability and conversion rates (% of entire cohort) according to RAS and BRAF mutational status. b Corresponding resection rates (% of entire cohort).

Fig. 4. Upfront resectable (left panels) and borderline resectable (right panels) in the central tertiary centre multidisciplinary team resectability assessment compared with resectability assessment in local hospitals done before systemic therapy and recruitment to the RAXO trial.

a and bRAS and BRAF wild type patients. c and dRAS mutated type patients. e and fBRAF mutated type patients.

Fig. 5. Overall survival from diagnosis of metastatic disease.

a Patients who were resected and/or treated with local ablative therapy. b Patients who received systemic therapy only.