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We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions., (© 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients' clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2-0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1-0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.

Background: Despite progress in resection for colorectal liver metastases (CLM), the majority of patients experience recurrence. We aimed to evaluate factors influencing time to recurrence (TTR), treatment and post-recurrence survival (PRS) related to site of recurrence., Methods: This is a retrospective population-based cohort study (1998-2012) of consecutive patients without extrahepatic disease treated with resection for CLM in a referral centre., Results: A total of 311 patients underwent resection for CLM. After a median follow-up of 4.2 years (range 1.2-15.2), 209 (67.4 %) patients developed recurrence, hepatic 90, extrahepatic 59 and both 60. Median TTR was 14.0 months, and 5-year recurrence-free status was 25.7 %. Five- and 10-year overall survival (OS) was 38.8 and 22.0 %, respectively. Median OS was 45 months. A multivariate analysis displayed synchronous disease (hazard ratio (HR) 1.50), American Society of Anaesthesiologists (ASA) score (HR 1.40), increasing number (HR 1.24) and size of metastases (HR 1.08) to shorten TTR (all p < 0.05). Perioperative chemotherapy (n = 59) increased overall TTR (HR 0.63) and overall survival (OS; HR 0.55). Hepatic TTR was correlated to synchronous disease (HR 2.07), number of lesions (HR 1.20), R1 resection (HR 2.00) and ASA score (HR 1.69), whereas extrahepatic TTR was correlated to N stage of the primary (HR 1.79), number (HR 1.27) and size of metastases (HR 1.16). Single-site recurrence was most common (135 of 209, 64.5 %), while 58 patients had double- and 16 triple-site relapses. Median PRS was 24.3 months. There was a difference in median PRS (months) according to site of relapse: liver 30.5, lung 32.3, abdominal 22.0, liver and lung 14.3, others 14.8 (p = 0.002). Repeated liver resections were performed in n = 57 patients resulting in 40.6 months median OS and 36.8 % 5-year OS., Conclusions: An adverse overall TTR was correlated to number and size of metastases, ASA score and synchronous disease. Perioperative chemotherapy increased TTR and OS after surgery for CLM. Patients with solitary post-resection relapse in the liver or lungs had the potential for longevity due to multimodal treatment.

Personalized cancer care requires reliable biomarkers. While the BRAF V600E mutation is implemented in the clinic, no method for its detection has so far been established as reference. We aimed to perform a comprehensive comparison of three methods currently being used for V600E detection in clinical samples. We analysed genomic DNA from 127 malignant melanomas (77 patients) and 389 tumours from 141 colorectal cancer patients (383 liver metastases and 6 primary tumours) by Sanger sequencing and a single probe-based high-resolution melting assay (LightMix). Formalin-fixed paraffin-embedded (FFPE) tissue from a subset of these lesions (n = 77 and 304, respectively) was analysed by immunohistochemistry (IHC) using the V600E-specific antibody VE1. In a dilution series of V600E-mutated DNA in wild-type DNA, the detection limit for the LightMix assay was 1:1000 mutated alleles while it was 1:10 for Sanger sequencing. In line with this, we detected 15 additional mutated melanoma samples and two additional mutated metastatic colorectal cancer samples by the LightMix assay compared to Sanger sequencing. For the melanoma samples, we observed high concordance between DNA-based methods and analysis by IHC. However, in colorectal samples, IHC performed poorly with 12 samples being scored as V600E positive exclusively by IHC and nine samples being scored as V600E negative exclusively by IHC. In conclusion, the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples. For melanoma samples, IHC may be useful as a screening tool guiding further analytical approaches.

Background: Several reports have presented conflicting results regarding the association between resection margins (RMs) and outcome after surgery for colorectal liver metastases (CLM), especially in the era of modern chemotherapy. The purpose of this study was to evaluate the impact of RMs on overall survival (OS), time to recurrence (TTR) and local recurrence (LR) status, particularly for patients treated with preoperative chemotherapy., Methods: A combined retrospective (1998 to 2008) and prospective (2008 to 2010) cohort study of consecutive patients with CLM without extrahepatic disease treated with primary resection at a medium volume centre., Results: A total of 253 patients with known R status and 242 patients with defined margin width were included in the study. Patients were stratified according to margin width; A: R1, <1 mm (n=48, 19%), B: 1 to 4 mm (n=77), C: 5 to 9 mm (n=46) and D: ≥10 mm (n=71). Median time to recurrence was 12.8 months, and after five years 21.5% had no recurrence. LR (inclusive combined recurrence in other hepatic sites or extrahepatic) occurred in 40 (16.5%) cases, most frequently seen with RMs below 5 mm. Five-year OS was 42.5% in R0 and 16.1% in R1 resections (P=0.011). Patients were also stratified according to preoperative chemotherapy (n=88), and the difference in five-year OS between R0 (45.1%) and R1 (14.7%) was maintained (P=0.037). By multiple Cox regression analysis R1 resections tended to an adverse outcome (P=0.067), also when adjusting for preoperative chemotherapy (P=0.081)., Conclusions: R1 resections for colorectal liver metastases predict adverse outcome. RMs below 5 mm increased the risk for LR and shortened the time to recurrence. Preoperative chemotherapy did not alter an adverse outcome in R1 vs. R0 patients.

Background: The liver is the most common location for metastases from colorectal cancer. Current treatment options (i.e. neo-adjuvant chemotherapy, pre-operative portal vein embolization), IMPROVED OPERATIVE TECHNIQUES: and combinations of modalities and have rendered more patients eligible for liver surgery., Material and Methods: Literature from 1996 to July 2007 was retrieved from Pubmed using the search terms "liver metastases", "liver resection", "colorectal cancer", "randomized controlled trial", "systematic review" and "meta-analysis"., Results: No randomized controlled trials were identified that compared liver resection with non-surgical treatment of these patients. Except for a few systematic review articles, the scientific basis for resection of liver metastases from colorectal cancer consists mainly of retrospective studies from single institutions. Median survival for patients with colorectal liver metastases is about 20 months; a five-year survival of 30-50% is reported in resected patients. Patients with non-resectable disease rarely survive for five years. 30-40% of the resected patients have post-operative complications (mostly minor) and postoperative mortality is 3-5%., Interpretation: Surgical treatment of liver metastases is established practice. Patients with colorectal liver metastases should be referred to a multidisciplinary team for appropriate evaluation. Neoadjuvant treatment and multimodal approaches may increase the proportion of patients with resectable liver metastases, and better preoperative imaging may help to more carefully select patients who can benefit from this treatment.