Therapy In Colorectal Cancer Patients Research Articles

Efficacy and tolerability of oxycodone for oxaliplatin-induced peripheral neuropathy and the extension of folfox therapy in colorectal cancer patients.

196 Background: The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. Methods: This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. Results: All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6–46) and 7 (range, 2–18), respectively (P < 0.05). The median cumulative oxaliplatin doses were 1072.3 mg/m2 (range, 408.7–3385.3 mg/m2) in the OXY group and 483.0 mg/m2 (range 76.2–1414.1 mg/m2) in the non-OXY group (P < 0.05). Conclusions: Our findings indicate that CR oxycodone might attenuate the severity of OIPN and extend the use of FOLFOX therapy.

Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-Egfr Antibodies Can Be Overcome By the Treatment with Regorafenib in Combination with Cetuximab

ABSTRACT Aim: Advances in the molecular understanding of colorectal cancer (CRC) have demonstrated that several signaling pathways have been implicated into the resistant mechanisms to anti-EGFR monoclonal antibodies (MoAbs) such as cetuximab, including EGFR, RAS/RAF and PI3K/AKT Methods: We have tested, in vitro and in vivo, the effects of regorafenib, a novel oral multikinase inhibitor that targets protein kinases involved in tumor angiogenesis [VEGFR1–3 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2)], oncogenesis (KIT, RET and RAF) and the tumor microenvironment [platelet- derived growth factor receptor-b and fibroblast growth factor receptor (FGFR)18], in a panel of human CRC cell lines with primary or acquired resistance to cetuximab Results: among the CRC cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, SW480) and one with a BRAF mutation (HT29) were resistant to the anti-proliferative effects of cetuximab, whereas two cell lines (GEO and SW48) were highly sensitive to cetuximab. Treatment with regorafenib determined dose-dependent growth inhibition in all cancer cell lines, including two human CRC cell lines with acquired resistance to cetuximab, that previously were generated in our laboratory (GEO-CR and SW48-CR). Combined treatment with cetuximab and regorafenib induced a synergistic anti-proliferative and apoptotic effects by blocking MAPK- and AKT-pathways in cell lines with either primary or acquired resistance to cetuximab. Nude mice were injected subcutaneously with SW48-CR cells. The combined treatment with cetuximab and regorafenib caused significant tumor growth inhibition and increased mice survival. We are currently performing an experiment on an in vivo orthotopic CRC model to validate the role of combined treatment of regorafenib plus cetuximab to overcome resistance to anti-EGFR inhibitors. Conclusions: These results suggest that the combined treatment with cetuximab and regorafenib could be a strategy for overcoming resistance to anti-EGFR therapies in CRC patients. Disclosure: All authors have declared no conflicts of interest.

Prevalence of KRAS, BRAF, NRAS, PIK3CA, and PTEN alterations in colorectal cancer: Analysis of a large international cohort of 5,900 patients.

399 Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with metastatic disease accounting for 40 to 50% of newly diagnosed patients. EGFR monoclonal antibodies (Mab), cetuximab and panitumumab, are effective treatment for KRAS wild type CRC. Although mutations in KRAS predict resistance to EGFR Mab therapy, only 80% of CRC patients with KRAS wild-type (WT) status respond to treatment. This study is a retrospective evaluation of genomic alterations in the EGFR pathway such as alterations in KRAS, BRAF, NRAS, PIK3CA and PTEN that may predict lack of response to EGFR Mab therapy in CRC patients. Methods: A large database of 5,900 consecutive CRC patients was analyzed from 2011 onwards for demographics (sex, age, geography, site of tumor) and biomarkers that might correlate with response to EGFR Mab therapy. Comprehensive testing included gene sequencing for KRAS, BRAF, NRAS, PTEN, and PIK3CA (next-generation sequencing, Sanger, pyrosequencing) and immunohistochemistry for PTEN protein expression. Results: Analysis revealed the incidence of KRAS mutation of 42% which is consistent with published literature. Analysis of the KRAS WT cohort revealed a mutation rate of 13.8 % for BRAF, 6.8% for NRAS, and 40% for patients with either PTEN loss of expression/mutation or a PIK3CA mutation. Earlier studies support that mutations in NRAS, BRAF and activation of the PI3K pathway by PTEN/PIK3CA analysis result in lower response rates to EGFR Mab therapy in CRC. Furthermore, multiplex biomarker testing revealed the rare occurrence of concurrent mutations: 1/5,900 subject harboring a BRAF and NRAS mutations, 7/5,900 others with BRAF and PIK3CA mutations, and 8/5,900 subjects with NRAS and PIK3CA mutations. Conclusions: This is a comprehensive analysis of a large international cohort evaluating the prevalence of predictive molecular aberrations suspected of lack of response to EGFR Mab therapy in patients with WT KRAS. Prospective controlled studies are in progress to validate the role of BRAF, NRAS, PIK3CA, and PTEN in clinical management of CRC. It is imperative to further explore the molecular pathology of CRC beyond KRAS in patient selection for EGFR Mab therapy.

Recent applications of chemosensitivity tests for colorectal cancer treatment.

The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culture-based chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyl-tetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.

Conversion therapy for colorectal cancer patients with potentially resectable liver metastases

Conversion therapy for colorectal cancer patients with potentially resectable liver metastases

O2–094 - Clinical Demographics and Multimodal Therapy for Colorectal Cancer Patients with Human Immunodeficiency Virus Infection

O2–094 - Clinical Demographics and Multimodal Therapy for Colorectal Cancer Patients with Human Immunodeficiency Virus Infection

Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding

Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)-based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3'-untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU. We tested 12 SNPs in the 3'-UTRs of five BER genes for colorectal cancer susceptibility in a case-control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set). SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36-0.81; P = 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU-based chemotherapy (P = 5.6 × 10(-5)). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk. We provide the first evidence that variations in miRNA-binding sites in BER genes 3'-UTR may modulate colorectal cancer prognosis and therapy response.

DUSP 4 expression identifies a subset of colorectal cancer tumors that differ in MAPK activation, regardless of the genotype

As dual-specificity phosphatase (DUSP) expression has been correlated to sensitivity to MEK inhibitors, DUSP expression levels may indicate activation of the mitogen-activated protein kinase (MAPK) pathway in many tumor types. In this study, we investigate if DUSP levels can indicate different levels of MAPK activation within colorectal cancer (CRC) patients. In three different CRC patient microarray datasets, we analyzed the expression of DUSP1. DUSP4 and DUSP6 according to mutational status, their correlation with survival and their association with different clinical characteristics. DUSP4 was significantly differentially expressed between all mutational subgroups with the highest expression in BRAF mutated tumors. Moreover, high DUSP4 expression was associated with a worse overall survival and with clinical characteristics typical for BRAF mutant patients. The use of DUSP expression as a predictive biomarker towards MAPK targeted therapy in CRC patients needs further investigation.

Prospect of cetuximab in the treatment of colorectal cancer

Colorectal cancer is one of the most common malignant tumors.With the improvement of living condition and peoples' life-span,the incidence rate of colorectal cancer has been ascending year by year.In developed countries and developed district of China,colorectal cancer has become the second common malignant tumor.More than one million people were diagnosed as with colorectal cancer,and 500,000 of them died yearly.Colorectal cancer is one of the most common reasons of the death of cancer patients.With the development of molecular targeted agents research,the therapeutic effects for colorectal cancer patients have been improved,and the current status and prospect of targeted therapy for colorectal cancer patients were introduced in this review. Key words: Colorectal neoplasms; Targeted therapy

Abstract LB-75: Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients.

Abstract The anti EGFR monoclonal antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancer patients. The clinical efficacy of EGFR inhibitors is limited by the development of acquired resistance, which typically occurs within 3-12 months since starting of therapy. We recently reported that secondary KRAS mutations are responsible for acquired resistance in approximately 50% of patients (Misale et al.; Diaz et al., Nature 2012). We reasoned that the detection of KRAS mutant alleles in the plasma of cetuximab treated patients may enable the early identification of secondary resistance to anti EGFR blockade before radiographic documentation of relapse. Using the highly sensitive BEAMing approach we have examined cell-free circulating tumor DNA (ctDNA), a form of "liquid biopsy". KRAS mutant alleles emerged in the circulation of approximately 50% of patients treated with anti-EGFR antibodies months before radiographic documentation of disease progression. The liquid biopsy approach was then used to select patients in which KRAS mutations did not emerge during anti-EGFR therapy. Exome sequencing identified amplification of the MET proto-oncogene in biopsies from patients who did not develop KRAS mutations. Using an innovative approach, we find that MET amplification can be identified in a non-invasive manner through the examination of ctDNA months before relapse becomes clinically manifest. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies. Citation Format: Giulia Siravegna, Andrea Sartore Bianchi, Andrea Cassingena, Katia Bencardino, Luis A. Diaz, Mark Sausen, Victor E. Velculescu, Federica Di Nicolantonio, Salvatore Siena, Alberto Bardelli. Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-75. doi:10.1158/1538-7445.AM2013-LB-75

Direct medical costs associated with different lines of therapy for colorectal cancer patients

SUMMARY Aim: To evaluate the disease-specific expenditures incurred by colorectal cancer (CRC) patients with one, two, and three or more lines of therapy. Methods: The Truven Health MarketScan® Research Databases were used to identify adults with incident CRC from 2005 to 2009. Healthcare expenditures were measured from initiation through to follow-up and individual therapy line. Results: Among 13,670 CRC patients, 67.5% had one line of therapy, 20.7% had two and 11.8% had three or more. Monthly expenditures averaged US$12,523. Monthly first-line therapy costs averaged US$12,067, increasing to US$13,315 during second-line therapy and to US$14,648 during third-line therapy. Patient out-of-pocket expenses were a small (1.9%) contributor to total costs. Conclusion: CRC presents a significant economic burden to payers with important cost differences according to how patients are treated.

Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance?

Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options.

Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer

Anecdotal reports of tumour regression with histamine type 2 receptor antagonists (H(2)RAs) have lead to a series of trials with this class of drug as adjuvant therapy to try and improve outcomes in patients with resected colorectal cancers. There was a plausible scientific rationale suggesting merit in this strategy. This included improved immune surveillance (by way of increasing tumour infiltrating lymphocytes), inhibiting the direct proliferative effect of histamine as a growth factor for colorectal cancer and, in the case of cimetidine, inhibiting endothelial expression of E-selectin (a cell adhesion molecule thought to be critical for metastatic spread). To determine if H(2)RAs improve overall survival when used as pre- and/or postoperative therapy in colorectal cancer patients who have had surgical resection with curative intent. We also stratified the results to see if there was an improvement in overall survival in terms of the specific H(2)RA used. Randomised controlled trials were identified using a sensitive search strategy in the following databases: MEDLINE (1964 to present), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009), EMBASE (1980 to present) and Cancerlit (1983 to present). Criteria for study selection included: patients with colorectal cancer surgically resected with curative intent; H(2)RAs used i) at any dose, ii) for any length of time, iii) with any other treatment modality and iv) in the pre-, peri- or post-operative period. The results were stratified for the H(2)RA used. The literature search retrieved 142 articles. There were six studies included in the final analysis, published from 1995 to 2007, including a total of 1229 patients. All patients were analysed by intention to treat according to their initial allocation. Log hazard ratios and standard errors of treatment effects (on overall survival) were calculated using the Cochrane statistical package RevMan Version 5. Hazard ratios and standard errors were recorded from trial publications or, if not provided, were estimated from published actuarial survival curves using a spreadsheet designed for this purpose (http://www.biomedcentral.com/content/supplementary/1745-6215-8-16-S1.xls). Of the six identified trials, five used cimetidine as the experimental H(2)RA, whereas one used ranitidine. There was a trend towards improved survival when H(2)RAs were utilised as adjuvant therapy in patients having curative-intent surgery for colorectal cancer (HR 0.70; 95% CI 0.48-1.03, P = 0.07). Analysis of the five cimetidine trials (n = 421) revealed a statistically significant improvement in overall survival (HR 0.53; 95% CI 0.32 to 0.87). Of the H(2)RAs evaluated cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers. The trial designs were heterogeneous and adjuvant therapy has evolved since these trials were performed. Further prospective randomised studies are warranted.

Increased Pontin expression is a potential predictor for outcome in sporadic colorectal carcinoma

Colorectal cancer is one of the leading causes of cancer-related death worldwide. Molecular biomarkers could help to predict patient outcome and to identify patients who benefit from adjuvant therapy. Pontin and Reptin are ATPases which are involved in transcriptional regulation, DNA damage repair and regulation of cell proliferation. Many interaction partners of Pontin and Reptin such as β-catenin and c-myc are important factors in carcinogenesis. We hypothesized that Pontin and Reptin expression may be a negative predictor for survival in colorectal carcinoma. Specimens from 115 patients with primary colon adenocarcinomas UICC stageIII and primary rectal adenocarcinomas UICC stage II and III curatively resected at the Department of Surgery, Charité Berlin, were evaluated. Clinical follow-up data were complete and mean follow-up time of patients was 51.8 months. We evaluated the expression of Pontin, Reptin and Ki-67 by immunohistochemistry. Patients with Pontin-positive carcinomas showed no differences in recurrence-free survival (p=0.109) and overall survival (p=0.197). There were no differences in Reptin-positive carcinomas and Ki-67-positive carcinomas in recurrence-free survival (p=0.443 and p=0.160) and overall survival (p=0.477 and p=0.687). Patients with Pontin-positive colorectal carcinomas receiving adjuvant therapy had a significantly worse recurrence-free survival (p=0.008) and overall survival (p=0.011) than Pontin-negative patients with adjuvant therapy. In UICC stage III, Pontin-positive colorectal carcinomas had a significantly worse recurrence-free survival (p=0.028). Pontin-positivity seems to be a negative predictor for response to adjuvant therapy in colorectal cancer patients and may help to identify patients with adverse outcome in advanced tumor stages.

Clinical Significance of Perineural Invasion in Colorectal Cancer

Purpose : Perineural invasion (PNI) is widely known to be correlated with poor survival in many type of malignancy but the connection between perineural invasion of colorectal cancer and the prognosis has not yet been clearly confirmed. Therefore, we examined perineural invasion in colorectal cancers and investigated its relationship to clinicopathological features such as tumor staging, lymph node metastasis, vascular invasion, lymphatic invasion and patient’s prognosis in this study Methods : The subjects were 148 colorectal cancer patients who underwent surgical resection in OOO. The pathologists who were not aware of the prognosis of the patients reexamined the existing biopsy results and reevaluated the perineural invasion. The presence of perineural invasion and the other clinicopathological factors were compared and the statistical significance of the correlation between these was examined. Results : Perineural invasion was confirmed in less than 10% of the patients in the initial biopsy results. However, it was confirmed in 20.9% of the patients reevaluating the biopsy. Perineural invasion in colorectal cancer was found to be unrelated to the T stage of the patients (p=0.114). On the other hand, perineural invasion appeared to be strongly related to lymph node metastasis of colorectal cancer (p more common in the patients with perineural invasion (p=0.001). Moreover, perineural invasion seemed to be related to the stage of cancer (p the level of differentiation nor to the distant metastasis since perineural invasion was expressed in 21% of the patients with distant metastasis and in 20% of the patients without distant metastasis. Conclusion : The correlation of perineural invasion in colorectal cancer to the clinicopathologic factors such as lymph node metastasis, lymphatic invasion, vascular invasion and the stage of disease were confirmed. And perineural invasion was significantly correlated with patient’s survival. This is thought to be that perineural invasion can be a prognostic factor of colorectal cancer and it should be utilized planning adjuvant therapy for colorectal cancer patients.

TOP1 gene copy number in stage III colorectal cancer (CRC) samples: Association to prognosis.

475 Background: TOP1 inhibitor treatment is frequently being used in combination therapy of metastatic CRC. This study aims to reveal whether TOP1 gene copy number associates with patient prognosis, since such a relationship may have significant implications for future studies aiming at validating the predictive value of TOP1 gene copy number. Methods: The study included TOP1 and CEN-20 FISH analyses (DAKO A/S Denmark) on FFPE tissue sections from 154 stage III CRC patients who did not receive adjuvant chemotherapy. TOP1 gene copy number, CEN-20 copy number and the TOP1/CEN-20 ratios were analyzed and correlated to overall survival (OS), to time to recurrence (TTR) of patients with CRC and to local recurrence (LR) in patients with rectal cancer (RC). Results: TOP1 copy number counts and the TOP1/CEN-20 ratios, age, gender and primary tumor location were separately added into a multivariate analysis as continuous variables. For OS and LR, TOP1 copy number was significant and the ratio was borderline significant with higher copy number associated with longer OS or longer time to LR. When the patients were dichotomized using the TOP1 median copy number, we found that patients with high TOP1 copy number in their tumor cells had a significant longer OS (HR: 0.68; 95% CI: 0.47-0.98; p = 0.04) compared to patients with low TOP1 copy number. Using the median TOP1/CEN-20 ratio to dichotomize, no significant differences were observed between patients with levels above or below the median ratio number for OS (HR: 0.76; 95% CI: 0.53-1.10; p = 0.14). TOP1 copy number divided the RC patients into two groups with a trend towards a significant difference in time to LR (HR: 0.56; 95% CI: 0.27-1.16; p = 0.11) with higher copy number. If the median ratio was used, a significant association with longer time to LR (HR: 0.43; 95% CI: 0.20-0.92; p = 0.03) was found. No significant associations between TOP1 copy number or ratio and TTR were observed. Conclusions: Increased TOP1 copy number is associated with longer OS in CRC patients and fewer LR in RC patients. Thus, future studies analyzing the association between TOP1 copy number and response to therapy in CRC patients should be planned in such a way that a prognostic and a predictive value of TOP1 can be separated.

Predictive and prognostic value of circulating nucleosomes and serum biomarkers in patients with metastasized colorectal cancer undergoing Selective Internal Radiation Therapy

BackgroundSelective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and prognosis are needed for the individual management of those patients undergoing SIRT.MethodsBlood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival.ResultsCirculating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model.ConclusionPanels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy.

No evidence for PML-RARa bcr1 fusion gene in colorectal cancer

Colorectal cancer is the third most prevalent cancer and a leading cause of cancer death. Metastatic colorectal cancer patients are treated with anti-EGFR monoclonal antibodies in combination with chemotherapy; however, the efficiency is only 10-20% of such patients. An increasing amount of data has demonstrated that response to anti-EGFR therapies is confined to patients with KRAS and BRAF wild type tumors but still some of these patients are non responders to this treatment. The presence of oncogenic deregulation of different members of EGFR downstream signaling or crosstalk molecules could predict the lack of response in these patients. In this study, 40 wild type KRAS and BRAF colorectal tumors were analyzed to elucidate whether PML-RARa bcr1 fusion gene may play a role in colorectal carcinogenesis. Specifically we want to determine if this fusion could be responsible for the inability to respond to anti-EGFR monoclonal antibodies. Here, for the first time it is reported, that PML-RARa bcr1 fusion is not responsible for colorectal tumor development and also, this translocation is not predicting the lack of efficacy of anti-EGFR therapies in wild type KRAS and BRAF colorectal cancer patients. These results also suggest that PML-RARa is unlikely to be a promising target for adjuvant therapy in colorectal cancer patients.

Peripheral blood guanylyl cyclase c (GCC) expressions are associated with prognostic parameters and response to therapy in colorectal cancer patients

Guanylyl cyclase C (GCC) is expressed exclusively in normal intestinal mucosal cells, primary and metastatic colorectal cancers (CRC). The aim of this study was to determine the possible association between the GCC expressions in peripheral blood, prognostic parameters and response to chemotherapy in CRC patients. Fourty-nine metastatic CRC patients and 41 healthy controls with similar age and sex were included to this study. Peripheral blood GCC expressions are measured by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Interstingly, no GCC expression was measured in healthy controls but GCC expressions of the patients were detectable. Although there was a significant reduction in GCC expressions in 30 patients with regression (from 5.46 ± 4.12 to 0.06 ± 0.03, p < 0.0001), marked increase in GCC expressions was observed in 19 patients with progression following chemotherapy (from 0.43 ± 0.19 to 1.38 ± 0.52, p = 0.0174). Significant correlation was found between the GCC expressions and carbohydrate antigen 19-9 (CA19-9) levels (p = 0.0041) in 30 patients with regression before chemotherapy. Marked correlation was also detected between the GCC expressions and carcinoembryonic antigen (CEA) levels (p = 0.0072) in 19 patients with progression before chemotherapy. The results of the present study suggest that peripheral blood GCC expressions along with CEA and CA19-9 can be used to determine the early respose to chemotherapy in patients with metastatic CRC. These findings imply that higher expression of GCC in peripheral blood seems to be an indicator of good therapeutic response to chemotherapy and remission. Monitoring the peripheral blood GCC expressions may allow employing different treatment options to metastatic CRC patients.

Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p&lt;0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p&lt;0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.