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BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap).PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed.RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C).CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results.CLINICALTRIALSGOV: NCT01229813.

Colorectal cancer is the third most common cancer type in the Western world. In search of new treatment possibilities, the inflammation mediators, know as cysteinyl leukotrienes (CysLTs), have been shown to regulate intestinal epithelial cell survival and proliferation via the CysLT(1)R, and cell differentiation via the CysLT(2)R. These results prompted us to investigate the significance of CysLT(1)R and CysLT(2)R expression in colorectal cancer tissue for patient survival. The CysLT(1)R, CysLT(2)R, beta-catenin and Bcl-xL protein expression levels were evaluated by immunohistochemistry in a tissue microarray of 329 colorectal patients. We found that high nuclear expression of CysLT(1)R is associated with a poor prognosis, whereas high nuclear expression of CysLT(2)R is associated with a good prognosis. We also observed that patients with colorectal tumours characterised by high CysLT(1)R but low CysLT(2)R nuclear expression had the lowest survival expectancy, whereas patients with colorectal tumours characterised by low CysLT(1)R but high CysLT(2)R nuclear expression had the best survival expectancy. Interestingly, beta-catenin as a single prognostic marker did not exhibit any prognostic value. However, in patients with tumours characterised by a high CysLT(1)R nuclear expression, an elevated beta-catenin nuclear expression had a significantly prognostic value. In conclusion these data indicate that nuclear expressions of CysLTRs are potential prognostic indicators of colorectal cancer.

AIMS: This study assessed radiotherapy combined with capecitabine and oxaliplatin in patients with primary, inextirpable colorectal adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients entered the trial. Two cycles of XELOX (capecitabine 1000mg/m(2) bid d1-14+oxaliplatin 130mg/m(2) d1, q3w) were followed by radiotherapy (50.4Gy), combined with capecitabine 825mg/m(2) bid every radiotherapy day and oxaliplatin 60mg/m(2) once weekly. The primary end-point was objective response. RESULTS: Forty-seven patients were evaluable. Twenty-nine (62% [95% CI: 46-75%]) achieved complete or partial response. Thirty-eight (81%) went through surgery of whom 37 (97%) had an R0 resection and five (13%) had a pathological complete response. Seventy-eight percent were alive and estimated local progression rate was 11% at 2 years. The most common grade 3+ toxicity during chemoradiotherapy was diarrhoea (24%). CONCLUSIONS: XELOX-RT was feasible and showed promising efficacy when treating patients with primary inextirpable colorectal cancer, establishing high local control rate.

The level of the tissue inhibitor of metalloproteinases 1 (TIMP-1) has previously been demonstrated to predict the survival of early stage colorectal cancer patients. The present study was undertaken to further validate plasma TIMP-1 as a prognostic marker in rectal cancer. Preoperative plasma from 352 rectal cancer patients were analysed using an immunoassay for TIMP-1. The TIMP-1 immunoassay demonstrated robustness and good reproducibility with low interassay coefficients of variation (CV). The rectal cancer patients had a mean plasma TIMP-1 level of 184 mug/l (standard deviation (SD): 70 mug/l). There were no significant differences in TIMP-1 levels between patients with Dukes' stage A, B or C disease, whereas Dukes' stage D patients had significantly increased TIMP-1 levels (P < 0.000 1); however, high levels of TIMP-1 were not restricted to those with advanced disease. Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels Hazard Ratio (HR)=2.9; 95% Confidence Interval (CI): 1.7-5.0; P

Colorectal cancer is one of the most common tumour types with approximately one third of the tumours located within the rectum. Rectal cancer differs somewhat from colon cancer, e.g. regarding the method of operation and the use of preoperative radiotherapy due to a tendency for local tumour recurrence. Proteolytic enzymes have been identified as key molecules in tumour invasion and metastasis, and factors within the urokinase-plasminogen activation (uPA) system have been associated with prognosis in several tumour types, including colorectal cancer. Recently, methods have been developed to analyse the soluble fraction of the plasminogen activator receptor (suPAR) in blood samples. An association between elevated suPAR levels and poor prognosis has recently been demonstrated in colorectal cancer. We have measured suPAR levels in pretreatment plasma samples from 173 rectal cancer patients in order to confirm its prognostic strength in this clinical entity. suPAR levels were determined in ethylenediamine tetraacetic acid (EDTA) plasma by a kinetic enzyme-linked immunosorbent assay (ELISA) and analysed with respect to sex, age, Dukes' stage, tumour differentiation grade and survival. In a univariate analysis, continuous suPAR plasma levels were associated with survival (P

Aim: Data from a phase III study of second-line panitumumab + FOLFIRI treatment showed that RAS mutations beyond those in KRAS exon 2 impact on the risk/benefit profile of panitumumab in pts with mCRC. Here we report a retrospective RAS/BRAF analysis of a mCRC study of first-line panitumumab + FOLFIRI (NCT00508404). Methods: In this phase II, single-arm study, first-line panitumumab (6 mg/kg) + FOLFIRI were administered every 14 days until progression to mCRC pts. Objective response rate (ORR) was the primary endpoint. Data were analysed descriptively by tumour RAS/BRAF status. Tumour specimens were assayed for mutations in KRAS exon 2 by DxS and KRAS exons 3/4, NRAS exons 2/3/4 and BRAF exon 15 by bidirectional Sanger sequencing. Results: RAS data were available for 143/154 (93%) pts of whom 69 (48%) had RAS WT (wild-type [WT] for exons 2, 3 and 4 of KRAS/NRAS) and 74 (52%) had RAS mutant (MT) tumours. Overall, median age was 63 years, 62% had primary colon cancer, 55% had moderately differentiated tumours and 76% had ≤2 metastatic sites. Baseline characteristics were generally well balanced between pts with RAS WT vs MT mCRC. ORRs (59% vs 41%; odds ratio: 2.05; 95% confidence interval [CI]: 0.99-4.23) and resection rates (13% vs 9%) were higher in pts with RAS WT vs MT mCRC. Disease control rates were similar (91% vs 92%; odds ratio: 0.93; 95% CI: 0.23-3.66). Longer median duration of response (DoR: 13.0 vs 5.8 months), progression-free survival (PFS: 11.2 vs 7.3 months) and time to progression (TTP: 13.2 vs 7.3 months) were also observed in RAS WT pts. Nine pts (6%) had BRAF MT mCRC. Pts with RAS/BRAF WT (n = 60) vs RAS WT/BRAF MT (n = 83) status had improved ORR (68% vs 36%; odds ratio: 3.81; 95% CI: 1.78-8.22), resection rates (15% vs 8%), median DoR (13.0 vs 5.8 months), PFS (13.2 vs 6.9 months) and TTP (13.3 vs 7.2 months). No new safety signals were identified. Conclusions: In line with recent studies, consistently favourable efficacy was observed in pts with RAS/BRAF WT vs MT mCRC tumours receiving first-line panitumumab + FOLFIRI treatment. KRAS mutation status appears insufficient for selecting pts for first-line panitumumab + FOLFIRI treatment; tumour RAS analysis aids optimum pt selection. Disclosure: M. Karthaus: Prof Karthaus has participated in Advisory boards (compensated) for Amgen; L. Mineur: has received research support from Amgen (but not in the context of this abstract), honoraria from Amgen for participation in advisory boards (but not for this study); R. Greil: has received honoraria from Amgen for participation in advisory boards and research support from Amgen (but not in the context of this abstract); J. Thaler: has received honoraria and research funding from Amgen; H. Kroning: did not declare any conflicts of interest; K.S. Oliner: is an Amgen Inc. employee and stockholder; J. Terwey: is an Amgen (Europe) GmbH employee and stockholder; All other authors have declared no conflicts of interest.

Cellular SRC (c-SRC), which is the human homolog of the Rous sarcoma viral oncogene, v-src, is highly activated in colorectal cancer. Recently, a subset of colon cancers have shown a nonsense mutation at codon 531, which truncates c-SRC directly C-terminal to the c-SRC kinase regulatory domain. This specific mutation has been demonstrated to be activating, transforming, and tumorigenic and to promote metastasis. We investigated 100 rectal cancers, half of which had tumor spread outside the rectum, for this mutation by using direct sequencing. None of these tumors displayed any genetic alteration at this locus, and we thus conclude that the codon 531 mutation is a rare cause of c-SRC activation in rectal cancer.