Biomarkers in colorectal liver metastases.

BACKGROUND: Despite a 5-year overall survival rate of 58 per cent after liver resection for colorectal liver metastases (CLMs), more than half of patients develop recurrence, highlighting the need for accurate risk stratification and prognostication. Traditional prognostic factors have been superseded by newer outcome predictors, including those defined by the molecular origin of the primary tumour. METHODS: This review synthesized findings in the literature using the PubMed database of articles in the English language published between 1998 and 2017 on prognostic and predictive biomarkers in patients undergoing resection of CLMs. RESULTS: Responses to preoperative chemotherapy define prognosis in patients undergoing CLM resection. There are differences by embryological origin too. Somatic mutations in the proto-oncogenes KRAS and NRAS are associated with positive surgical margins and tumour regrowth after ablation. Other mutations (such as BRAF) and co-occurring mutations in RAS/TP53 and APC/PIK3CA have emerged as important biomarkers that determine an individual patient's tumour biology and may be used to predict outcome after CLM resection. CONCLUSION: Knowledge of somatic mutations can guide the use of preoperative therapy, extent of surgical margin and selection for ablation alone.

Local tumour progression after percutaneous ablation of colorectal liver metastases according to RAS mutation status.

BACKGROUND: Percutaneous ablation is a common treatment for colorectal liver metastasis (CLM). However, the effect of rat sarcoma viral oncogene homologue (RAS) mutation on outcome after ablation of CLMs is unclear. METHODS: Patients who underwent image-guided percutaneous ablation of CLMs from 2004 to 2015 and had known RAS mutation status were analysed. Patients were evaluated for local tumour progression as observed on imaging of CLMs treated with ablation. Multivariable Cox regression analysis was performed to determine factors associated with local tumour progression-free survival. RESULTS: The study included 92 patients who underwent ablation of 137 CLMs. Thirty-six patients (39 per cent) had mutant RAS. Rates of local tumour progression were 14 per cent (8 of 56) for patients with wild-type RAS and 39 per cent (14 of 36) for patients with mutant RAS (P = 0·007). The actuarial 3-year local tumour progression-free survival rate after percutaneous ablation was worse in patients with mutant RAS than in those with wild-type RAS (35 versus 71 per cent respectively; P = 0·001). In multivariable analysis, negative predictors of local tumour progression-free survival were a minimum ablation margin of less than 5 mm (hazard ratio (HR) 2·48, 95 per cent c.i. 1·31 to 4·72; P = 0·006) and mutant RAS (HR 3·01, 1·60 to 5·77; P = 0·001). CONCLUSION: Mutant RAS is associated with an earlier and higher rate of local tumour progression in patients undergoing ablation of CLMs.

Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases.

BACKGROUND: In patients with advanced colorectal cancer, KRAS mutation status predicts response to treatment with monoclonal antibody targeting the epithelial growth factor receptor (EGFR). Recent reports have provided evidence that KRAS mutation status has prognostic value in patients with resectable colorectal liver metastases (CLM) irrespective of treatment with chemotherapy or anti-EGFR therapy. A meta-analysis was undertaken to clarify the impact of KRAS mutation on outcomes in patients with resectable CLM. METHODS: PubMed, Embase and Cochrane Library databases were searched systematically to identify full-text articles reporting KRAS-stratified overall (OS) or recurrence-free (RFS) survival after resection of CLM. Hazard ratios (HRs) and 95 per cent c.i. from multivariable analyses were pooled in meta-analyses, and a random-effects model was used to calculate weight and overall results. RESULTS: The search returned 355 articles, of which 14, including 1809 patients, met the inclusion criteria. Eight studies reported OS after resection of CLM in 1181 patients. The mutation rate was 27.6 per cent, and KRAS mutation was negatively associated with OS (HR 2.24, 95 per cent c.i. 1.76 to 2.85). Seven studies reported RFS after resection of CLM in 906 patients. The mutation rate was 28.0 per cent, and KRAS mutation was negatively associated with RFS (HR 1.89, 1.54 to 2.32). CONCLUSION: KRAS mutation status is a prognostic factor in patients undergoing resection of colorectal liver metastases and should be considered in the evaluation of patients having liver resection.

Embryonic origin of primary colon cancer predicts survival in patients undergoing ablation for colorectal liver metastases.

BACKGROUND: In patients with primary colorectal cancer (CRC) or unresectable metastatic CRC, midgut embryonic origin is associated with worse prognosis. The impact of embryonic origin on survival after ablation of colorectal liver metastases (CLM) is unclear. METHODS: We identified 74 patients with CLM who underwent percutaneous ablation during 2004-2015. Survival and recurrence after ablation of CLM from midgut origin (n = 18) and hindgut origin (n = 56) were analyzed. Prognostic value of embryonic origin was evaluated. RESULTS: Recurrence-free survival (RFS) and overall survival (OS) after percutaneous ablation were worse in patients from midgut origin (3-year RFS: 5.6% vs. 24%, P = 0.004; 3-year OS: 25% vs. 70%, P 0.001). In multivariable analysis, factors associated with worse OS were midgut origin (hazard ratio [HR] 4.87, 95% CI 2.14-10.9, P 0.001), multiple CLM (HR 2.35, 95% CI 1.02-5.39, P = 0.044), and RAS mutation (HR 2.78, 95% CI 1.25-6.36, P = 0.013). At a median follow-up of 25 months, 56 patients (76%) had developed recurrence, 16 (89%) with midgut origin and 40 (71%) with hindgut origin (P = 0.133). Recurrent disease was treated with local therapy in 20 patients (36%), 2 (13%) with midgut origin and 18 (45%) with hindgut origin (P = 0.022). CONCLUSION: Compared to CLM from hindgut origin tumors, CLM from midgut origin tumors were associated with worse survival after ablation, which was partly attributable to the fact that patients with hindgut origin were more frequently candidates for local therapy at recurrence.

Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations.

BACKGROUND: After resection of colorectal liver metastases (CLM), RAS mutations are associated with modest survival benefit and second-line chemotherapy confers limited hope for cure. OBJECTIVE: To evaluate the impact of RAS mutation after second-line chemotherapy for patients undergoing potentially curative liver resection for CLM. METHODS: Among 1357 patients operated for CLM between January 2005 and November 2014, patients with known RAS mutational status were identified. Outcomes after second-line chemotherapy were analyzed by RAS status. RESULTS: Among 635 patients undergoing resection of CLM, 46 received second-line chemotherapy before resection, including 14 patients (30%) with RAS mutations. Patients who received second-line chemotherapy had significantly larger and greater number of liver metastases and were more likely to undergo major hepatectomy. Median overall (OS) and recurrence free survival (RFS) were significantly worse among patients requiring second-line chemotherapy (OS: 44.4 vs. 61.1 months, p = 0.021; RFS: 7.3 vs. 12.0 months, p = 0.001). Among patients undergoing liver resection after second-line chemotherapy, RAS mutations were associated with worse median OS and RFS (OS: 35.2 vs. 60.7 months, p = 0.038; RFS: 3.6 vs. 8.3 months, p = 0.015). RAS mutation was the only independent factor associated with OS and RFS. All patients with RAS mutations recurred within 18 months. Among patients with RAS wild-type tumors, the receipt of second-line chemotherapy did not affect OS (p = 0.493). CONCLUSION: Among patients undergoing resection of CLM after second-line chemotherapy, RAS mutational status is an independent predictor of survival and outweighs other factors to select patients for liver resection.