bluuebunny/crossref_metadata_2025 huggingface dataset:
Colorectal cancer presentation in eastern Bay of Plenty, New Zealand.
Authors: Khan Afrasyab , Prasad Jagdish
Published: February 2017

370

Background: New Zealand has a high incidence of colorectal cancer; the death rate is the highest amongst developed countries. New Zealand does not have a national screening program for colorectal cancer yet. This study was done in a region with a higher proportion Maori ethnicity. We hypothesized that there are differences in presentation and pathology of colorectal cancer between Maori and European people. Methods: A review of new cases of colorectal cancer presenting over a period of three years (2008-2011) at Whakatane Hospital was done. Data was collected from clinical records and entered into SPSS software. Results: 113 new cases of colorectal cancer were identified. Median age was 73 years. Maori patients were younger than the rest (median age 60 vs 74.5; p < 0.05). 95 patients were of European ethnicity and 15 were Maori. The predominant sign/symptom on presentation was PR bleeding (32%). Only 5 cases were asymptomatic and diagnosed on surveillance colonoscopy. The histologic type of tumor was adenocarcinoma in 111 cases. The most common site of the tumors was the rectum (18.6%). 34.5% cases had localized disease (stage 1, 2A) with no significant difference between Maori and the rest.18.6% cases had distant metastasis with no significant difference between Maori and the rest. Curative surgery was not done in 16 patients due to advanced disease, comorbidities or patient refusal. Conclusions: A higher proportion of patients were diagnosed with localized disease at presentation compared to the rest of New Zealand.. Fewer Maori patients had colorectal cancer in view of the higher proportion of Maori in the area (42-61%). The age of Maori was significantly lower than the rest. Colorectal cancer screening in New Zealand will likely detect cancer earlier. [Table: see text]
Characteristics of colorectal cancer in patients younger than 40 years compared to older patients.
Authors: Salem Mohamed E. , Arun Monica , Dyson Greg , Saad Chadi , Arbabi Cassra , Jain Tania , Taylor Stephanie , Kunz Sara , Choi Minsig , Shields Anthony Frank , Philip Philip Agop
Published: February 2017

371

Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is increasing. There is limited data on tumor characteristics and treatment outcome in this population. Methods: Patients with CRC treated at the Karmanos Cancer Center from 2005 to 2011 were studied. Younger (≤40 years) and older (>40 years) groups from a predominantly inner city population were compared for patient and tumor characteristics, treatment patterns, and survivals. T-tests and Fisher’s exact tests were used to determine statistical differences between age groups while the Kaplan-Meier method was used to estimate survival. Results: 42 pts were ≤ 40 (range, 17-40 years) and 96 pts were > 40 (range, 42-88 years). Mean ages for the groups were 33 and 60 years, respectively. There was no statistically significant difference in the distribution of race, gender, stage or KRAS mutation status between the two groups; however, older pts had a higher mean body mass index compared to younger pts (28 versus 23, p<0.001). Older pts were more likely to have a right colon primary (OR = 7.5, p = 0.04), while younger pts had higher likelihood of having sigmoid primary (OR = 3.4, p = 0.002) and worse grade (poorly differentiated) tumors (OR = 8.3, p <0.001). There were no significant differences between metastatic status or sites of metastases between the two groups. Significantly more young pts underwent surgery than older pts (92% versus 62%, p = 0.005). FOLFOX plus bevacizumab was the most commonly used first line treatment for both groups. The median survival estimates were 16.9 (8.1-23.9) and 17.1 months (13.3-31.0) for the younger and older pts, respectively. Importantly, the one-year survival rates were similar for both groups: 41% for both (p = 1). On the multivariate analysis, whether pts had a primary in the right or sigmoid colon was the only independent predictor of survival. Conclusions: Younger pts with colon cancer were diagnosed at a similar stage of the disease as older pts, but more likely to have poorly differentiated tumors. Younger pts were more likely to receive surgical interventions; however, both groups had equivalent one-year survivals. These results support the need for further prospective investigation in a larger population.
Uptake of genetic testing by relatives in Lynch syndrome: A systematic review.
Authors: Sharaf Ravi , Myer Parvathi , Stave Christopher , Diamond Lisa , Ladabaum Uri
Published: February 2017

374

Background: Screening of persons with newly diagnosed colorectal cancer (CRC) for Lynch Syndrome (LS) can yield substantial population-level benefits at acceptable costs, presuming sufficient uptake of genetic testing by first-degree relatives (FDRs) of LS probands. We reviewed systematically the published literature addressing the frequency and predictors of uptake of genetic testing by FDRs of LS probands. Methods: A literature search was conducted in four electronic databases (CINAHL, PsycInfo, PUBMED, and SCOPUS) for articles published through May 2011 that reported the uptake of genetic testing by relatives of LS probands. Two investigators independently screened articles to determine whether they met inclusion criteria, and abstracted data inthree broad categories: study population, methodology, and uptake of genetic testing. A narrative, qualitative systematic review was performed. The data were not amenable to meta-analysis. Results: 1,258 potentially relevant articles were identified with 533 studies undergoing full text review. Eight articles met inclusion criteria. 52% or less of FDRs of LS probands underwent genetic testing. For each LS proband, 4.6 or fewer relatives underwent genetic testing. Demographic factors (age <50 years, female gender, parenthood, education level, employment, participation in past medical studies), psychological factors (lack of depressive symptoms), and family history (greater number of relatives with cancer) were associated with uptake of genetic testing. Conclusions: Genetic testing may be underutilized by FDRs at risk for LS. The economic feasibility of screening persons with CRC for LS depends on optimizing family-wide uptake of genetic testing. Future research and clinical efforts should focus on ways to overcome barriers to genetic testing.
Genomic classifiers (ColoPrint/MSI-Print) predict outcome and chemotherapy benefit in stage II and III colon cancer patients.
Authors: Kopetz Scott , Jiang Zhi-Qin , Overman Michael J. , Dreezen Christa , Tian Sun , Li Ying , Simon Iris , Chang George J. , Maru Dipen M
Published: February 2017

378

Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment
Second-line therapy of KRAS-mutated (KRASm) metastatic colorectal cancer (CRC) with the MEK inihibitor selumetinib ([SEL], AZ6244, ARRY-142886) in combination with irinotecan (IRI): An AGICC study.
Authors: Hochster Howard S. , Messersmith Wells A. , O'Neil Bert H. , Groshen Susan G. , Cohen Deirdre Jill , Denlinger Crystal Shereen , Gold Philip Jordan , Eckhardt S. Gail , Locker Gershon Y. , Ames Patricia , McKinley Marti , Leichman Lawrence P. ,   Academic GI Cancer Consortium
Published: February 2017

380

Background: 2nd-line therapy of KRASm CRC is limited; targeting downstream signal transduction enzymes is rational here. Use of the MEK inhibitor SEL is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI plus SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin-based chemo + bevacizumab regimen, PS 0-1, acceptable organ function. Patients were treated with IRI 180 mg/m2 iv q2w and SEL 50-75 mg po bid. First 3 patients of run-in portion were treated with SEL 50 mg and if no DLTs, next 3-6 patients at 75 mg po bid. If no DLTs, then phase II dose of SEL 75 mg po bid would be used. Primary endpoint was RECIST 1.0, investigator determined response rate (RR). As compared to the historical RR of 4% (and median PFS 2.5 mos) for 2nd-line FOLFIRI (Tournigand), with alpha 0.10 & beta 0.90, a sample size of 45 would have the power to detect improvement in RR to 15%, and 79% power to demonstrate improved med PFS to 4.0 mos. Early stopping would occur for responses of 0 of 20 patients. Results: 32 patients were entered and treated. Median age was 54 (40-71) yrs, 18 were male and 22 Caucasian, all KRASm. The first 3 tolerated SEL 50 mg bid without SAE and the remaining 29 were treated at 75 bid. Median number of cycles on study was 3.5 and median TTP approximately 4.0 months. Observed grade 3 AEs included: diarrhea 3, fatigue 2, neutropenia 2, and 1 each PLTS, enteritis, GI bleed, rash; one grade 4 ANC. Grade 2 AEs: diarrhea 12, rash 8 pts. Best response (investigator reported) included 3 (9%) confirmed PR and 15 (47%) SD [including 2 unconfirmed PR] of 32 entered. Six patients were on study for > 6 months (6, 6, 8, 9, 12.5, 14.5 months). The study was terminated early due to non-protocol considerations. These data are not yet verified. Conclusions: Despite early termination, the higher RR and PFS noted for 32 patients with KRASm CRC treated with IRI and SEL as 2nd-line therapy of CRC (and treated for up to 14.5 months), are promising compared with historical controls. The strategy of MEK inhibition in KRAS mutated CRC should be explored further. Clinical trial information: NCT01116271.
Mice on trial: Are xenografts using human tissue a better model of cancer than xenografts formed from cell lines?
Authors: Sadadcharam Gaitri , McCourt Morgan , Ryan Ciara , O'Connor Kate , Bennett Michael William , Power Derek Gerard , O'Reilly Seamus , Wang Jinghuai , Redmond Henry Paul , Andrews Emmet J
Published: February 2017

386

Background: Xenograft tumours are validated models using either patient samples (primary xenografts) or cell lines (secondary xenografts) grown in a murine host. Repeated culturing of cancer cell lines results in epigenetic changes and subsequent behaviour changes distinct from primary human cancers. The aim of this study is to form both models and compare their responses to chemotherapy agents. Methods: Fresh primary colorectal adenocarcinoma tissue or colorectal cell lines (SW480 non metastatic line / SW620 metastatic line) were inoculated subcutaneously into immunodeficient mice to form primary and secondary xenografts respectively. Both models were subjected to either a 5-fluorouracil (5-FU) or irinotecan trial. The clinical response and biological features were evaluated. Results: Secondary xenografts were more aggressive with a shorter time to tumour formation, higher uptake rate and more aggressive histological features. The mice were randomised to either the control group (saline) or to the treatment group [60mg/kg of 5FU (SW620 / primary xenografts) or 60 mg/kg of Irinotecan (SW480 / primary xenografts)] via intraperitoneal injection. In the 5FU group, the primary xenografts began regressing after Day 2 but the secondary xenografts continued to grow until Day 8. The decrease from the maximal tumor volume to the study end point (Day 12 in primary xenograft group and Day 10 in secondary xenograft group) was evaluated with primary xenografts showing a greater decrease compared to secondary xenografts (56.6% vs. 10.4%; p =0.002). Conclusions: We demonstrated the ability to grow tumours in mice from fresh human colonic adenocarcinomas. Tumours formed in mice from patient derived adenocarcinomas produce more clinically accurate testing than tumours formed from cell line and may allow for drug screening in order to personalise an individual’s chemotherapy regime.
Expression analysis of MET, EGFR, and HER2, and K-ras mutation status in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Ochiai Atsushi , Kitada Koji , Ichikawa Wataru , Terashima Masanori , Kurahashi Issei , Katai Hitoshi , Kushima Ryoji , Sasako Mitsuru
Published: February 2017

40

Background: Exploratory biomarker analysis was conducted to identify factors related to outcomes of patients enrolled in the ACTS-GC study, a randomized controlled trial comparing surgery followed by adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: Formalin-fixed paraffin-embedded specimens obtained from 105 patients, an institutional subset of this biomarker study of 829 patients, were extensively examined for EGFR and HER2 by immunohistochemistry (IHC), MET amplification by FISH, and K-ras mutation status (codon 12, 13) by PNA-enriched direct sequencing. The expressions of 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were measured by quantitative real-time RT-PCR. The relations of the expressions of these genes to clinicopathological features such as histological type, T grade, N grade, tumor stage, gender, and age were also investigated. Results: The rates of K-ras mutation, EGFR overexpression, HER2 overexpression, and MET amplification were 6.7% (7/105), 14.3% (15/105), 11.4% (12/105), and 21.0% (22/105), respectively. These factors were almost mutually exclusive. Co-expressions were seen in 2 (EGFR & HER2), 4 (HER2 & MET), 5 (MET and EGFR) and 1 (EGFR & HER2 & MET) of the 105 patients. MET amplification and EGFR overexpression were associated with worse outcomes. In contrast, KRAS and HER2 status were not associated with overall survival or relapse-free survival. Expression levels of PCAM1, ESR1, MUC2, CAV1, ITGB3, and APC mRNA were significantly higher in diffuse-type cancer than in intestinal-type cancer, whereas expression levels of HER2, E2F1, LDHA and TOP2A mRNA were significantly higher in intestinal-type than in diffuse-type cancer (FDR P<0.05). Associations of other clinically significant genes with clinicopathological features other than histologic type were not screened. Conclusions: Many clinical, pathological, molecular, and genetic factors have been investigated with a growing understanding of the molecular pathogenesis of gastric cancer. We review and discuss such prognostic markers in the ACTS-GC study.
Investigation of a possible link between epithelial four-and-a-half LIM domains protein 2 expression and prognosis in colorectal cancer.
Authors: Verset Laurine , Tommelein Joke , Moles Lopez Xavier , Decaestecker Christine , Mareel Marc , Bracke Marc , Salmon Isabelle , De Wever Olivier , Demetter Pieter
Published: February 2017

401

Background: Four-and-a-half LIM domains protein 2 (FHL2) is a component of the focal adhesion structures and has been suggested to play a role in cancer progression. It has been shown to be overexpressed in colorectal cancer (CRC). Here we examined a possible prognostic value of FHL2 in CRC. Methods: Immunohistochemistry for FHL2 was performed on 296 CRCs without distant metastases at time of surgery. Staining in the epithelial compartment was quantitatively evaluated using image analysis, and results were related to clinical variables. Antibody specificity was tested using siRNA transfection in hTERT-immortalised myofibroblasts. FHL2 expression was investigated also by Western blotting in sporadic (HT29) and HNPCC-derived (HCT116 and HCT8/E11) colon cancer cell lines. Results: Varying degrees of cytoplasmic FHL2 expression by neoplastic epithelial cells were detectable in all cases. Higher FHL2 expression in the epithelial compartment was an independent adverse prognostic factor. Expression in the tumour invasion front (p < 0.001) as well as in the centre of the tumour (p < 0.001) was associated with metachronous metastases. No relation between FHL2 expression and microsatellite instability could be demonstrated. Conclusions: Higher FHL2 expression is involved in CRC progression and correlates with the development of metachronous metastases, suggesting that FHL2 is an independent adverse prognostic indicator for CRC.
The critical role of dysregulated FOXM1–PLAUR signaling in human colon cancer progression and metastasis.
Authors: Li Dawei , Wei Ping , Peng Zhihai , Huang Chen , Tang Huamei , Jia Zhiliang , Cui Jiujie , Le Xiangdong , Huang Suyun , Xie Keping
Published: February 2017

405

Background: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. Methods: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.
Evaluating variability in fluorouracil (FU) exposure in obese and non-obese patients with colorectal cancer using full weight-based dosing.
Authors: Patel Jai Narendra , Deal Allison Mary , McLeod Howard L. , O'Neil Bert H. , Walko Christine Marie
Published: February 2017

409

Background: Approximately 30% of cancer patients are obese. Controversy exists on how to best use body weight to safely and effectively dose chemotherapy. Additionally, body surface area (BSA)-based dosing is associated with high pharmacokinetic (PK) variability and is a poor indicator of optimal drug exposure. Methods: We estimated FU exposure post cycle 1, as indicated by area under the curve (AUC), in 58 colorectal cancer patients receiving mFOLFOX6 (FU 2400 mg/m2 [BSA calculated using actual body weight (ABW)] over 46 hours) +/- bevacizumab. AUCs were determined using an immunoassay at Myriad Laboratories. The primary objective was to identify variability in FU exposure in obese and non-obese patients using body mass index (BMI), BSA, and ABW. Groups were compared using two group t-tests. Results: No significant difference in AUC was observed between obese (BMI ≥ 30 kg/m2) and non-obese (< 30 kg/m2) patients. A significantly lower AUC was observed in patients with a BSA ≥ 2.0 m2 compared to those < 2.0 m2 (p=0.02). The AUC for obese and non-obese patients ranged from 7-34 and 12-38 mg*hr/L, respectively. Only 32% and 28% of obese and non-obese patients, respectively, were within the previously reported therapeutic target AUC 20-25 mg*hr/L. Males had significantly lower AUCs compared to females (mean 18.7 v 22.4, p=0.03). FU AUC was not strongly correlated with BMI, BSA, or ABW (Pearson correlation of -0.03, -0.26, and -0.15, respectively). Conclusions: BSA-based dosing is associated with variable FU exposure. Lower AUCs in patients with a BSA ≥ 2.0 m2 supports both ASCO recommendations for full-weight-based dosing in obese patients and the value of dosing assessment across patient populations. Further study of AUC-based dosing is warranted as our data do not support a reduction in variable exposure based on BMI, BSA, or ABW dosing. [Table: see text]
Can systemic inflammation at diagnosis predict benefit from primary resection in metastatic colorectal cancer (mCRC)?
Authors: Tran Ben , Wong Hui-Li , Desai Jayesh , Tie Jeanne , Field Kathryn Maree , Kosmider Suzanne , Bae Susie , Wong Shu Fen , Gibbs Peter
Published: February 2017

410

Background: In CRC, the tumor associated immune response can manifest as, (1) a good prognostic anti-tumor local (intra-tumoral) inflammatory response; or (2) a poor prognostic tumor promoting systemic inflammatory response. As suggested for renal cancer, the survival advantage associated with primary resection in mCRC patients (pts) might relate to modification of the tumor associated immune response, through reduction in tumor bulk and the resulting reduction in tumor promoting cytokines. We examine if systemic inflammation at diagnosis predicts benefit from primary resection in mCRC. Methods: A prospectively collected multi-disciplinary CRC database was used to explore clinicopathological data from pts diagnosed with de novo mCRC from Jan 2009 to Jul 2012. Evidence of systemic inflammation was defined as serum albumin (SA) <35g/L or neutrophil-lymphocyte ratio (NLR) >4 at diagnosis. Pts with primary resection >42 days from diagnosis were excluded. Survival analyses utilised the Kaplan-Meier method and log-rank test. Results: Of 212 pts diagnosed with mCRC, 154 (72%) had de novo mCRC. 92 (60%) of these underwent primary resection, 62 (40%) had primary left in situ. SA was available in 141 pts, 71 (50%) had SA <35g/L. NLR was available in all pts, 93 (60%) had NLR >4. Primary resection was associated with superior overall survival (OS): median 32.5mo v 8.4mo (HR 0.29, p<0.001). Systemic inflammation was associated with inferior OS using either SA <35g/L (median 8.4mo v 19.8mo, HR 2.54, p<0.001) or NLR >4 (median 16.8 mo v 13.1 mo, HR 1.59, p=0.03). There was no difference in OS advantages associated with primary resection in pts with SA <35g/L (HR 0.25, p<0.001) compared to normal SA (HR 0.28, p<0.001) at diagnosis; a non significant difference was observed for NLR ≤4 (HR 0.15, p<0.001) compared to NLR >4 (HR 0.42, p=0.001). Data regarding resolution of systemic inflammation following primary resection will be presented. Conclusions: Our study confirms the OS benefit from primary resection in mCRC and the adverse prognostic impact of systemic inflammation. Based on our current data, any benefit from primary tumour resection cannot be explained by an impact on the tumor associated immune response.
Impact of DNA mismatch repair deficiency on relapse rate in early-stage, sporadic colorectal cancer.
Authors: Buxhofer-Ausch Veronika , Bauer Heike , Mollik Marina , Reiner-Concin Angelika , Nirnberger Guenther , Sebesta Christian , Kriwanek Stephan , Zeillinger Robert , Ausch Christoph A.
Published: February 2017

415

Background: 15-20% of sporadic colorectal cancers (CRC) are characterized by DNA mismatch repair (MMR) deficiency resulting in the phenomenon of microsatellite instability (MSI). There is evidence that CRC with MSI have a significant better prognosis compared to those with intact MMR. We investigated MMR gene expression in patients (pat.) with CRC and correlated it with early relapse rate. Methods: The study relates to 146 pat. with primary CRC UICC stage 0-II who underwent surgical resection at the Donauspital in Vienna and had a complete follow up of at least 60 months. Expression of the MMR genes MLH1, PMS2, MSH2, MSH6 was detected by immunohistochemical staining. Expression of MMR genes was correlated with pat. and disease characteristics as well as relapse frequency within the first 5 years after diagnosis. Chi-squared test was used to compare the distribution of the given variables between MMR gene proficient and deficient pat. Results: Mean age of the total group was 66.14 years, 45.2% were females and 54.8 males. Localization of the tumor was the colon in 69.2% and the rectum in 30.8% of pat., respectively. 33.6% of diseases were classified as UICC stage 0-I, and 66.4% as UICC stage II. 37/ 146 pat. experienced relapse, mean duration to relapse was 2.17 years. 13.7% of all pat. displayed a MMR deficient state. All MMR deficiencies occurred in the colon, none in rectum tumors. MLH1 was always associated with PMS2 deficiency and occurred in 9.6% of pat. There was a significant difference in sex distribution between the proficient and deficient group with 71.4% females with MLH1/PMS2 deficiency (p= 0.038). MSH2 deficiency was detected in 1 pat. only. MSH6 deficiency occurred in 5.5% of pat., none of the variables was significantly different distributed between the proficient and deficient group. None of the MMR deficiencies correlated with relapse rate. Conclusions: Our data suggest that the supposed better prognosis of MMR deficient compared to proficient pat. might not be explained by a different relapse rate within 5 years from diagnosis. Larger and prospective trials are warranted to elucidate plausible explanations for the proposed survival benefit of a MMR deficient state.
HER-2 in high risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.
Authors: Sclafani Francesco , Roy Amitesh Chandra , Chau Ian , Wotherspoon Andrew , Peckitt Clare , Dewdney Alice , Oates Jacqueline Rose , Cunningham David
Published: February 2017

420

Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression in this disease have been reported. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in the EXPERT-C trial. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%), with 3 patients with discordant results (1 patient with HER-2 negative biopsy/positive surgical specimen, 2 patients with HER-2 positive biopsy/negative surgical specimen). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. Conclusions: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER-2 does not appear to represent a useful therapeutic target for high-risk rectal cancer. However, the role of HER-2 as prognostic factor and potential predictive biomarker for cetuximab-based treatment in rectal cancer warrants further investigation. A more comprehensive B-DISH analysis in IHC 0/1+ tumours is currently ongoing and data will be presented at the meeting.
Analysis of predictive and prognostic value of clinical and pathological factors in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT): Bologna multidisciplinary rectal cancer group study (BMRG-B01-Study).
Authors: Pini Sara , Di Fabio Francesca , Ceccarelli Claudio , Iacopino Bruno , Lecce Ferdinando , Cuicchi Dajana , Ugolini Giampaolo , Varrese Francesco , Guido Alessandra , Rojas Llimpe Fabiola Lorena , Giaquinta Stefania , Pinto Carmine
Published: February 2017

421

Background: Preoperative fluoropyrimidine based CRT is standard treatment in LARC patients. The aim of this study was to evaluate prognostic and predictive role of clinical and pathological factors in this setting Methods: Between December 2001 and January 2012 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma located ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions + 5-fluorouracil or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after the end of neoadjuvant treatment. Pathological examination of surgical specimens included TRG according to the Dworak criteria. TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pre-treatment biopsies and surgical specimens. For immunohistochemistry evaluation serial sections of formalin-fixed, paraffin-embedded tissues were stained with specific antibodies using a biotin-free ready-to-use amplification system Results: After a median follow-up of 60 months (2-122) we observed 4.7% local recurrences, 12.7% distant recurrences, and 13.4% deaths. In surgical specimens TRG 1, 2, 3 and 4 were observed respectively in 22.5%, 35.3%, 25.6% and 16.6% of patients. ypN and TRG were independent prognostic factors of DFS (p=0.020, p=0.027). CRM and TRG were independent prognostic factors of OS (p=0.016, p=0.010). High pre-treatment biopsy expression of TS was associated with poor TRG (0-1) (p=0.007); high biopsy expression of Ki-67 was associated with good TRG (2-4) (p=0.039); decrease between pre-treatment biopsy and surgical specimen of Ki-67 (Δ Ki-67 ≥ 0) was associated with good TRG (2-4) (p=0.02). Decrease in Ki-67 (Δ Ki-67 ≥ 0) was associated with good DFS (p=0.011) and confirmed by multivariate analysis as an independent prognostic factor (p=0.035). Conclusions: In our analysis ypN, CRM and TRG were independent prognostic factors; baseline expression of TS, Ki-67 and decrease in Ki-67 were predictive of TRG; decrease in Ki-67 was an independent prognostic factor of DFS.
Cancer spectrum among Irish DNA mismatch repair gene mutation carriers.
Authors: Farrell Michael P. , Lyons Tomas , Gogarty Darragh S , Dorman Naoise Maria , O' Brien Loretto , Mac Mathuna Padraic M. , Gallagher David J.
Published: February 2017

424

Background: Pathogenic germline mismatch repair (MMR) mutations confer a high lifetime risk of colorectal cancer (CRC). Certain extra-colonic malignancies are also considered part of the Lynch syndrome (LS) spectrum including endometrial cancer, gastric, ovarian, small intestine, uroepithelial, pancreas, brain and skin cancer. A genotype-phenotype association has been reported. MSH2 mutation carriers appear to have a higher risk of developing extra-colonic cancer than individuals with a MLH1 mutation. We investigated the cancer spectrum in Irish LS kindreds and the likely association of these cancers with MMR deficiency. Methods: We identified 52 LS patients and family members with confirmed pathogenic DNA MMR mutations among 14 kindreds. Clinical data was extracted from the medical records and cancer diagnoses were confirmed from medical records and pathology reports. Tumour tissue was acquired. Immunohistochemistry (IHC) was completed for 4 MMR proteins and tumour lymphocyte infiltration is ongoing. Results: Spectrum of cancers identified include: CRC, endometrial , gastric, ovarian, renal, breast, prostate, urothelial, NHL, CML, lung, vocal cord, sebaceous carcinoma and cervix. Median age of diagnosis was 44. Thirteen individuals were diagnosed with two primary malignancies, 11 individuals were diagnosed with three primaries and one individual had four cancers. IHC analysis of three breast cancer cases demonstrated loss of MMR protein expression consistent with familial mutation. Conclusions: Early-onset cancers not traditionally considered manifestations of LS were identified in 14 LS kindreds. An additional 60 pedigrees are being worked up and further IHC and lymphocyte quantification will be reported at the meeting. An expanded LS-associated spectrum of malignancies may exist in certain families.
Impact of diabetes on clinicopathologic and genetic features of colorectal cancer formation.
Authors: Wong Hui-li , Jorissen Robert N. , Sieber Oliver , Lipton Lara Rachel , Desai Jayesh , Tie Jeanne , Kosmider Suzanne , Bae Susie , Jones Ian , Croxford Matthew , Steel Malcolm , Bui Andrew , Gibbs Peter
Published: February 2017

426

Background: Diabetes mellitus is reported to increase the risk of colorectal cancer (CRC) development and has been associated with poor tumour-specific outcomes. Here we assessed the impact of diabetes on the clinicopathologic features and tumour mutation profiles of CRC. Methods: Analysis of a prospective series of patients diagnosed with CRC between January 2000 and December 2010. Fresh-frozen and formalin-fixed, paraffin-embedded tumour specimens were retrieved and genomic DNA extracted for analysis of microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and mutations in BRAF, KRAS, PIK3CA, TP53 and APC genes. Propensity-score matching and logistic regression were used to estimate the association of diabetes with tumour molecular profile, controlling for age, sex, tumour stage, body mass index (BMI), smoking and socio-economic status. Results: Of the 1,348 patients assessed, 288 (21.4%) had a history of diabetes mellitus. Compared to patients without diabetes, diabetics were more likely to be older (age > 70 yrs: 56% vs 47%, p = 0.006), male (57% vs 47%, p = 0.002) and have a higher BMI (BMI > 25: 82% vs 65%, p < 0.0001). There were no statistically significant differences in tumour site, differentiation or lymphovascular invasion. Propensity scores were used to match 260 diabetic patients to an equal number of nondiabetics. In multivariate regression analysis, diabetes was associated with BRAF-mutated tumours (OR 2.81, 95% CI 1.16-7.59, p = 0.029) and showed a trend towards MSI-high tumours (OR 1.54, 95% CI 0.91-2.63, p = 0.110). Results are shown in the Table. Survival analysis is planned. Conclusions: CRC patients with diabetes are older, more likely male and have higher BMI than non-diabetics. In this preliminary analysis, an association between diabetes and BRAF-mutant CRC was found, and may explain reported differences in outcomes for diabetic CRC patients. [Table: see text]
STAT3 as a potential molecular target to sensitize colorectal cancer cells to chemoradiotherapy.
Authors: Grade Marian
Published: February 2017

434

Background: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of molecular biomarkers that differentiate responsive and resistant tumors is exceedingly important, because this may lead to the identification of novel molecular targets whose modification could be harnessed to sensitize a priori resistant tumors to multimodal treatment. Methods: We recently established an in vitro model for 5-FU based chemoradiotherapy, and correlated differences in treatment sensitivity of 12 colorectal cancer cell lines with pretherapeutic gene expression profiles. One gene the expression of which correlated positively with treatment resistance was the signal transducer and activator of transcription 3, STAT3. To test the functional relevance of this observation, we first determined STAT3 mRNA and protein expression levels in all cell lines. Next, we established doxycycline-inducible stable shRNA single-cell clone (SCC) populations. Successful silencing of STAT3 was detected by Western blot analysis. The induced SCCs were treated with 3 µM 5-FU, and subsequently exposed to 0, 1, 2, 4, 6, and 8 Gy of X-rays. In addition, STAT3 was inhibited using two different siRNAs, and a small-molecular inhibitor (STATTIC). Results: STAT3 was significantly overexpressed in resistant cells. In SW480 and SW837 cells, both shRNA- and siRNA-mediated silencing as well as STATTIC-induced inhibition of STAT3-phosphorylation resulted in a significantly increased chemoradiosensitivity, with dose-reduction factors of 1.8 to 2. Conclusions: These results highlight the potential relevance of STAT3 as a novel molecular target to sensitize a priori resistant tumor cells to chemoradiotherapy.
Distant recurrences of colorectal cancer: Incidence, systemic treatment, and survival in daily practice.
Authors: van Gestel Yvette , van Herk-Sukel Myrthe , de Hingh Ignace , Rutten Harm , Creemers Geert-Jan , Lemmens Valery E. P.
Published: February 2017

441

Background: To provide population-based data on the patterns, risk factors, treatment, and survival of distant recurrences of colorectal cancer (CRC). Methods: All patients (n=6,066) diagnosed with CRC M0 in 10 large Dutch non-academic hospitals between 2003 and 2008 were included. By means of active follow-up, data on distant recurrences and systemic treatment were collected. Median follow-up was 4.4 year. Results: 1,074 (18%) patients were diagnosed with distant recurrent disease during follow-up of which 85% within 3 years. Most common affected sites were liver (60%), lung (39%), extra-regional lymph nodes (22%) and peritoneum (19%) (multiple sites possible). Male sex (female=ref (17%), 19%/HR 1.1 95%CI 1.0-1.3), advanced primary tumor stage (T1=ref (4%), T2 9%/HR 3.0 95%CI 1.8-4.9, T3 21%/HR 6.1 95%CI 3.8-9.9, T4 29%/HR 11.0 95%CI 6.7-18.1), advanced lymph node stage (N0=ref (11%), N1 29%/HR 2.8 95%CI 2.4-3.3, N2 41%/HR 4.5 95%CI 3.7-5.4), primary tumor localization (left colon=ref (17%), right colon 16%/HR 0.8 95%CI 0.7-1.0, rectum 25%/HR 1.2 95%CI 1.0-1.4), and tumor differentiation grade (well differentiated=ref [16%], poorly differentiated 26%/HR 1.4 95%CI 1.2-1.7) were associated with increased risk recurrences while chemotherapy for the primary tumor was associated with reduced risk (HR 0.8 95%CI 0.7-0.9). Recurrence rates did not differ between hospitals. 52% of patients with recurrences received systemic therapy, ranging from 34-62% between the 10 hospitals (p<0.01). Half of these patients (52%) was also treated with bevacizumab, ranging from 39-73% between hospitals (p<0.05). Median survival since diagnosis of recurrence was 31 months for patients with lung metastases only, 16 months for liver metastases only, 14 months for lung metastases only, and 5 months for metastases confined to the peritoneum. Conclusions: The development of distant recurrent disease was strongly related to tumor characteristics, but not correlated with hospital of primary treatment. Population-based data on distant recurrences may ultimately contribute to more accurate patient information, and more efficient follow-up schemes.
Role of overexpressions of ALEX1 gene in human colorectal tumorigenesis.
Authors: Takeda Akihiko
Published: February 2017

443

Background: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo family which has several ARM repeat domain. Our studies have revealed that overexpression of ALEX1 suppressed colony formation ability of stable human colorectal carcinoma cell lines. But clinical significance of ALEX1 expression in colorectal cancer patients is largely unknown. Methods: We examined the expression level of ALEX1 mRNA in matched tissue pairs of normal colorectal mucosa and colorectal tumor tissue by quantitative real-time RT-PCR Tumor specimens along with adjacent normal tissues were obtained from 49 patients with primary colorectal cancer undergoing complete surgical resection of tumors and lymph nodes, followed by adjuvant systemic therapy in some cases. All tissue samples were stored at -80°C until use. The 49 colorectal specimens comprised 26 well-differentiated and 23 moderately-differentiated adenocarcinoma. Corresponding extraneoplastic normal colon tissues from the same 49 patients were also examined. The pathological stages of the patients were as follows: stage I, 9 patients; stage II, 16 patients and stage III, 24 patients by pTNM classification. The post-surgical treatment observation period was from 277 to 3,631 days (1625.0 ± 1033.0 days). Results: In 34 cases out of 49 (69%) colorectal tumor tissues, greater than a 50% reduction of the ALEX1 mRNA level was observed in comparison to adjacent normal mucosa tissues. ALEX1 mRNA was significantly reduced in colorectal tumor tissues than those in normal mucosa (p=0.01459, Mann–Whitney U-test). The 17 cases with higher ALEX1 gene expression (tumor/normal value ³a0.20) significantly revealed a better disease-free survival rate than the other 32 cases (< 0.20; p = 0.045, log-rank test), which showed significant correlations between ALEX1 expression and better prognosis. There was no significant relationship between ALEX1 expression and the other clinicopathological features. Conclusions: Our findings may support that ALEX1 functions as a tumor suppressor in colorectal cancer progression. Examination of ALEX1 expression might be helpful for predicting the prognosis of patients with curative resected colorectal cancer.
A case of the utilization of genomic information in the management of metastatic colorectal cancer.
Authors: Peixoto Renata D'Alpino , Li Yvonne , Pleasance Erin , Yip Stephen , Zhao Yongjun , Schein Jacquie , Shen Yaoqing , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Huntsman David , Jones Steven , Marra Marco , Laskin Janessa J.
Published: February 2017

444

Background: Anectodal success using genomic information to personalize and guide cancer therapy in rare tumours has been reported. This is a case report of the use of genomic information in the management of metastatic colorectal cancer. Methods: A 31 year old female presented with metastatic disease from the colon to the liver and retroperitoneal lymph nodes. She was treated with aspirin and 4 cycles of 5FU/Irinotecan/Bevacizumab before blood and liver biopsies were taken. Sections from the primary tissue embedded in paraffin were compared to metastatic disease in the liver and blood. Two platforms were used: a targeted deep sequencing of 46 genes via a cancer specific amplicon assay and whole genome sequencing and RNA sequencing followed by bioinformatics approaches were employed to identify genes with somatic variants, copy number variations, losses of heterozygosity, structural variation, and expression changes. Results: Genome sequencing followed by bioinformatics analysis detected ~100 somatic mutations, ~100 amplified genes with increased expression, and ~90 down-regulated genes with copy number loss in the metastasis. Other interesting observations included increased allelic frequencies in BRAF V600E, and SMAD4 R361C as well as high gene copy amplifications in VEGFA and MAGI from the primary to the metastasis, and lack of somatic mutation in KRAS. Conclusions: The upregulation of VEGF pathways from the primary compared to the metastasis suggests a significant shift in tumour biology likely as a result of the bevacizumab and COX-2 inhibition from aspirin; this may have implications when anti-VEGF therapy is withdrawn. The BRAF mutation and wild type KRAS status may suggest that combination of a BRAF inhibitor with EGFR inhibition is warranted. This information demonstrated the benefit of therapy on a genomic level and aided in determining possible future targets and modifications to conventional therapy.
Outcome of patients (pts) with relapsed, advanced upper gastrointestinal (GI) carcinoma treated in a specialist oncology phase I unit.
Authors: Khan Khurum Hayat , Ang Joo Ern , Starling Naureen , Shah Krunal Jitendrakumar , Molife L. Rhoda , Banerji Udai , De Bono Johann Sebastian , Cunningham David , Kaye Stanley B.
Published: February 2017

45

Background: Conventional chemotherapy in advanced upper GI cancer after progression on first line therapy yields low response rates and no clear survival benefit. In this context, some pts are offered experimental treatments, including participation in Phase I clinical trials. Methods: Baseline pt and tumour characteristics, toxicity, response and outcome data of pts with upper GI cancers consecutively treated within the Drug Development Unit, Royal Marsden Hospital, from 2005 to 2009, were documented. Results: Ninety-six pts (median age 59 years [range 24-77]; male/female ratio 3.6, median of 2 [range 0-4] prior lines of chemotherapy) with oesophageal (42%), gastric (14.5%), pancreatic (26%) and oesphagogastric junction (7%) carcinomas were treated in 30 Phase I trials; of these, 36% participated in studies containing conventional cytotoxic chemotherapies. The overall response rate by RECIST was 11% with a disease control rate of 49%. The overall clinical benefit rate (i.e. no disease progression at 6 months) was 14%, respectively. In all pts, the median progression free survival (PFS) and overall survival (OS) were 7.0 weeks (95% CI: 5.6-8.4) and 19 weeks (95% CI: 17-21), respectively; these were not superior in pts who received chemotherapy-containing regimens (p=0.364, p=0.897). Pts with CBR ≥6 months a median OS of 55 weeks (95% CI: 46-64); 59% of them were treated with single-agent molecular targeting agents. Grade 3 or 4 toxicities were observed in 37 pts (39%) and led to trial discontinuation in nine (9%); no toxicity-related death occurred in these pts. In the multivariate analysis of baseline factors, serum albumin (<35 g/dl, HR 2.0 [95%CI: 1.3-3.2] p=0.002) and serum lactate dehydrogenase (LDH) (>192 umol/l, HR 1.7 [95% CI: 1.1-2.6], p=0.016) were prognostic of OS. Conclusions: Phase I clinical trials should be considered a valid option in pts with advanced upper GI cancers with disease relapse after first-line chemotherapy In our experience the risk of toxicity is low/moderate and there is the potential for clinical benefit.