Consecutive Colorectal Cancer Research Articles

Preoperative anxiety in Chinese colorectal cancer patients: The role of social support, self-esteem and coping styles

BackgroundRelatively little is known about preoperative anxiety and its associated factors with colorectal cancer, which is one of the most prevalent cancers. We aimed to investigate preoperative anxiety and its associated social, psychological and coping factors based on the disclosure/nondisclosure of cancer diagnosis. MethodsA cross-sectional study was conducted in consecutive colorectal cancer inpatients (N = 434), whose anxiety was assessed based on semi-structured interview, demographic-clinical variables, social support, self-esteem and coping styles (acceptance-resignation, confrontation, avoidance). Hierarchical regression analyses were conducted to explore the relationships between social, psychological, coping factors and preoperative anxiety. ResultsThere was no significant difference in preoperative anxiety (χ2 = 1.031, p = .31) between the disclosure and nondisclosure groups. Social, psychological and coping factors together accounted for an additional variance of preoperative anxiety (disclosure: 22%; nondisclosure: 20.8%). Social support (β = −0.17, p = .004), self-esteem (β = −0.22, p = .001) and coping styles (acceptance-resignation: β = 0.32, p < .001; confrontation: β = 0.13, p = .06; avoidance: β = −0.17, p = .04) were associated with preoperative anxiety in the nondisclosure group. For the disclosure group, acceptance-resignation was the only significantly associated factor of preoperative anxiety (β = 0.37, p < .001). ConclusionsCoping styles, such as acceptance-resignation and confrontation, could aggravate preoperative anxiety. Avoidance, social support and self-esteem might be helpful in preventing preoperative anxiety. These findings highlight the importance of providing psychological interventions for cancer patients by integrating social support, self-esteem and coping styles when disclosing a cancer diagnosis.

Expression of NDRG2 in Human Colorectal Cancer and its Association with Prognosis.

Objective: As a member of the N-myc downregulated gene family, N-Myc downstream-regulated gene 2 (NDRG2) contributes to tumorigenesis of various types of cancer. The expression status of NDRG2 in colorectal cancer (CRC) and its prognostic value remain to be elucidated. The goal of this study was to determine the expression pattern of NDRG2 in human CRC and its association of NDRG2 expression with prognosis.Methods: Immunohistochemistry was used to determine the level of NDRG2 expressions in 316 CRC tissues. The medical records of consecutive CRC patients undergoing primary tumor resection from September 2000 to February 2015 were retrospectively selected. Then, we compared to specific clinicopathological features in patients with different level of NDRG2 expressions. The correlation of NDRG2 expression with 3-year survival rate was assessed by Kaplan-Meier method and Cox regression modeling.Results: NDRG2 was expressed in 94.6% (299/316) of CRC tissues. The median IHC score of NDRG2 expression was significantly lower in tumor tissues compared with that of tumor-adjacent normal tissues [4.50(range 0.00-12.00) vs. 10.00 (range 0.00-12.00), P < 0.001].Survival analysis indicated that patients with low NDRG2 expression had poorer 3-year OS than those with high NDRG2 expression (59.9% vs. 76.6%, P = 0.017). Low NDRG2 expression also presented a significantly poorer 3-year OS rate in patient with stage IV disease (29.4% vs. 56.5%, P = 0.002), liver metastasis(32.2% vs. 54.7%, P = 0.005) and those receiving liver resection(56.5% vs. 71.9% , P = 0.012). Multivariate analysis indicated that high NDRG2 expression was independently associated with poor OS (hazard ratio [HR]: 1.499; 95% confidence interval [CI]: 1.037-2.165; P = 0.031).Conclusions: Low expression of NDRG2 was associated with unfavorable prognosis in CRC patients with primary tumor resection. Detection of NDRG2 expression might be useful for providing valuable information of individualized therapy for CRC patients.

Testing strategies to reduce morbidity and mortality from Lynch syndrome

Objective: Lynch syndrome (LS) has an autosomal dominant inheritance pattern and is associated with increased risk for colorectal cancer (CRC) and other cancers. Various strategies are used to identify patients at risk and offer surveillance and preventive programs, the cost effectiveness of which is much dependent on the prevalence of LS in a population. Universal testing (UT) is proposed as an effective measure, targeting all newly diagnosed CRC patients under a certain age.Materials and methods: LS cases were identified in a cohort of 572 consecutive CRC patients. Immunohistochemistry was performed in 539 cases, using antibodies against mismatch repair proteins MLH1, PMS2, MSH2, and MSH6. Microsatellite instability and gene mutation screening were performed in 57 cases.Results: In total 11 pathogenic variants were detected, identifying LS in 1.9% of new CRC cases. Comparing the results with current clinical methods, 2 pathogenic variants were found with Amsterdam criteria and 9 when using either Bethesda guidelines or our institution’s prior clinical criteria. Pathogenic variants in MSH6 were the most common in our series. We also found different outcomes using different age cut offs.Conclusion: Our study demonstrates that UT of tumors before age on onset at 75 years would most likely be cost-efficient and essentially equivalent to applying the Bethesda guidelines or our institution’s prior clinical criteria on all new CRC.

Is It Possible to Maintain High Compliance with the Enhanced Recovery after Surgery (ERAS) Protocol?-A Cohort Study of 400 Consecutive Colorectal Cancer Patients.

The aim of our study was to evaluate the implementation and degree of adherence to the Enhanced Recovery after Surgery (ERAS) protocol in a group of 400 patients operated laparoscopically for colorectal cancer, and to assess its impact on the short-term results. The prospective study included patients with histologically confirmed colorectal cancer undergoing elective laparoscopic resection from years 2012 to 2017. For the purpose of further analysis, patients were divided into four groups: 100 consecutive patients were in each group. There were no statistically significant differences between groups in demographic parameters. The mean compliance with the ERAS protocol in the entire study group was 84.8%. Median adherence differed between the groups 76.9% vs. 92.3% vs. 84.6% vs. 84.6%, respectively (p < 0.0001). There were statistically significant differences between groups in the tolerance of oral diet (54% vs. 83% vs. 83% vs. 64%) and mobilization (74% vs. 92% vs. 91% vs. 94%) on the first postoperative day. In subsequent groups, time to first flatus decreased (2.5 vs. 2.1 vs. 2.0 vs. 1.7 days, p = 0.0001). There were no statistical differences in the postoperative morbidity rate between groups (p = 0.4649). The median length of hospital stay in groups was 5 vs. 4 vs. 4 vs. 4 days, respectively (p = 0.0025). Maintaining high compliance with the ERAS protocol is possible, despite the slight decrease that occurs within a few years after its implementation. This decrease in compliance does not affect short-term results, which are comparable to those shortly after overcoming the learning curve.

Low Serum Levels of miR-101 Are Associated with Poor Prognosis of Colorectal Cancer Patients After Curative Resection.

BackgroundRecent studies showed low expression of microRNA (miR)-101 in various malignancies. However, the association of serum miR-101 and colorectal cancer (CRC) remains unknown. We investigated diagnostic and prognostic significance of serum miR-101 in CRC.Material/MethodsA total of 263 consecutive CRC patients and 126 healthy controls were enrolled in this study. Serum miR-101 levels were measured using real-time quantitative reverse transcription polymerase chain reactions. The association between serum miR-101 level and survival outcome was analyzed.ResultsSerum miR-101 in CRC patients was significantly lower than in healthy volunteers (P<0.001). Low serum miR-101 level was significantly associated with advanced cancer stage. Moreover, survival analysis demonstrated that patients with a low serum miR-101 had poorer 5-year overall survival than patients with a high serum miR-101 level (p=0.041). Serum miR-101 level also were confirmed as an independent risk factor for CRC in multivariate analysis (hazard ratio, 1.468; 95%CI, 0.981–1.976; p<0.001).ConclusionsSerum miR-101 level was significantly downregulated in CRC patients and was closely correlated with poor clinical outcome, suggesting that serum miR-101 might be a useful diagnostic and prognostic marker for CRC.

Colorectal cancer outcomes in nonagenarian patients: A case series

BackgroundIncreased life expectancy and improved medical management of co-morbidities has led to an increasing number of nonagenarian patients with colorectal cancer being considered for surgical intervention. This study aims to describe the morbidity and mortality of nonagenarians who had operative and non-operative management for colorectal cancer. Materials and MethodsA retrospective study of consecutive colorectal cancer patients from 2010 to 2016 in a district general hospital in Scotland who were 90 years old or above was performed. Demographic and perioperative data were obtained from case note review. Survival analysis and multivariable regression was conducted to determine factors associated with cancer-specific and all-cause mortality. ResultsForty-nine patients were identified; 24 patients underwent operative management (median age: 91) while 25 received non-operative management (median age: 92). Fifteen patients (62.5%) had an elective operation, and 8 (37.5%) had an urgent or emergency procedure. None of the patients treated operatively suffered a significant complication or anastomotic leakage. Median hospital stay was 14 days. Five patients (20.8%) required a higher level of care in the community following discharge. Surgical mortality within 30 days was 4.2%. Patients undergoing an elective operation had a significantly improved survival compared to those undergoing an emergency operation or non-operative management. On multivariable analyses, non-operative management, and presence of metastases at diagnosis were associated with higher cancer-specific mortality. ConclusionElective operative management for carefully selected nonagenarian patients with colorectal cancer is generally acceptable in terms of morbidity and mortality. The majority of operatively managed patients returned to the same functional level of care following discharge. Patients with metastases at the outset and those requiring emergency surgery have a poorer prognosis.

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer

Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS. Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS. Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS. In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection. Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer.

PurposeMolecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients’ survival with CRC.Materials and MethodsThe expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH.ResultsUnlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands‒/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis.ConclusionLigand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.

Elevated mean platelet volume predicts poor prognosis in colorectal cancer

Altered mean platelet volume (MPV) is implicated in several malignancies. However, the clinicopathological significance and prognostic value of MPV in colorectal cancer (CRC) is still elusive. The purpose of this study was to elucidate the predictive significance of MPV in CRC. The retrospective study recruited 509 consecutive CRC patients between January 2009 and December 2009. The relationships between MPV and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of MPV. Of the 509 CRC patients, high MPV levels were detected in 150 (29.5%) patients. Elevated MPV was associated with tumor differentiation (p < 0.001). Patients with increased MPV had poor overall survival compared with those with normal level (60.0% vs. 83.6%, log-rank test, p = 0.035). Cox regression analysis showed that MPV was an independent prognostic factor in CRC (HR = 1.452, 95% CI = 1.118–1.884, p = 0.005). In conclusion, MPV is easily available in routine blood test. Elevated MPV might act as a marker of prognosis and therapeutic target for CRC.

Preoperative management of colorectal cancer-induced iron deficiency anemia in clinical practice: data from a large observational cohort.

Preoperative anemia prevalence among colorectal cancer (CRC) patients is high and may adversely influence postoperative outcome. This study assesses the efficacy of a preoperative anemia managing protocol in CRC. This was a retrospective analysis of consecutive CRC resections at two Spanish centers (January 2012 to December 2013). Preoperative anemia was defined as a hemoglobin (Hb) level of less than 13 g/dL and treated with intravenous iron (IVI) or standard care (oral iron or no iron). Red blood cell transfusion (RBCT) requirements was the primary outcome variable. Postoperative infection rate and length of hospital stay (LOS) were secondary outcome variables. Patients were managed with a restrictive transfusion trigger (Hb < 8 g/dL). Infection was diagnosed clinically and confirmed by laboratory, microbiologic, and/or radiologic evidence. Overall, 322 of 571 patients (56%) presented with anemia: 232 received IVI and 90 standard care. There were differences in RBCT rate between no anemia and anemia (2% vs. 16%; p < 0.01), but not in postoperative infections (19% vs. 22%; p = NS) or LOS. Compared to those on standard care, anemic patients on IVI presented with lower Hb (10.8 g/dL vs. 12.0 g/dL; p < 0.001) at baseline, but similar Hb on day of surgery and Postoperative Day 30. There were no between-group differences in RBCT rates (16% vs. 17%; p = NS), but infection rates were lower among IVI-treated patients (18% vs. 29%; p < 0.05). No relevant IVI-related side effects were recorded. Compared to standard care, IVI was more effective in treating preoperative anemia in CRC patients and appeared to reduce infection rate, although it did not reduce postoperative RBCT.

Elevated tumor-to-liver uptake ratio (TLR) from 18F\u2013FDG-PET/CT predicts poor prognosis in stage IIA colorectal cancer following curative resection

PurposeThe prognostic value of the tumor-to-liver uptake ratio (TLR) from 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F–FDG-PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from 18F–FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection.MethodsFrom April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent 18F–FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative 18F–FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS).ResultsROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P < 0.001, respectively). The 1-, 3-, and 5-year DFS rates were 98.4%, 96.9%, and 96.9% for stage IIA CRC patients with lower TLR (≤6.2) versus 77.8%, 60.6%, and 60.6% for those with elevated TLR (>6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with elevated TLR. Cox regression analysis showed that elevated TLR [>6.2; hazard ratio (HR): 3.109–57.463; P < 0.001] and tumor size (>4.4 cm; HR: 1.636–19.155; P = 0.006) were independent risk factors for DFS. Meanwhile, elevated TLR (>6.2; HR: 1.398–84.945; P = 0.023) and lymphovascular/neural invasion (positive; HR: 1.278–12.777; P = 0.017) were independent risk factors for OS.ConclusionElevated TLR predicted worse DFS and OS for stage IIA CRC patients and might serve as a potential radiological index to identify candidates for neoadjuvant or adjuvant chemotherapy. Stage IIA CRC patients with elevated TLR should be monitored carefully for early detection of possible recurrence.

Systematic immunohistochemical screening for mismatch repair and ERCC1 gene expression from colorectal cancers in China: Clinicopathological characteristics and effects on survival.

BackgroundWe performed a systematic screening of colorectal cancer (CRC) tissues to investigate whether mismatch repair (MMR) status and ERCC1 protein expression could be predictive of clinical outcomes for these patients following the recommendation of The Evaluation of Genomic Applications in Practice of Prevention (EGAPP).MethodsThe expression of four MMR genes and ERCC1 were assessed by immunohistochemistry (IHC) from cancer tissue samples of 2233 consecutive CRC patients.ResultsWe observed that most CRC patients with a proficient MMR (pMMR) status tended to have simultaneous ERCC1 protein expression (P< 0.001). Stage III CRC patients with deficient MMR (dMMR) had higher prognoses than the same stage patients with pMMR (DFS: 74% vs 65%, P = 0.04; OS: 79% vs 69%, P = 0.04). Here, dMMR is also associated with poorer survival for stage II patients after chemotherapy (DFS: 66% vs 78%, P = 0.04). Stage II and III patients that were shown to express ERCC1 protein had higher DFS and OS than those that were deficient in expression (stage II, DFS: 83% vs 70%, P = 0.006; OS 85% vs 73%, P = 0.02. Stage III, DFS: 67% vs56%, P = 0.03; OS: 71% vs 57%, P = 0.04).ConclusionsOur results indicate that dMMR appeared to predictive of a survival benefit for stage III CRC patients. We also found the determination of ERCC1 expression to be useful for predicting DFS or OS for stage II and III CRC patients. In addition, the expression of MMR genes and ERCC1 showed a significant relationship.

Abstract 4858: AK4 promotes colorectal cancer progression and metastasis

Abstract Metastatic colorectal cancer (CRC) is a fatal disease with a poor prognosis. It is crucial to understanding the underlying pathogenesis to battle this dismal condition. We previously identified that AK4, a gene on chromosome 1p31.3 encoding a member of adenylate kinase family enzymes, was progressively up-regulated from normal colon, primary CRC to metastasis by mRNA gene expression microarray of paired CRC samples. This study was aimed to validate the overexpression of AK4 and explore in-vitro effects in CRC. We firstly examined the mRNA expression level of AK4 in a panel of CRC cell lines. AK4 mRNA expression was higher in CRC cell lines (n=8) than normal colon cell line, and significantly higher in advanced stage cell lines (n=4, Dukes’ C and D) than early stage ones (n=4, Dukes’ A and B) (P=0.03). We further evaluated expression level of AK4 in two different cohorts of clinical samples. The first cohort consisted of 18 paired primary CRCs and its corresponding normal colonic mucosa, and 27 metastatic CRC (including 15 cases with paired primary CRC and normal colonic mucosa). AK4 mRNA level was significantly higher in metastatic CRC than normal colon (P&amp;lt;0.001), and metastatic CRC than primary CRC (P&amp;lt;0.001). Among 15 cases with paired primary and metastatic tumors, 14 (93.3%) demonstrated higher AK4 in metastatic tumors than their primary counterparts(P&amp;lt;0.05). The second cohort composed of 190 consecutive primary CRCs. Upregulation of AK4 protein expression evaluated by immunohistochemistry was found in 68.4% of CRC, and associated with advanced AJCC stage (P&amp;lt;0.001), poorer overall survival (P=0.002) and worse disease-free survival (P&amp;lt;0.001). To evaluate functional properties of AK4 in CRC, we knocked down AK4 on a CRC cell lines with high endogenous AK4 expression (DLD1, HCT116 and SW620) by siRNA. knockdown of AK4 significantly reduced anchorage-dependent colony forming ability (P&amp;lt;0.05) and eliminated migratory (P&amp;lt;0.05) and invasive (P&amp;lt;0.05) abilities. In conclusion, AK4 is a potential oncogene upregulated in metastatic CRC and exhibiting in-vitro oncogenic properties. AK4 may play an important role in tumor progression and metastasis. Citation Format: Yau Hei Yu, Joanna Hung Man Tong, Yi Pan, Raymond Wai Ming Lung, Ka Fai To, Anthony Wing Hung Chan. AK4 promotes colorectal cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4858. doi:10.1158/1538-7445.AM2017-4858

Oncologic and surgical outcomes in colorectal cancer patients with liver cirrhosis: A propensity-matched study.

The management of colorectal cancer in patients with liver cirrhosis requires a thorough understanding of both diseases. This study evaluated the effect of liver cirrhosis on oncologic and surgical outcomes and prognostic factors in colorectal cancer patients. Fifty-five consecutive colorectal cancer patients with liver cirrhosis underwent colorectal resection (LC group). Using a prospectively maintained database, these patients were matched 1:4 using propensity scoring with R programming language, package "MatchIt" and "optmatch" by sex, age, cancer location, and tumor stage with 220 patients without liver cirrhosis (non-LC group), resulting in 275 patients. The 5-year overall survival (OS) was significantly worse in the LC group than in the non-LC group (46.7% vs. 76.2% respectively, P < 0.001); however, the 5-year proportion of recurrence free (PRF) rates were similar (73.1% vs. 84.5% respectively, P = 0.094). On multivariate analysis of the LC group, tumor-node-metastasis (TNM) stage ≥III disease, venous invasion, and a model for end-stage liver disease plus serum sodium (MELD-Na) score >10 were prognostic factors for OS. However, the OS was not different between the LC group with MELD-Na score ≤10 and the non-LC group (5-year OS rate, TNM stage ≤II, 85.7 vs 89.5%, p = 0.356; TNM stage ≥III, 41.1 vs 66.2%, p = 0.061). Colorectal cancer patients with liver cirrhosis have poorer OS compared to those without liver cirrhosis; however, the PRF rates are similar. It might be due to the mortality from the liver, and surgical treatment should be actively considered for patients with MELD-Na score <10.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers.

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5‐markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni‐ and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60‐74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31‐2.63] and 1.89 [1.34‐2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors (P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis (P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors.

Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers.

Microsatellite instability in colorectal cancer (CRC) and its long-term outcomes remains poorly studied in Asians. We investigate the prognostic significance of microsatellite instability in an Asian population and assess its clinical impact in patients who undergo adjuvant chemotherapy. Six hundred fifty-four consecutive CRC patients who underwent surgical resection between January 2010 and December 2012 were recruited. Survival was estimated using the Kaplan-Meier approach. Univariate Cox proportional hazard models were used to estimate the hazard ratios for variables associated with survival. A subgroup analyses was performed for stage III patients who underwent chemotherapy to evaluate the prognostic significance of microsatellite instability in this group. Five hundred ninety-one (90.4%) patients were microsatellite stable (MSS) while 63 (9.6%) were microsatellite instable (MSI). Three years recurrence-free survival (RFS) and disease-specific survival (DSS) were 83.7 versus 73.7% (p=0.295) and 87.1 versus 91.2% (p=0.307) in MSS and MSI tumors, respectively. Among stage III patients who received adjuvant therapy, MSI status was found to be an adverse prognostic factor for RFS (HR 2.74 (95% CI 1.43-5.26), p=0.002). This remained significant on multivariate analysis (HR 2.38 (95% CI 1.15-4.93), p=0.018). Adjuvant chemotherapy was associated with survival benefit for patients with MSS tumors (HR 0.35, 95% CI 0.17-0.69, p=0.002) but not MSI tumors (HR 0.67, 95% CI 0.08-8.15, p=0.750). MSI status is not a prognostic indicator in the general CRC population but appears to be an adverse prognostic indicator for RFS in stage III CRC patients who received adjuvant chemotherapy.

Defining New Colorectal Cancer Syndromes in a Population-based Cohort of the Disease.

Most known cancer syndromes confer an increased risk of more than one tumour types, and families with more than one colorectal cancer often segregate other cancers as well. The aim of this study was to examine if there is a general increased risk of other cancers in colorectal cancer families, which are defined as having two or more cases of colorectal cancer in close relatives. The study used a detailed family history of cancer diagnoses in a cohort of more than 3,000 consecutive colorectal cancer cases. A comparison was made between families with sporadic and those with familial colorectal cancer cases. Detailed morphology data were used to find further support for putative syndromes. There were significantly more non-colorectal cancers in the family history of the familial CRC cases (p<0.001), with significantly more gastric cancers (p<0.001), prostate cancers (p<0.001), urinary bladder cancers (p<0.001) and melanomas (p=0.002), leukaemia/lymphomas (p=0.004), gynaecological cancers (p=0.007) and breast cancers (p=0.023). There was also some support for different morphological profiles for four of the five tested syndromes. This study found support for a general increased risk of one or more different cancer syndromes involving families with colorectal cancer and other cancers. Further studies will define the different possible syndromes and determine the genetic background.

What about the guys? An assessment of gender differences in hereditary colorectal cancer testing.

537 Background: Approximately 5-10% of colorectal cancer (CRC) is due to hereditary causes. Identification of an inherited cause may impact surgical and treatment decisions for CRC patients and may identify increased risks for other cancers that warrant increased screening and/or risk reduction measures. Men have testing for hereditary breast and ovarian cancer less often than women, even though these genes may also cause increased risk for cancer in men and men are as likely as women to carry mutations in these genes and pass them onto their children. We aimed to explore whether similar gender differences exist related to testing for hereditary CRC. Methods: We retrospectively reviewed clinical data and test results from consecutive CRC cases, who had a multi-gene panel with 13-49 genes at our laboratory, between March 2012 and June 2016. Statistical comparisons between males and females were conducted using Fisher’s exact test. Results: Of CRC cases (n = 7142), 61.1% were female and 12.8% were positive for mutation or likely pathogenic variant. Average age of CRC onset for men was 47.2, and for women was 49.5. Women with CRC before age 20 had the highest mutation rate (31.8%), but men were more likely to test positive than women overall (14.1% vs 12.0%, p = 1.1e-2). Mutations were most frequent in the same three genes for both men and women, but in different orders: MLH1, CHEK2, and MSH2 for males and CHEK2, MSH2, and MLH1 for females. The only genes with significant differences in mutation rates between men and women were MLH1 (3.2% vs 1.5%, p = 2.0e-6) and MSH6(1.7% vs 0.8%, p = 3.0e-3). Conclusions: Hereditary CRC is expected to affect men and women equally. In our cohort, however, the majority of individuals tested were women, while men were more likely to test positive. Possible explanations include smaller sample size and earlier age of onset in men, perceptions of referring clinicians, and different levels of interest in genetic counseling and testing between male and female patients. These data highlight an important opportunity for educating and identifying more men with hereditary CRC who may benefit from genetic information. Further studies are needed to confirm these results and explore reasons for the differences.

Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients

BackgroundAfter analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer.MethodsOf the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status.ResultsThe ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab.ConclusionsPatient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.

Clinicopathological Associations of K-RAS and N-RAS Mutations in Indonesian Colorectal Cancer Cohort.

K-RAS and recently N-RAS gene mutation testing are mandatory requirements prior to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment of metastatic CRC. Mutation prevalence and distribution in Indonesian colorectal cancer (CRC) are not known. Combined methods of PCR high-resolution melt (HRM), restriction fragment length polymorphism (RFLP), and direct DNA sequencing were used to genotype exons 2, 3, and 4 of both K-RAS and N-RAS genes for routine clinical testing of CRC patients. Descriptive analytical review of 595 consecutive CRC patients (years 2013 to 2016) was performed to find associations between gene mutations and clinicopathologic features. This retrospective study revealed overall K-RAS gene mutation in exon 2 (codon 12 and 13) rates being 34.9%. Women (42.5%), stages I and II (43.4%), and well and moderate differentiations (37.7%) had higher frequency of K-RAS exon 2 mutations than men (29%, p=0.006), stages (III and IV 31.9%, p=0.05), and poor differentiation (11.8%, p=0.002), respectively. At later period (2015-2016), 121 of 595 patients were genotyped for the remaining exons 3 and 4 of K-RAS as well as exons 2, 3, and 4 of N-RAS mutations resulting in overall RAS mutation prevalence of 41%. Mucinous histology had highest frequency of N-RAS mutation. Combination of PCR HRM with either RFLP or direct DNA sequencing was useful to detect K-RAS exon 2 and extended RAS mutations, respectively. Frequency of all RAS mutations in stage IV Indonesian (41%) was similar among Asians (41-49%), which tend to be lower than western (55%) CRC.