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Biliary tract cancers (BTC) are rare and often diagnosed in late stages with advanced, nonresectable disease. The targeted agents panitumumab and bevacizumab have shown promising outcomes in combination with chemotherapy in other gastrointestinal (GI) cancers. We wanted to investigate if panitumumab or bevacizumab was the most promising drug to add to chemotherapy. Eighty-eight patients were randomized to combination chemotherapy supplemented by either panitumumab 6 mg/kg or bevacizumab 10 mg/kg on Day 1 in Arm A and Arm B, respectively. All patients received gemcitabine 1000 mg/m 2 on Day 1, oxaliplatin 60 mg/m 2 on Day 1 and capecitabine 1000 mg/m 2 twice daily from Days 1 to 7. Treatment was repeated every 2 weeks until progression or for a maximum of 6 months. At progression, crossover was made to the other treatment arm. The primary endpoint was progression-free survival (PFS) at 6 months. With 19 of 45 in Arm A and 23 of 43 in Arm B PFS at 6 months, the primary endpoint was not met. The overall response rate (ORR) was 45% vs 20% (P = .03), median PFS was 6.1 months vs 8.2 months (P = .13) and median overall survival (OS) was 9.5 months vs 12.3 months (P = .47) in Arm A and Arm B, respectively. Our study showed no consistent differences between adding panitumumab or bevacizumab to chemotherapy in nonresectable BTC and none of the two regimens qualify for testing in Phase III. However, we found a higher response rate in the panitumumab arm with potential implication for future trials in the neoadjuvant setting.

Background: Molecular markers may identify subgroups of patients with clinically distinct behavior and response to treatment. In some gastrointestinal tumors, KRAS has prognostic value and negative predictive value. This is the first prospective study to report the outcome of combination chemotherapy in biliary tract cancer patients with KRAS mutation. Methods: From 2009 to 2015, 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, ECOG performance status 0–2 and tumor KRAS mutation. A bi-weekly cycle of chemotherapy was administered as gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1, followed by 7 days of oral capecitabine 1000 mg/m2. Response evaluation was done every six treatment and the primary endpoint was the fraction with progression free survival (PFS) at 6 months. The study also included a non-preplanned analysis of circulating tumor specific DNA. Results: Chemotherapy was given for a median of 5 months (range 0–14) and among 17 patients evaluable for response, best responses were complete response (1), partial response (2), and stable disease (14). Eighteen patients had CT-verified progression, six died between evaluations and one patient is still progression-free. Median PFS was 6.8 months (95% CI 3.1–11.0) and median overall survival (OS) was 11.2 months (95% CI 6.6–14.3). The fraction with PFS at 6 months was 52% (95% CI 31–69%). Exploratory analyses found an improved survival in patients with a low level of plasma DNA. Conclusion: Pretreatment molecular characterization was feasible in BTC, but the rate of KRAS mutations was low. The study met its primary endpoint with a fraction of PFS at six months of 52%. The effect of combination chemotherapy with gemcitabine, oxaliplatin and capecitabine in this selected population was comparable to results from unselected groups with PFS and OS of 6.8 and 11.2 months, respectively. ClinicalTrials.gov NCT00779454

Background: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). Methods: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. Results: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. Conclusions: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated.

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.

Background and aimsSince approximately 30% of patients with Dukes’ stage B colorectal cancer will experience disease recurrence within five years of primary treatment, current staging of patients with early colorectal cancer apparently fails to adequately predict patient outcome. It has previously been shown that the preoperative plasma concentration of soluble urokinase plasminogen activator receptor (suPAR) is associated with the survival of patients with early colorectal cancer. In this study we sought to confirm the independent prognostic value of suPAR in rectal cancer.MethodssuPAR was retrospectively determined by two different versions of a suPAR ELISA in preoperatively collected plasma samples from a Swedish (n=354) and a Danish (n=255) cohort of rectal cancer patients.ResultsIn both cohorts the suPAR concentration was significantly higher in Dukes’ stage D patients than in Dukes’ stage A-C patients (pConclusionsThis study confirms that the preoperative concentration of plasma suPAR contains independent prognostic information on patients with rectal cancer. This result was independent of the two different versions of an in-house suPAR ELISA used to perform the analyses. The next step in the evaluation of suPAR as a prognostic parameter in rectal cancer will be to launch an appropriately dimensioned prospective study where the benefit of applying preoperative plasma suPAR measurement to clinical decision-making regarding adjuvant therapy is assessed.

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.In this phase II, single-arm study, panitumumab (6 mg/kg) and FOLFIRI [irinotecan (180 mg/m(2)) and leucovorin (400 mg/m(2)) followed by a 5-fluorouracil 400 mg/m(2) bolus and a 2,400-3,000 mg/m(2) continuous infusion] were administered every 14 days until progression. Data were analysed descriptively overall and by tumour KRAS status.KRAS data were available for 145/154 (94%) patients: 59% KRAS WT and 41% mutant (MT); mean follow-up was 39.5 versus 35.8 weeks, respectively. Objective responses occurred in 49% of patients: 56% versus 38% in the KRAS WT versus MT groups [(18% difference (95% CI 1-35%); odds ratio 2.1 (95% CI 1.0-4.4)]; median duration of response was 13.0 versus 7.4 months. More patients in the WT group underwent R0 resection (8% vs. 5%); median progression-free survival also favoured this group (8.9 vs. 7.2 months). The most common adverse events (any grade) were integument toxicities (98%), diarrhoea (79%) and stomatitis/oral mucositis (51%).As expected, consistently favourable efficacy was observed in patients with KRAS WT versus MT tumours receiving first-line panitumumab plus FOLFIRI treatment.

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.

We utilized the high-throughput tissue microarray method to characterize immunohistochemical expression patterns with correlations to prognosis in rectal cancer. Immunostaining for the markers Ki-67, Bcl-2, p53, EGFR, E-cadherin, beta-catenin, MLH1 and MSH2 was performed in 269 rectal cancers. Expression profiles were correlated to metastasis-free survival. Immunostaining revealed frequent upregulation and/or aberrant staining patterns for several of the markers, but Ki-67, p53, Bcl-2 and EGFR did not show any correlation to prognosis. However, reduced membranous staining for beta-catenin (p = 0.04), lack of cytoplasmic staining for beta-catenin (p = 0.04), reduced membranous staining for E-cadherin (p = 0.02) and lack of cytoplasmic staining for E-cadherin (p = 0.02) correlated with metastatic disease. Multivariate analysis including the factors Dukes' stage and tumor differentiation grade demonstrated increased risk of metastatic disease in tumors with lack of cytoplasmic staining for beta-catenin (HR = 3.1, p = 0.02), reduced membranous staining for beta-catenin (HR = 1.7, p = 0.06) and reduced membranous staining for E-cadherin (HR = 2.1, p = 0.06). Loss of MMR protein expression was confirmed to be a rare event in rectal cancer with loss of MLH1 staining in 3% and MSH2 in 1% of the tumors. The lack of prognostic information contributed by most of these markers suggests that single markers for prognosis may be of limited value in rectal cancer. However, altered expression of beta-catenin and E-cadherin correlated with metastatic disease, and these markers may have prognostic importance in rectal cancer.

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

We have screened 17 Southern Sweden individuals/families with suspected hereditary non-polyposis colorectal cancer (HNPCC) for mutations in the DNA-mismatch repair genes hMLH1, hMSH2 and hMSH6 using denaturing gradient gel electrophoresis, protein truncation test and direct DNA sequencing. The families were selected on the basis of a family history of HNPCC-related tumors or the occurrence of metachronous colorectal cancer/endometrial cancer at young age in an individual with a weak family history of cancer. Furthermore, we required that tumor tissue from at least one individual in the family had to display microsatellite instability. We identified germ-line mutations in 9 individuals from 8 families. Five families had mutations in hMLH1, 4 of which were splice site mutations, 2 had frameshift mutations in hMSH2 and 1 patient with metachronous endometrial and rectal cancer but with a weak family history of cancer had a nonsense mutation in hMSH6. Our results present novel germ-line DNA-repair gene mutations, one of these in hMSH6, and demonstrate the diversified mutation spectrum in Sweden, where no founder mutation has so far been identified.

The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC).Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect.Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms.The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting.NCT00598156.

e15620Background: KRAS mutations occur in biliary tract cancer (BTC) at a low rate and little is known as to prognosis and response to chemotherapy for this subgroup. This is the first prospective ...

Background Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Methods Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. Results 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. Conclusions First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity. Trial registration ClinicalTrials.gov NCT00508404

Background. The optimal chemotherapy in patients with advanced gastric carcinoma (GC) is yet to be determined. We compared sequential administration of docetaxel and irinotecan, both in combination with infused 5-fluorouracil/leucovorin (5-Fu/Lv), and randomly assigned patients to start with either of the two. Methods. Patients with previously untreated locally advanced or metastatic GC and with measurable lesions (response evaluation criteria in solid tumors; RECIST) were randomly assigned to start with docetaxel 45 m (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus/44-h infusion of 5-Fu/Lv (day 1 every 2 weeks). After four courses, there was a pre-scheduled crossover to the alternative regimen for four additional courses. Results. Eighty-one patients were randomized and 78 started treatment. Complete and partial responses were seen in 31 (40%) patients after 8 weeks and in 32 (41%) after 16 weeks, with similar results in both study arms. The median overall survival (OS) was 11.5 and 10.6 months in arms T and C, respectively (P = 0.3). The two schedules were feasible and did not differ in the overall rate of severe adverse events (SAEs). Conclusion. This is the first randomized comparison of two of the newer cytostatic drugs in GC therapy. No differences favoring either arm T or arm C were found with respect to response rate, OS, or toxicity. The median OS of 11 months indicates that sequential administration of the two combinations is effective and is similar to triple combinations. Thus, comparable efficacy to platinum combinations appears to be obtained with newer, less toxic regimens when given sequentially.

Background Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways. Colorectal cancers in patients under 50 years of age represent about 5% of the total number of tumors and have been associated with an increased frequency of MSI tumors. However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age. Methods Thirty rectal cancers diagnosed before the age of 50 were characterized for DNA-ploidy, MSI, mutations of KRAS and CTNNB1 and immunohistochemical expression of p53, β-catenin and of the mismatch repair (MMR) proteins MLH1 and MSH2. Results DNA aneuploidy was detected in 21/30 tumors, KRAS mutations in 6 tumors, no mutations of CTNNB1 were detected but immunohistochemical staining for β-catenin showed nuclear staining in 6 tumors, and immunohistochemical expression of p53 was detected in 18 tumors. MSI was detected in 3/30 tumors, all of which showed and immunohistochemical loss of staining for the MMR protein MSH2, which strongly indicates a phenotype associated with hereditary nonpolyposis colorectal cancer (HNPCC). Conclusions MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients.

Publisher Summary This chapter reviews the tissue microarray (TMA) technique for immunohistochemistry with respect to reproducibility and technical advantages (1) to provide detailed methodologic data and (2) to discuss experiences from applying TMA and immunostaining in rectal cancer with specific focus on the proliferation marker (Ki-67) and the tumor-suppressor protein (p53). The TMA technique was developed in 1998 for high-throughput analysis of multiple tumor samples in a single experiment. The TMA technology uses 0.6 mm core needle biopsies, which are obtained from archival paraffin-embedded tissue blocks and thereafter re-embedded in a novel paraffin array block. The introduction of TMA facilitates studies of molecular alterations at the DNA, RNA, and protein level in large tumor materials and thereby provides a powerful tool to detect associations among molecular markers, histopathologic subsets, and clinical end points. Because the frequencies of the different genetic alterations vary depending on the tumor location within the large bowel, studies aiming to investigate a possible prognostic role of biologic parameters should optimally analyze these tumor types separately.

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.

We analysed microsatellite instability (MSI) in a consecutive series of 165 rectal carcinomas. Data on a personal and/or family history of cancer were collected from all patients and revealed metachronous cancer in 9 patients, 2 of whom had developed colorectal cancer, and a suspected familial aggregation of colorectal cancer in three families. Only three of the 165 (2%) rectal cancers showed MSI. The patients whose tumours displayed MSI had clinical histories suggesting hereditary cancer—a family history of colorectal cancer and/or synchronous colorectal cancers. Denaturing gradient gel (DGGE) analysis was used to screen the MSI+ patients for mutations in the hMLH1 and hMSH2 genes and revealed two new germline mutations; a 1 bp deletion in exon 10 of hMSH2 creating a premature stop-codon and a splice donor site mutation in intron 16 of hMLH1 . Considering colorectal carcinomas as a group, MSI has been reported to occur in approximately 10–20% of the tumours and thus can not, per se be used for clinical detection of hereditary tumours. This study shows, however, that MSI is rare in rectal carcinomas and when present strongly suggests a hereditary predisposition for colorectal cancer development.

3634 Background: Study 314 was a phase II, single-arm, multicenter study designed to assess the efficacy/safety by KRAS tumor status of first-line pmab plus FOLFIRI in pts with mCRC. Here, we investigate the relationship between QoL and tumor response. Methods: Pmab (6mg/kg) and FOLFIRI were administered every 14 days until disease progression, consent withdrawal, or unacceptable toxicity. EUROQOL EQ-5D Index scores were recorded at screening, every 8 wks until wk 32, every 3 months thereafter until disease progression, and 56 days after stopping study treatment (safety follow up visit). EQ-5D scores range from –0.594 to 1 (1=perfect health). A change of ≥0.08 may be considered clinically meaningful. Data were analyzed descriptively by tumor KRAS status (wild type [WT] or mutant [MT]) and by best overall response. Results: A trend for better tumor response in pts with higher baseline EQ-5D scores was observed. In pts who achieved CR/PR, the difference in EQ-5D score between the WT group and the MT group e...

3545 Background: Pmab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is approved in Europe as monotherapy for pts with chemotherapy-refractory, EGFR-expressing, KRAS wild-type (WT) mCRC. Methods: Ptsreceived pmab (6 mg/kg) and FOLFIRI every 2 weeks. Eligibility criteria included histologically confirmed mCRC (no prior systemic treatment for metastatic disease), ECOG PS 0–2 and availability of tumor tissue for biomarker analysis. The primary endpoint was objective response rate and secondary endpoints included progression-free survival and safety. All analyses are descriptive, this abstract discusses resections. Results: A total of 154 pts were enrolled. At time of primary analysis (June 09), KRAS evaluable samples were available for 94% (n = 145) of pts: 86 (59%) pts had KRAS WT tumors and 59 (41%) pts had KRAS mutant (MT) tumors. Demographics in the primary analysis set (all KRAS evaluable pts) by KRAS WT and MT were: 78%/54% male; median age (range) 63.5...

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.

4579 Background: The optimal chemotherapy combination in patients with metastatic gastric adenocarcinoma (GA) is yet to be determined. We compared two newer drugs, docetaxel (arm T) and irinotecan ...