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BACKGROUND: Primary tumour location (PTL) is being adopted by clinicians to guide treatment decisions in metastatic colorectal cancer (mCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumours as a separate location. PATIENTS AND METHODS: mCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab (IrPan). PTL was classified as right-PTL, left-PTL or rectal-PTL. PTL was assessed as a predictive biomarker for IrPan effect in RAS-wild-type (RAS-wt) patients (compared with irinotecan alone), then tested for independence alongside an extended biomarker profile (BRAF, epiregulin/amphiregulin (EREG/AREG) and HER3 mRNA expression). RESULTS: PTL data were available for 1180 patients (98.5%), of whom 558 were RAS-wt. High HER3 expression was independently predictive of panitumumab overall survival improvement, but PTL and EREG/AREG were not. IrPan progression-free survival (PFS) improvement compared with irinotecan was seen in left-PTL [hazard ratio (HR) = 0.61, P = 0.002) but not right-PTL (HR = 0.98, P = 0.90) (interaction P = 0.05; RAS/BRAF-wt interaction P = 0.10), or in rectal-PTL (HR = 0.82, P = 0.20) (interaction P = 0.14 compared with left-PTL; RAS/BRAF-wt interaction P = 0.04). Patients with right-PTL and high EREG/AREG or HER3 expression, had IrPan PFS improvement (high EREG/AREG HR = 0.20, P = 0.04; high HER3 HR = 0.33, P = 0.10) compared with irinotecan. Similar effect was seen for rectal-PTL patients (high EREG/AREG HR = 0.44, P = 0.03; high HER3 HR = 0.34, P = 0.05). CONCLUSIONS: RAS-wt patients with left-PTL are more likely to have panitumumab PFS advantage than those with right-PTL or rectal-PTL. However, an extended biomarker panel demonstrated significant heterogeneity in panitumumab PFS effect within a tumour location. AREG/EREG and HER3 mRNA expression identifies patients with right-PTL or rectal-PTL who achieve similar PFS effect with panitumumab as left-colon patients. Testing could provide a more reliable basis for clinical decision making. Further validation and development of these biomarkers is required to optimise routine patient care. CLINICAL TRIAL REGISTRATION: ISRCTN identifier: ISRCTN93248876. ispartof: ANNALS OF ONCOLOGY vol:31 issue:8 pages:1021-1029 ispartof: location:England status: published

BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. PATIENTS AND METHODS: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. RESULTS: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P

BACKGROUND & AIMS: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear. METHODS: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes. RESULTS: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-negative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 × 10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster-specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families. CONCLUSIONS: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression. ispartof: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY vol:8 issue:2 pages:269-290 ispartof: location:United States status: published

Background The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients and Methods Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. Results From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. Conclusion In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.

Background: The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359). ispartof: Ann Oncol vol:29 issue:11 pages:2240-2246 ispartof: location:England status: published

Immuno-therapeutics aim to activate the body's own immune system against cancer and are one of the most promising cancer treatment strategies, but currently limited by a variable response rate. Biomarkers may help to distinguish those patients most likely to respond to therapy; they may also help guide clinical decision making for combination therapies, dosing schedules, and determining progression versus relapse. However, there is a need to confirm such biomarkers in preferably prospective clinical trials before they can be used in practice. Accordingly, it is essential that clinical trials for immuno-therapeutics incorporate biomarkers. Here, focusing on the specific setting of immune therapies, we discuss both the scientific and logistical hurdles to identifying potential biomarkers and testing them in clinical trials.

Objectif La FAPA (association belge pour la polypose adenomateuse familiale) a ete creee en 1993 dans le but d’enregistrer les patients atteints de polypose adenomateuse familiale (FAP) Methode Les donnees de tous les patients inclus de maniere prospective dans le registre belge FAPA entre 1993 et 2018 ont ete analysees. Resultats Il y avait 442 patients de 199 familles avec un âge median de 47 (2–88) et un âge median au diagnostic de 23,5 (1–69) au moment du diagnostic. Un nombre median de 1 (1–7) tumeurs desmoides, principalement intra-abdominales, etaient presentes chez 78 patients (18 %). Un cancer du tractus gastro-intestinal superieur a ete diagnostique a l’âge median de 57 (22 a 83) ans chez 36 (8,1 %) des patients. Un cancer colorectal a ete diagnostique chez 100 patients (22,6 %) a un âge median de 43,5 ans (15 a 72 ans) et etait reparti entre 62/159 (39 %) probands versus 38/283 (13 %) patients depistes (p Conclusion Depuis la creation du registre belge de la polypose, l’enregistrement centralise avec identification et examen prophylactique des apparentes a risque a permis une amelioration substantielle du pronostic.

An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team. publisher: Elsevier articletitle: Managing synchronous liver metastases from colorectal cancer: A multidisciplinary international consensus journaltitle: Cancer Treatment Reviews articlelink: http://dx.doi.org/10.1016/j.ctrv.2015.06.006 content_type: article copyright: Copyright © 2015 The Authors. Published by Elsevier Ltd. ispartof: Cancer Treatment Reviews vol:41 issue:9 pages:729-41 ispartof: location:Netherlands status: published

Background & AimsCategorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes.MethodsWe used a polymerase chain reaction–based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models.ResultsTumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAFV600E were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAFV600E or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11–1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27–1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort.ConclusionsWe identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAFV600E or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.

Background To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). Patients and methods In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. Results Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5 mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. Conclusion Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Summary Background No biomarkers that could guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab have been identified. We assessed whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome. Methods We investigated DNA from white patients from two phase 3 randomised studies. In AViTA, patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine and erlotinib plus either bevacizumab or placebo. In AVOREN, patients with metastatic renal-cell carcinoma were randomly assigned to receive interferon alfa-2a plus either bevacizumab or placebo. We assessed the correlation of 138 SNPs in the VEGF pathway with progression-free survival and overall survival in a subpopulation of patients from AViTA. Significant findings were confirmed in a subpopulation of patients from AVOREN and functionally studied at the molecular level. Findings We investigated DNA of 154 patients from AViTA, of whom 77 received bevacizumab, and 110 patients from AVOREN, of whom 59 received bevacizumab. Only rs9582036, a SNP in VEGF receptor 1 ( VEGFR1 or FLT1 ), was significantly associated with overall survival in the bevacizumab group of AViTA after correction for multiplicity (per-allele hazard ratio [HR] 2·1, 95% CI 1·45–3·06, p=0·00014). This SNP was also associated with progression-free survival (per-allele HR 1·89, 1·31–2·71, p=0·00081) in bevacizumab-treated patients from AViTA. AC and CC carriers of this SNP exhibited HRs for overall survival of 2·0 (1·19–3·36; p=0·0091) and 4·72 (2·08–10·68; p=0·0002) relative to AA carriers. No effects were seen in placebo-treated patients and a significant genotype by treatment interaction (p=0·041) was recorded, indicating that the VEGFR1 locus containing this SNP serves as a predictive marker for bevacizumab treatment outcome in AViTA. Fine-mapping experiments of this locus identified rs7993418, a synonymous SNP affecting tyrosine 1213 in the VEGFR1 tyrosine-kinase domain, as the functional variant underlying the association. This SNP causes a shift in codon usage, leading to increased VEGFR1 expression and downstream VEGFR1 signalling. This VEGFR1 locus correlated significantly with progression-free survival (HR 1·81, 1·08–3·05; p=0·033) but not overall survival (HR 0·91, 0·45–1·82, p=0·78) in the bevacizumab group in AVOREN. Interpretation A locus in VEGFR1 correlates with increased VEGFR1 expression and poor outcome of bevacizumab treatment. Prospective assessment is underway to validate the predictive value of this novel biomarker. Funding F Hoffmann-La Roche.

Anti-Epidermal Growth Factor Receptor (EGFR) therapies have been recently developed for the treatment of multiple cancer types. At the time when they were introduced in clinical practice, there was little knowledge of the molecular bases of tumor sensitivity and resistance to these novel targeted compounds. By using the framework of anti-EGFR inhibitors as treatment for colorectal cancer patients, we will review the knowledge we have reached until now in improving the development of a personalized cancer therapy and we will try to indicate the future challenges this field will face in the future.

The Zic transcription factors play critical roles during embryonic development. Mutations in the ZIC2 gene are associated with human holoprosencephaly, but the etiology is still unclear. Here, we report a novel function for ZIC2 as a regulator of β-catenin·TCF4-mediated transcription. We show that ZIC2 can bind directly to the DNA-binding high mobility group box of TCF4 via its zinc finger domain and inhibit the transcriptional activity of the β-catenin·TCF4 complex. However, the binding of TCF4 to DNA was not affected by ZIC2. Zic2 RNA injection completely inhibited β-catenin-induced axis duplication in Xenopus embryos and strongly blocked the ability of β-catenin to induce expression of known Wnt targets in animal caps. Moreover, Zic2 knockdown in transgenic Xenopus Wnt reporter embryos led to ectopic Wnt signaling activity mainly at the midbrain-hindbrain boundary. Together, our results demonstrate a previously unknown role for ZIC2 as a transcriptional regulator of the β-catenin·TCF4 complex.

Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy.40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00, 0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population.While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.Belgian Federation against Cancer (Stichting tegen Kanker).

Over the last few years, EGFR inhibitors have successfully joined the armamentarium of anti-cancer drugs with an increasing number of indications such as colorectal cancer, head and neck cancer, nonsmall cell lung cancer and breast cancer [1]. EGFRtargeted drugs consist of monoclonal antibodies to EGFR (e.g. cetuximab, panitumumab), small-molecule tyrosine kinase inhibitors specific for EGFR (e.g. erlotinib, gefitinib), dual kinase inhibitors inhibiting EGFR and HER2 (lapatinib), pan-erbB inhibitors inhibiting EGFR and other erbB receptors (canertinib) and other less specific inhibitors such as vandetanib inhibiting EGFR, vascular endothelial growth factor receptor (VEGFR) and RET [1].

Rapidly growing insights into the molecular biology of colorectal cancer led to high hopes for the identification of molecular markers to be used in optimised and tailored treatment regimens for this disorder. However, no molecular marker has yet made it into daily practice. In this review we will discuss some of the potential molecular markers, focus on the lessons learnt from marker development and identify strategies for the future.

Here for the first time we showed, despite the oncogenic mutations in beta-Catenin, that TGF-beta is a modulator of beta-Catenin levels in tumoral fibroblasts as well as non-tumoral fibroblasts. The results show that the TGF-beta pathway is active in desmoids cells and in in situ tumors. A dose dependent increase in beta-Catenin protein levels was observed after TGF-beta treatment in combination with an increased repression of GSK-3beta both in normal and tumoral fibroblasts. TGF-beta stimulation also led to an altered -- up to 5 fold -- transcriptional activity of beta-Catenin responsive promoters, such as IGFBP6 as well as increase of TOPflash activity. TGF-beta stimulation increased cell proliferation and BrdU incorporation 2.5 times. Taken together, we propose that TGF-beta is a modulator of beta-Catenin levels in tumoral fibroblasts and non-tumoral fibroblasts, despite the oncogenic mutations already present in this gene in tumoral fibroblasts of desmoid tumors. This modulation of beta-Catenin levels by TGF-beta may be involved in determining the tumoral phenotype of the cells.

Item does not contain fulltext BACKGROUND: Preliminary evidence suggests that magnesium wasting occurs in patients who are treated with epidermal-growth-factor receptor (EGFR)-targeting antibodies for colorectal cancer. The mechanism of this side-effect is unknown, and if all or a subset of patients are affected is also unclear. We aimed to assess the incidence, characteristics, and predictive factors of magnesium wasting during treatment with EGFR-targeting antibodies, and to study the pathophysiology of this phenomenon. METHODS: We measured prospectively magnesium concentrations in a cohort of 98 patients with colorectal cancer treated with EGFR-targeting antibodies with or without combined chemotherapy. The primary outcome measure was the slope of the serum magnesium concentrations over time. In 35 patients, 24-h urinary magnesium excretion was measured. In a subset of patients (n=5), an intravenous magnesium load test was done. 16 patients who had chemotherapy alone acted as controls. A clinical protocol was written before initiation of the study, but because this was a non-interventional study, the protocol was not formally registered. FINDINGS: 95 (97%) patients had decreasing serum magnesium concentrations during EGFR-targeting treatment compared with baseline measurements. The mean serum magnesium slope during EGFR-targeting treatment (with or without combined chemotherapy) was significantly lower compared with chemotherapy alone (-0.00157 mmol/L/day, SD 0.00162 [95% CI -0.00191 to -0.00123] vs 0.00014 mmol/L/day, SD -00076 [-0.00026 to 0.00055]; (t test, p < 0.0001). 24-h urine analysis and intravenous magnesium load tests showed a defect in renal magnesium reabsorption. INTERPRETATION: EGFR-inhibiting antibodies compromised the renal magnesium retention capacity, leading to hypomagnesaemia in most patients. Future studies should address the effects of exposure and target affinity. Our study suggests a pivotal role of the EGFR-signalling pathway in regulating magnesium homoeostasis.

5-Fluorouracil (5-FU) plus leucovorin (LV) has been the mainstay of treatment for colorectal cancer (CRC), with infused schedules more widely adopted in Europe and bolus schedules preferred in North America. However, the effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV on both sides of the Atlantic. Capecitabine generates 5-FU preferentially in tumor and is a well-established, first-line treatment for metastatic CRC. In this setting, capecitabine achieves a superior response rate, at least equivalent time to disease progression (TTP) and overall survival, and favorable safety compared with bolus 5-FU/LV. The benefits of capecitabine have been transfered into the adjuvant setting. Recent data from a large, international, randomized trial (Xeloda Adjuvant Chemotherapy Trial [X-ACT]) confirm that capecitabine (Xeloda, Roche Laboratories, Nutley, NJ) achieves favorable safety versus 5-FU/LV (Mayo Clinic regimen) and is at least as effective as IV 5-FU/LV in the adjuvant treatment of patients with resected stage III colon cancer. Capecitabine is also an effective and well-tolerated combination partner for oxaliplatin (XELOX) and irinotecan (XELIRI), achieving high efficacy with a good safety profile. An extensive phase III clinical trial program is further establishing the potential of the simplified capecitabine combinations to improve outcomes and unify treatment practices in the metastatic and adjuvant settings. New combinations with novel agents such as capecitabine/oxaliplatin plus erlotinib or bevacizumab are currently under investigation. Capecitabine has also shown promising activity and good tolerability in combination with radiotherapy in rectal cancer.

Colorectal cancers, whether sporadic or hereditary, are caused by a defined set of molecular events. There are at least two different pathogenetic pathways for colorectal cancer: the chromosomal instability pathway and the microsatellite instability pathway; the two major inherited syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), are examples of these two mechanisms. These different pathways, however, converge on common pathological entities that have crucial functions in the regulation of normal crypt homeostasis. Preventive strategies aimed at reversing these changes, or therapeutic interventions targeting cell populations with these alterations, should be most efficacious. Genetic testing for inherited syndromes is now available and allows appropriate management of these disorders. Further insight into colorectal tumorigenesis pathways can lead to the development of useful prognostic indicators and target preventive and therapeutic strategies in the management of colorectal cancer.

Background Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit. Patients and Methods Formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 ( IGFBP2 ), insulin growth factor receptor 1 ( IGF1R ), cMET , EphA2 , human epidermal growth factor receptor 2 ( HER2 ), HER3 , and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR). Results Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin ( AREG ) mRNA levels in KRAS wild-type tumors (HR, 0.17; P EREG ) mRNA levels (HR, 0.38; P = .006). Conclusion High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC.

Background This study was carried out to assess the effect of cetuximab plus chemotherapy in first-line treatment of unresectable colorectal liver metastases (CLM). Methods After resection of the primary focus, patients from Zhongshan Hospital with non-resectable synchronous liver-limited metastases from wild-type KRAS colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI or mFOLFOX6) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of secondary resection for liver metastases. Secondary end points included tumor response, survival and BRAF analysis. Results From June 2008 to December 2011, 116 patients were assessable (59 in arm A and 57 in arm B). The 3-year overall survival (OS) rate and median survival time (MST) of the total patients was 32% and 27.5 months, respectively. The R0 resection rate for liver metastases was 30.5% (18/59) in arm A and 8.8% (5/57) in arm B, with significant difference (P Conclusions For initially unresectable CLM with KRAS wild-type, cetuximab combined with chemotherapy could improve resectability of liver metastases, response rates and survival compared with chemotherapy alone. The mutation status of the BRAF gene may be a predictor of outcome in the cetuximab group (ClinicalTrials.gov number NCT01564810).

Background Cetuximab has improved outcome of patients (pts) with mCRC. KRAS has emerged as a marker of resistance to monoclonal antibodies against EGFR, including cetuximab. Further biomarkers for response to cetuximab are being explored. Methods In a heterogeneous cetuximab-treated population we retrospectively evaluated formalin-fixed paraffin-embedded tissue for EGFR and PTEN by Fluorescence In Situ Hybridization (FISH) and for PIK3CA and KRAS mutations by PCR and examined the association of these markers with patient outcome. Results Two hundred twenty-three cetuximab-treated mCRC pts were identified, of which 38 were treated in first line, 107 in second and 78 in ≥ 3rd line. Cetuximab was used with irinotecan-based therapy in 54.3% and with oxaliplatin in 26.9% of the cases. Two pts achieved a complete response, 53 a partial response and 65 stable disease for a clinical benefit rate of 63.2%. EGFR amplification was noted in 5 cases, PTEN deletion in 58 and PTEN gain in 2. Finally, KRAS was mutated in 72 cases, and PIK3CA in 37. The mutations detected for KRAS were G12 (45 pts, 62.5%), G13 (16 pts, 22.2%), G61 (4 pts, 5.6%) and A146 (7 pts, 9.7%) and for PIK3CA Exon9 (20 pts, 54.1%), Exon20 (5 pts, 13.5%) and other (12 pts, 32.4%). No associations were found between these markers. PTEN deletion was associated with a higher overall response rate (ORR) (p = 0.031), while the other markers were not. Progression-free survival (PFS) and survival were calculated from initiation of cetuximab. PFS was numerically associated with EGFR gain but the numbers (5 gain vs. 138 normal) do not allow for a sound result. Additionally, given the different impact of diverse KRAS mutations on outcome, we evaluated the outcome in relation to the G12 mutations. The latter exhibited a trend for decreased survival (p = 0.057). Conclusions After a median follow up of 55.3 months (5.8-88.4 months), PTEN deletion was associated with improved ORR to cetuximab. Further examination of EGFR and PTEN by immunohistochemistry is in progress. Disclosure E. Razis: Dr E. Razis received research grant from Merck S.A. and Roche (Hellas) S.A. All other authors have declared no conflicts of interest.

Cancer patients receiving chemotherapy are at increased risk of venous thromboembolism (VTE). The presence of cancer and anticoagulant use are risk factors for bleeding, yet data on bleeding risk are limited in these patients. This analysis evaluated the risk of major bleeding in cancer patients receiving chemotherapy using a US claims database. This retrospective cohort study used the MarketScan® databases, a nationwide database containing data from about 100 payers and covering > 30 million patients annually. Adult cancer patients receiving chemotherapy within 6 months of cancer diagnosis between January 2004 and December 2010 were included. Cancers of interest were: lung, colon/rectum, pancreas, bladder, stomach, and ovary. The index date was the first date of chemotherapy. Patients were followed until the earliest of: 1) first diagnosis of major bleeding; 2) termination of enrolment in the health plan; 3) end of study. The primary outcome was the first occurrence of major bleeding, based on selected ICD-9-CM/CPT codes, following chemotherapy initiation. Of 74,575 patients identified, exclusion of those with prior history of bleeding at baseline (∼5%) resulted in 70,822 patients included in the analysis. Mean age was 62 years, 37% were ≥ 65 years, and 52% were male. Average time of follow up and chemotherapy were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months prior to the index date. Major bleeding occurred in 5.8% of patients and the incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5, 9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456) developed VTE after chemotherapy initiation (> half in the first 3 months of chemotherapy treatment). Of these, 7.8% experienced major bleeding with incidence rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer patients receiving chemotherapy varies by cancer type with the highest rates in patients with upper gastrointestinal cancer. Compared to the overall cohort, major bleeding risk was higher in cancer patients who developed VTE. Disclosure J.H. Zong: Employee of Sanofi. L. Eckert: Employee of Sanofi. L. Zhang: Employee of Sanofi. W.S. Dai: Employee of Sanofi. A.T. Cohen: Consult: Astellas, AZ, Bayer, BI, BMS, Daiichi, GSK, JJ ResFund: AZ, Bayer, BI, BMS, Daiichi, GSK, JJ BoardSpeakerAdvis comm: Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

Background The identification of biomarkers predictive for the efficacy of targeted anticancer agents allows for the tailoring of treatment to maximize patient (pt) benefit and outcomes. It is important that information about the potential for the personalization of anticancer therapy is available to pts so that they are fully informed about treatment and biomarker screening options. The current survey assessed pt awareness and understanding of these issues. Methods Pts with a diagnosis of late-stage breast cancer (BC), stage III/IV non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (mCRC) within the previous 5 years were eligible. Participating physicians or pt organizations in seven countries (Argentina, China, France, Germany, Italy, Spain and the UK) identified potentially suitable pts and invited them to take part. Written informed consent was obtained from all pts, with those confirmed as eligible then completing a telephone-based questionnaire. Results Questionnaires were completed by 811 pts: 164 previously diagnosed with BC; 157 with NSCLC and 490 with mCRC. Of those interviewed: 260/811 pts (32%) thought that there was no method of testing to determine which cancer treatments might work (or work better) in certain people, while 430/811 pts (53%) thought that such testing might be possible (62% of pts with BC, 48% with NSCLC and 52% with mCRC). Most pts (532/811, 66%) were willing to delay treatment if that helped select the most effective drug, 286/532 (54%) of those, by more than two weeks, and most (557/811, 69%) were willing to undergo a tumor re-biopsy as part of any such treatment selection process. Almost all pts (737/811, 91%) would allow a hospital to retain a tumor sample for future research. The internet was cited as a useful source of information regarding disease and treatment options by 192/811 pts (24%). Conclusions Pts are generally willing to participate in biomarker test procedures to facilitate the personalization of their treatment. There is considerable scope for physicians and support groups to better inform pts that not all cancers are the same and that new tests may be able to identify which treatments will work most effectively for them. Disclosure S. Tejpar: The author declares research and speakers' bureau funding from Merck Serono. T. Teague: The author is an employee of Merck KGaA. J. Tabernero: The author declares: Consultant or Advisory Role (compensated): Amgen, Bristol-Myers Squibb, Genentech, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche and Sanofi Honoraria: Amgen, Merck KGaA, Novartis, Roche and Sanofi. S. Vlassak: I am an employee for Merck Serono in the medical department. All other authors have declared no conflicts of interest.

Introduction Pimasertib is a highly selective inhibitor of the MEK1/2 kinases of the MAPK pathway. It demonstrates potent antitumor activity in cell lines and xenograft models with activating (mainly BRAF and KRAS) mutations. A two-part study, comprising a safety run-in part followed by a randomized phase II part, was designed to investigate FOLFIRI plus pimasertib as second-line treatment for patients with KRAS mutated (mt) metastatic colorectal cancer (mCRC). The results of the safety run-in part, conducted primarily to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), are reported here. Methods Patients with KRAS mt mCRC progressing on first-line oxaliplatin plus fluoropyrimidine ± bevacizumab were eligible. A 3 + 3 design, with fixed dose-escalation based on dose-limiting toxicities (DLTs) occurring during the first cycle (28 days) of treatment, was used to investigate FOLFIRI plus daily oral pimasertib (dosed 5 days on 2 days off, starting dose 45 mg/day). The decision to proceed to the next dose level was made by a safety monitoring committee, comprising investigators and representatives of the sponsor. Results Sixteen atients (median age 64 years [range 38-81] and ECOG performance status 0-1) received FOLFIRI plus pimasertib 45 mg/day (n = 10) or 60 mg/day (n = 6) (safety population). Two patients were not evaluable for the dose escalation and DLT analysis (n = 14). No DLTs were observed in the first 3 patients treated at 45 mg/day, allowing dose escalation to 60 mg/day. On pimasertib 60 mg/day, 2/5 patients had DLTs, both grade 3 mucositis/stomatitis. This led to a per-protocol expansion of the 45 mg/day cohort, during which 1/6 patients had a DLT (grade 3 hyponatremia). The median number of pimasertib cycles initiated was 3 (1-11). Over both doses, the most common treatment-emergent adverse events (TEAEs) were asthenia (44%), diarrhea (44%), mucosal inflammation (38%), ocular events (38%, mainly grade 1/2 macular degeneration) and nausea, rash and vomiting (31% each). Seven patients had at least one ≥ grade 3 treatment-related TEAE: diarrhea (2 patients), mucosal inflammation (3 patients) and neutropenia (3 patients). Eight patients had ≥ 1 serious TEAE: 4 on pimasertib 45 mg/day and 4 on pimasertib 60 mg/day. Five patients had ≥ 1 TEAE leading to permanent treatment discontinuation, 3 on pimasertib 45 mg/day and 2 on 60 mg/day. Over both doses, 9 patients had on-treatment electrocardiogram changes compared with baseline readings. Reasons for stopping treatment included AE (3 patients), disease progression (6 patients) and consent withdrawal (3 patients). As of 23 November 2011, 3 patients remained on treatment with FOLFIRI plus pimasertib. Pimasertib dosed once-daily concomitantly with FOLFIRI exhibited a pharmacokinetic profile comparable to pimasertib monotherapy. Conclusion In combination with FOLFIRI, dose escalation of pimasertib from 45 mg/day to 60 mg/day was limited by toxicity. Due to the fact that 45 mg/day is not considered to be an active dose in this setting, progression to the phase II part of the study was not recommended by the sponsor.

Introduction Previous analysis of the gene expression data of mutational subgroups in the PETACC3 trial, revealed a very homogenous gene expression pattern in BRAF mutant CRC patients; while KRAS mutant CRC contain at least three different patient groups in terms of gene expression. One of these KRAS mutant groups together with 10% of KRAS/BRAF WT (WT2) patients, resembled the gene expression found in the BRAF mutants. This BRAF-like subgroup is characterized by poor prognosis. In this article we investigate, if heterogeneity in CRC patients can be partly explained by diverse signaling downstream of KRAS, to which the DUSPs take part. Material and methods The expression of DUSP1, DUSP4 and DUSP6, DUSPs previously shown to be induced by mutations in genes of the MAPK pathway, was analyzed in 4 different CRC patient microarray datasets (PETACC3, cetuximab, TCGA and Agendia dataset). We investigated, if patients with low and high DUSP expression behave differently in terms of response, OS, PFS and differ in clinical characteristics both in PETACC3 and TCGA dataset. Findings Unlike DUSP1, DUSP4 and DUSP6 were differentially overexpressed between BRAF mutants and KRAS mutants on one side and between BRAF mutants and WT2 patients on the other side. When we subdivided the patients into low and high DUSP expression within KRAS mutant and WT2 patients, we found a significant difference in OS in both mutational subgroups with high DUSP4 expression in KRAS mutants associated with a better OS and in WT2 associated with a worse OS. Multivariate analysis in the BRAF WT patients in both PETACC3 and cetuximab dataset showed that high DUSP4 expression was still associated with a worse OS (HR = 1.23; p Conclusions DUSP4 is predictive for OS in CRC patients with KRAS mutations. Interestingly, within KRAS mutant and WT2 patients high DUSP4 expression correlates with clinical characteristics that are typical for BRAF mutant CRC patients. If DUSP4 may represent a novel biomarker for a subset of CRC patients needs further research. Download : Download full-size image Fig. 1 . Box plots with DUSP4 expression according to different mutational groups in PETACC3 dataset. Download : Download full-size image Fig. 2 . Kaplan-Meier curve for overall survival according to DUSP4 expression (low and high) in KRAS WT patients.

I-SCAN Detects More Polyps in Lynch Syndrome (HNPCC) Patients: A Prospective Controlled Randomized Back-to-Back Study Raf Bisschops*, Sabine Tejpar, Hilde Willekens, Gert De Hertogh, Eric Van Cutsem Gastroenterology/Endoscopy, University Hospital UZ Leuven, Leuven, Belgium; Pathology, University Hospital UZ Leuven, Leuven, Belgium Background: Narrow-band imaging and chromo-endoscopy have been reported to detect more polyps in comparison to (high definition) white light endoscopy (HDWL) in hereditary non-polyposis colonic cancer (HNPCC) patients in a backto-back study. However, no randomisation for the order of imaging method was applied. I-scan with tone enhancement (TE) is a new form of digital chromoendoscopy. We aimed to assess the additional value of the i-scan TE system in polyp detection in HNPCC. Method: 49 HNPCC patients underwent a back-toback colonoscopy (Pentax EC3890Fi) with two imaging modalities and were randomized in 2 groups. Group 1 underwent HDWL first followed by i-scan, group 2 i-scan first followed by HDWL. For HDWL, standard settings and for i scan, the i-scan 2 preset (surface enhancement 4, TE c-modus) were used on a Pentax Hi-line processor. Patients with clinical diagnosis or proven gene abnormality for HNPCC were included in the study. Patients with known neoplasia or colectomy with 50cm remaining colon were excluded. Bowel preparation after PEG solution was assessed using the Bristol Bowel preparation scale (BBPS). Patients with a BBPS 6 were excluded. Total inspection time was calculated after subtracting the time needed for polypectomy. Lesion detection rate (total number of lesions for each method/total procedures) and the miss rate ( number of lesions/adenomas detected during second inspection/total number of lesions/adenomas in that group) were assessed. Results: 25 and 24 patients were included in group 1 and 2 respectively (mean age 45.3 1.69, 25 male). There was no difference in age or BBPS. The lesion detection rate was 0.73 019 for i-scan and 0.36 0.12 for HDWL (p 0.095). In group 1, 14 lesions were detected with HDWL first and 15 with subsequent i-scan. In group 2, 21 lesions were detected with i-scan first and 4 with subsequent HDWL. The miss rate for endoscopic lesions was 52% and 16 % respectively and was significantly different in favor of i-scan (p 0.01 95% CI 0.38 to 0.87). Similarly, 5 adenomas were detected with HDWL vs 7 with i-scan in group 1. In group 2, i-scan detected 13 of the 15 adenomas, resulting in a miss rate of 58% and 13% respectively (p 0.05 95% CI 0.24 to 0.96). The higher miss rate in group 1 was not due to a shorter inspection time. On the contrary, in general the second inspection time was significantly shorter than the first one (407 19 vs 503 24 sec, p 0.01) and inspection time during the second pass was not significantly different between group 1 and 2 (427 24 vs 384 32 sec resp p 0.27). Conclusion: In patients with HNPCC the miss rate for polyps is significantly reduced during colonoscopy performed with i-scan in comparison to HDWL, independently from inspection time. These findings add to the evidence that HNPCC may be a good indication for (virtual) chromoendoscopy.