Localized Colorectal Cancer Research Articles

Identification of differential metabolic characteristics between tumor and normal tissue from colorectal cancer patients by gas chromatography-mass spectrometry.

Colorectal cancer (CRC) is one of the most common human malignancies and encompasses cancers of the colon and rectum. Although the gold-standard colonoscopy screening method is effective in detecting CRC, this method is invasive and can result in severe complications for patients. The purpose of this study was to determine differences in metabolites between CRC and matched adjacent nontumor tissues from CRC patients, to identify potential biomarkers that may be informative and developed screening methods. Metabolomic analysis was performed on clinically localized CRC tissue and matched adjacent nontumor tissue from 20 CRC patients. Unsupervised analysis, supervised analysis, univariate analysis and pathway analysis were used to identify potential metabolic biomarkers of CRC. The levels of 25 metabolites in CRC tissues were significantly altered compared with the matched adjacent nontumor tissues. Four metabolites (lactic acid, alanine, phosphate and aspartic acid) demonstrated good area under the curve of receiver-operator characteristic with acceptable sensitivities and specificities, indicating their potential as important biomarkers for CRC. Alterations of amino acid metabolism and enhanced glycolysis may be major factors in the development and progression of CRC. Lactic acid, alanine, phosphate, and aspartic acid could be effective diagnostic indicators for CRC.

The maturation stage of tumoral tertiary lymphoid structures to predict recurrence risk in localized colorectal cancer.

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II & III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25th-75th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1st, 2nd, and 3rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.

An administrative stage inference algorithm for use in patients receiving chemotherapy for colorectal cancer.

e18121 Background: Claims data are often used for evaluating cancer care outcomes; however, such data lack information about cancer stage. We developed a claims-based stage inference algorithm to classify chemotherapy-treated patients with localized vs. metastatic colorectal cancer (CRC). Methods: We used the SEER-Medicare linked data (2010-‘11) to develop and validate an algorithm to predict cancer stage (localized vs. metastatic) among patients receiving chemotherapy within 6 months of CRC diagnosis. We used claims to identify treatments received (surgery, radiation, and chemotherapy agents) during the 6 months before and after the first dose of chemotherapy. The sample was split 1:1 into development and validation cohorts. After testing in the development cohort, the final algorithm was evaluated in the validation cohort. SEER data served as the gold standard for cancer stage. Results: We identified 25,258 patients with fee-for-service Medicare and a new diagnosis of CRC. 6,907 patients (27%) received chemotherapy for CRC within 6 months of diagnosis. The median age of chemotherapy-treated patients was 73, 49% were female, and 76% were white; 69% had localized cancer (AJCC stage 1-3) and 31% had metastasis at diagnosis (stage 4). Split-sample validation of the final classification algorithm demonstrated sensitivity and specificity of 87% (95% CI 86-89%) and 76% (73-78%) for localized cancer and 73% (70-75%) and 91% (90-92%) for metastatic cancer. The overall accuracy of classification was 83%. Stratified analyses demonstrated preserved algorithm performance across subgroups of age, sex, race, geography, and comorbidity. Misclassification was most common among patients with metastatic disease who were treated with surgery followed by fluoropyrimidine chemotherapy with or without oxaliplatin. 2-year overall survival was 79.8% (stage 1-3) and 35.4% (stage 4) for SEER stage groups, vs. 79.6% and 35.8% for predicted stage groups. Conclusions: A claims-based algorithm can classify extent of disease in chemotherapy-treated CRC patients with an accuracy of 83%. This algorithm will allow more clinically-relevant patient stratification for claims-based evaluations of cancer care outcomes.

Immunomonitoring in patients with stage II and III colon cancer.

e23038 Background: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Immunoscore has been shown to be a very powerful prognositc indicator in patients with clinically localized colorectal cancer, with no detectable tumour spread to lymph nodes or distant organs. These patients are usually treated with only surgical removal of the tumour; however, approximately 25% of these patients will have recurrence of their disease, indicating that occult metastases were already present at the time of curative surgery. VEGF is the factor responsible for neoangiogenesis and it is being considered as a possible prognostic marker of disease progression. Transforming growth factor-beta (TGF-beta) is also neoangiogenic and a highly immunosuppressive factor. The purpose of this study was to monitor the immune response in patients with stage II and III CRC, with a focus on cellular as well as humoral immunity. TGF-beta and VEGF levels were followed. Methods: 25 patients with stage II and III colon cancer included in the research project received routine cancer teratment. Basic parameters - histological type and grade - were established at baseline. Patients were evaluated by a clinical immunooncolgist to exclude any immune disorders of allergic or autoimmune origin. TGF-beta and VEGF were measured using ELISA, and anti-tumour cellular immunity (CD4, CD8, T-reg, B cells ) were measured via flow cytometry. Results: In patients with stage II and III colorectal cancer, predominantly a depression in cellular immunity was seen. Plasma levels of immunglobulins were also reduced, particularly the IgG4 subtype. Most patients showed some clinical symptoms of immunodeficiency, such as frequent respiratory tract infections and/or herpetic infections. TGF-beta and VEGF plasma levels were increased. Conclusions: The correlation of these neoangiogenic and immunosuppressive factors, as well as the state of anticancer immunity with the clinical outcome of the patients, could help in the future as a prognostic marker and contribute to the selection of targeted immune therapy in patients with colorectal cancer. Dedication: Ggrant of Czech Ministery of Health, 15-28188A, League against cancer and PRVOUK-P-27/LF1/1

Targeted metabolomics in colorectal cancer: a strategic approach using standardized laboratory tests of the blood and urine.

BackgroundGlycolytic markers have been detected in colorectal cancer (CRC) using advanced analytical methods.MethodsUsing commercially available assays, by-products of anaerobic metabolism were prospectively measured in the blood and urine of 20 patients with metastatic colorectal cancer (mCRC) and 20 patients with local disease. Twenty-four-hour urine citrate, plasma lactate, ketones, venous blood gas, anion gap, and osmolar gap were investigated. Results of patients with metastatic and local CRC were compared using two-sample t-tests or equivalent nonparametric tests. In addition, plasma total CO2 concentrations in our local hospital (5,931 inpatients and 1,783 outpatients) were compared retrospectively with those in our dedicated cancer center (1,825 outpatients) over 1 year.ResultsThe average venous pCO2 was higher in patients with mCRC (50.2 mmHg; standard deviation [SD]=9.36) compared with those with local disease (42.8 mmHg; SD=8.98), p=0.045. Calculated serum osmolarity was higher in mCRC and attributed to concomitant sodium and urea elevations. In our retrospective analysis, plasma total CO2 concentrations (median=27 mmol/L) were higher in cancer patients compared to both hospital inpatients (median=23 mmol/L) and outpatients (median=24 mmol/L), p<0.0001.ConclusionPatients with mCRC had higher venous pCO2 levels than those with local disease. Although causation cannot be established, we hypothesize that pCO2 elevation may stem from a perturbed metabolism in mCRC.

Adjuvant treatment in extreme elderly patients with colorectal cancer.

784 Background: Surgical and adjuvant treatment in extreme elderly ( &gt; 80 years) patients with localized colorectal cancer is an unresolved issue. Owing to the lack of available neither clinical practice nor investigational data in this field we present our experience in this scenario. Methods: We retrospectively reviewed data regarding surgical and complementary treatment for colorectal cancer patients aged more than 80 consecutively attended by General Surgery Department in Vega Baja Hospital between 2008 and 2013. Results: A total number of 115 colorectal cancer patients were registered. 95 patients diagnosed of localized disease were selected for analysis. Colon vs rectal cancer ratio was 4:1. Median age was 83.6 years (80-94). Male sex was predominant (60 patients, 63.2%). Emergency surgery was performed in 15 patients (15.8%). Complementary treatment to surgery was advised, according to international guidelines, in 53 patients (55.8%). 10 patients (18.9%) with an advise of adjuvant treatment finally received it. More patients with rectal cancer received recommended treatment (41.7% rectal vs 12.2% colon cancer). Patients with stage III disease were more frequently finally treated according to guidelines (22.2 % stage III vs 11.8% stage II). More patients with stage II rectal cancer were advised and received treatment (recommendation: 66.7% rectal vs 36.1% colon cancer; administration: 25% rectal vs 7.7% colon cancer). Treatment was also more frequently administered to stage III rectal cancer (50% rectal vs 14.3% rectal cancer) (Table). Conclusions: Our experience in localized colorectal cancer in extreme elderly patients ( &gt; 80 years) showed that, although advised according to guidelines, most of them did not receive adjuvant treatment to surgery. Complementary treatment administration was more common in rectal cancer patients and with more advanced disease. [Table: see text]

Abstract IA17: Non-invasive detection of somatic mutations in the management of CRC

Abstract Somatic mutations are exquisitely specific cancer biomarkers that are not merely associated with cancer, rather they are the root cause of cancer. The realization that this markers are present in bodily fluids of individuals with cancer and the development of digital methods for their detection ushered a new era in the management of cancer patients providing opportunities for the development of noninvasive methods for early detection, detection of minimal residual disease, monitoring of response to therapy, early detection of resistance and diagnosis. There are both technical and biological challenges for the development of noninvasive tests for the detection of somatic mutations. The number of circulating tumor DNA (ctDNA) molecules is very low compared to that of DNA molecules with wild-type sequence and requires very sensitive methods for their detection. To this end, we have developed a method called SafeSeqS that is able to reliably resolve mutations at 0.01% in background of wild-type DNA across multiple regions of interest. To determine the spectrum of cancers in which ctDNA measurements could prove clinically useful, we evaluated the detection of ctDNA in plasma (liquid biopsy) from patients with a large number of tumor types. ctDNA was detectable in the plasma of most patients with advanced tumor, but in less than 50% in patients with certain tumor types, like primary brain cancers. More than half of the patients with localized colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, had detectable ctDNA in their plasma. The sensitivity of detection of advanced colorectal cancer (CRC) was close to 100% and greater than 75% for localized cancers indicating that liquid biopsy could be utilized for a number of clinical applications. One such application is the detection of minimal residual disease after surgery or therapy with curative intent. Currently, there are not efficient ways to determine which patients are cured and which have residual disease that will result in recurrence. In a prospective cohort of 230 patients with resected stage II colon cancer, ctDNA detection after surgery provided direct evidence of residual disease and identified patients at very high risk of recurrence. Another application of liquid biopsy in CRC is monitoring resistance to therapies, like EGFR, providing an early indication that resistance ensues. The holy grail of non-invasive detection of cancer is early detection. Most tumors are incurable because they are detected at a late stage. Early detection of cancer, before symptoms appear, at a stage curable by surgery, holds great promise for decreasing the rate of deaths due to cancer. We will share our efforts on the development of tests for the early detection of cancer. Our overall vision is that non-invasive, somatic mutation based tests become routine in the clinical management of cancer patients. Citation Format: Nickolas Papadopoulos, Yuxuan Wang, Joshua Cohen, Ralph Hruban, Peter Gibbs, Jeanne Tie, Luis Diaz, Kenneth Kinzler, Bert Vogelstein. Non-invasive detection of somatic mutations in the management of CRC. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA17.

The prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review.

The detection of a simple and reliable prognostic biomarker for colorectal cancer (CRC) outcomes remains a significant challenge. The use of neutrophil-to-lymphocyte ratio (NLR), has been reported to predict surgical and survival outcomes. The aim of our review was to assess the predictive value of pre-operative NLR in predicting post-operative outcomes in CRC. A systematic review of the available studies on NLR in CRC was performed. Primarily, we assessed its ability to predict survival outcomes, and highlight values that would help adjuvant therapy choices. 19 studies comprising 10 259 patients were included. Eleven and eight studies reported on patients with localized CRC and colorectal liver metastasis, respectively. Five-year survival for those with localized CRC was 77.2% in patients with a "low" pre-operative NLR versus 50.8% in those with a "high" pre-operative NLR value. Alternatively, for patients with colorectal liver metastasis, patients with a "high" pre-operative NLR value had a 5-year survival of 27%. Elevated pre-operative NLR>5 is associated with poorer long-term survival in both patients with localized CRC and those with liver metastasis. NLR is a useful biomarker in delineating those patients with poorer prognosis and whom may benefit from adjuvant therapies.

Predicting the effectiveness of the Finnish population-based colorectal cancer screening programme.

Objective Because colorectal cancer (CRC) has a long natural history, estimating the effectiveness of CRC screening programmes requires long-term follow-up. As an alternative, we here demonstrate the use of a temporal multi-state natural history model to predict the effectiveness of CRC screening. Methods In the Finnish population-based biennial CRC screening programme using faecal occult blood tests (FOBT), which was conducted in a randomised health services study, we estimated the pre-clinical incidence, the mean sojourn time (MST), and the sensitivity of FOBT using a Markov model to analyse data from 2004 to 2007. These estimates were applied to predict, through simulation, the effects of five rounds of screening on the relative rate of reducing advanced CRC with 6 years of follow-up, and on the reduction in mortality with 10 years of follow-up, in a cohort of 500,000 subjects aged 60 to 69. Results For localised and non-localised CRC, respectively, the MST was 2.06 and 1.36 years and the sensitivity estimates were 65.12% and 73.70%. The predicted relative risk of non-localised CRC and death from CRC in the screened compared with the control population was 0.86 (95% CI: 0.79-0.98) and 0.91 (95% CI: 0.85-1.02), respectively. Conclusion Based on the preliminary results of the Finnish CRC screening programme, our model predicted a 9% reduction in CRC mortality and a 14% reduction in advanced CRC.

Characterisation and risk assessment of venous thromboembolism in gastrointestinal cancers.

AIMTo characterise venous thromboembolism (VTE) in gastrointestinal cancer and assess the clinical utility of risk stratification scoring.METHODSWe performed a retrospective analysis using electronic patient records of 910 gastro-oesophageal (GO) cancer and 1299 colorectal cancer (CRC) patients referred to a tertiary cancer centre to identify the incidence of VTE, its relationship to chemotherapy and impact on survival. VTE risk scores were calculated using the Khorana index. Patients were classified as low risk (0 points), intermediate risk (1 to 2 points) or high risk (3 points). Data was analysed to determine the sensitivity of the Khorana score to predict VTE.RESULTSThe incidence of VTE was 8.9% for CRC patients and 9.7% for GO cancer patients. Pulmonary emboli (PE) were more common in advanced than in localised CRC (50% vs 21% of events respectively) and lower limb deep vein thrombosis (DVT) were more common in localised than in advanced CRC (62% vs 39% of events respectively). The median time to VTE from cancer diagnosis was 8.3 mo for CRC patients compared to 6.7 mo in GO cancer. In localised CRC median time to VTE was 7.1 mo compared with 10.1 mo in advanced CRC. In contrast in GO cancer, the median time to VTE was 12.5 mo in localised disease and 6.8 mo in advanced disease. No survival difference was seen between patients with and without VTE in this cohort. The majority of patients with CRC in whom VTE was diagnosed had low or intermediate Khorana risk score (94% for localised and 97% in advanced CRC). In GO cancer, all patients scored either intermediate or high risk due to the primary site demonstrating a limitation of the risk assessment score in discriminating high and low risk patients with GO cancers. Additional risk factors were identified in this cohort including surgery, chemotherapy or hospital admission. Overall, 81% of patients with CRC and 77% of patients with GO cancer had one or more of these factors within 4 wk prior to diagnosis VTE. These should be factored into clinical risk assessment scores.CONCLUSIONThe Khorana score has low sensitivity for thrombotic events in CRC and cannot discriminate low risk patients in high risk cancer sites such as GO cancer.

Monitoring Tumor Response after Liposomal Doxorubicin in Combination with Liposomal Vinorelbine Treatment Using 3'-Deoxy-3'-[18F]Fluorothymidine PET.

Surgical resection is the standard treatment for localized colorectal cancer, which is the most common type of gastrointestinal cancer. However, over 40% cases are diagnosed metastasized and apparently inoperable. Systemic chemotherapy provides an alternative to these patients. This study aims to evaluate the therapeutic potential of liposomal doxorubicin (lipoDox) in combination with liposomal vinorelbine (lipoVNB) in a CT-26 colon carcinoma-bearing mouse model. The in vitro cytotoxicity of Dox and VNB on CT-26 cancer cells was determined by MTT and colony formation assays. Mice were subcutaneously inoculated with 2×105 of CT-26 cells in the right hind flank. When tumor size reached 200±50mm3, mice were assigned to receive different treatment protocols. The pharmacokinetics, micro single-photon emission computed tomography/x-ray computed tomography imaging, biodistribution, and immunohistochemical staining studies were performed to survey the therapeutic efficacy of each regimen. Based on the results of pharmacokinetic study, co-administration of lipoDox and lipoVNB did not affect their individual systemic distribution, while lipoDox retained longer in blood than lipoVNB did. Superior tumor growth retardation was observed in the group received lipoDox plus lipoVNB administration (1mg/kg each, namely D1V1) than those injected with lipoDox plus VNB (1mg/kg each, namely D1fV1). No severe side effects were detected in each group. The tumor-to-muscle ratio (T/M) derived from 3'-dexoy-3'-[18F]fluorothymidine ([18F]FLT) micro positron emission tomography (PET) images of D1V1- and D1fV1-treated mice and the controls on day 7 was 6.88±0.54, 7.50±0.84, and 9.87±0.73, respectively, suggesting that D1V1 is a more efficacious regimen against CT-26 xenografts. The results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining were consistent with those findings obtained from [18F]FLT microPET imaging. This study demonstrated that lipoDox in combination with lipoVNB was more efficacious than clinically used regimen, lipoDox plus VNB, in the treatment of colon carcinoma and [18F]FLT-PET is a promising approach in monitoring the treatment outcome at early stage.

559P - Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance

559P - Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance

Fatigue in people with localized colorectal cancer who do and do not receive chemotherapy: a longitudinal prospective study

Fatigue is associated with cancer and chemotherapy and may be sustained. Here, we describe a prospective longitudinal study evaluating fatigue and putative mechanisms in people with colorectal cancer (CRC). People with localized CRC completed the Functional Assessment of Cancer Treatment-Fatigue (FACT-F) questionnaire at baseline (before chemotherapy, if given), 6, 12, and 24 months. Healthy controls (HCs) were assessed at the first three time points. Fatigue was defined by standardized FACT-F scores ≤68/100. Quality-of-life (QoL, assessed by the FACT-G questionnaire), affective, and cognitive symptoms were evaluated. Associations were sought between fatigue, baseline factors, and blood tests (including hemoglobin, cytokines, and sex hormones). Regression analyses, Fisher's exact tests, and Wilcoxon rank-sum tests assessed levels of fatigue at each time point and change in fatigue from baseline. A repeated-measures analysis investigated prognostic factors of fatigue across all time points. A total of 289 subjects with localized CRC (173 received chemotherapy) and 72 HCs were assessed. More CRC patients had fatigue than HCs at baseline (52% versus 26%, P < 0.001). Fatigue was increased in the chemotherapy (CTh) group at 6 months [CTh+ 70% versus CTh- 31% (P < 0.001), HCs 22%] and remained more common at 12 [CTh+ 44% versus CTh- 31% (P = 0.079)] and 24 months [CTh+ 39% versus CTh- 24% (P = 0.047)]. There was no significant difference between those not receiving chemotherapy and HCs at follow-up assessments. Fatigue was associated with poor QoL, affective and cognitive symptoms, but not consistently with cytokine levels. Predictors for sustained fatigue were baseline fatigue, treatment group, cognitive and affective symptoms, poorer QoL, and comorbidities. CRC patients have more fatigue than HCs at baseline. Fatigue peaks immediately after adjuvant chemotherapy, but remains common for 2 years in those who receive chemotherapy. Cognitive and affective symptoms, QoL, comorbidities, chemotherapy, and baseline fatigue predict for longer term fatigue.

A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker.

Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored. We analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up. Hypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution. These results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.

Abstract LB-361: Serology of Streptococcus gallolyticus subsp. gallolyticus and risk of colorectal cancer

Abstract Background: The colonic opportunist Streptococcus gallolyticus subsp. gallolyticus (S. gallolyticus) has been hypothesized to be associated with colorectal cancer (CRC). A recent case-control study (Butt et al., Int J Cancer. 2015 doi: 10.1002/ijc.29914.) showed an association of high antibody levels to S. gallolyticus pilus proteins with prevalent CRC. However, no study has yet explored this association in a prospective study. Objective: To determine whether antibody responses to S. gallolyticus are associated with CRC risk 1 to 8 (median 3) years before diagnosis. Methods: A case-control study was nested within the prospective Southern Community Cohort Study (SCCS) which has enrolled 86,000 men and women between 2002 and 2009 primarily from community health centers (CHC). Participants included here comprised 181 incident CRC cases that were identified until end of 2011 and 348 controls matched by sex, age, race, menopausal status, CHC site and date of blood collection. Antibodies to 11 recombinant affinity-purified S. gallolyticus proteins, including 4 S. gallolyticus pilus proteins, were quantified by multiplex serology. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results: Overall, there was no significant association of high antibody levels to any S. gallolyticus protein (OR: 1.11, 95% CI: 0.77-1.58) or any pilus protein (OR: 1.34, 95% CI: 0.91-1.96) with CRC. However, when stratifying by stage at diagnosis, the association with high antibody levels to any pilus protein was significant for CRC diagnosed with regional or distant stage (OR: 1.68, 95% CI: 1.01-2.78), whereby no association was found for localized CRC (OR: 0.85, 95% CI: 0.45-1.63). Epplein et al. showed that seropositivity to the gastric cancer virulence factor Helicobacter pylori (H. pylori) VacA is significantly associated with CRC (Epplein et al., Cancer Epidemiol Biomarkers Prev. 22(11):1964-74. 2013). Under the assumption that different bacteria may be involved in CRC and that they may interact with each other, we performed an analysis stratified by H. pylori VacA serostatus. Here, the association with high antibody levels to any S. gallolyticus protein with CRC was significant among H. pylori VacA negative individuals (OR: 2.40, 95% CI: 1.12-5.15) but absent among H. pylori VacA positives (OR: 0.83, 95% CI: 0.54-1.29; interaction p = 0.019). Conclusion: This prospective study failed to find a significant overall association of antibodies to S. gallolyticus proteins with CRC. However, among individuals (and their matched controls) who would go on to be diagnosed with later stage tumors, seropositivity to S. gallolyticus was associated with a significant 1.7-fold increase in risk for CRC. In addition we found an interaction between seropositivity to H. pylori VacA with S. gallolyticus in the association with CRC, whereby the increase in risk for seropositivity to S. gallolyticus was seen only among individuals not also infected with VacA-positive H. pylori. This finding supports the idea that different bacteria are involved in CRC and that they may influence each other in their association. Further research with larger study sizes is needed to examine the outcome by both time from blood collection to diagnosis and stage to more precisely shed light on the timing of the association, as well as to consider interaction with infection by other bacteria. Citation Format: Julia Butt, Michael Pawlita, Meira Epplein. Serology of Streptococcus gallolyticus subsp. gallolyticus and risk of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-361.

Synchronous polyps predict metachronous colorectal lesions after curative resection of colorectal cancer

Background: The principal aim of endoscopic follow-up programs after curative resection of colorectal cancer (CRC) is to improve survival and identify local recurrence and metachronous CRC. The aim of our study was to identify the possible predictors of metachronous colorectal lesions.Methods: The records of 348 consecutive patients with CRC and who completed at least 1 year of endoscopic follow-up after surgery were analyzed. In this group, 336 patients underwent surgery for primitive CRC and 12 for metachronous cancer. Patients’ characteristics, operative details, and endoscopical follow-up findings were retrieved. Multivariate survival analyses were used to identify patient categories at risk of metachronous colonic lesions.Results: 128 patients presented a metachronous lesion: 118 adenomas and 10 adenocarcinomas. At multivariate analysis, active smoke (HR = 1.84, p = 0.03), neoadjuvant therapy (HR = 0.24, p = 0.01), and presence of synchronous polyps (HR = 1.55, p = 0.04) resulted independent predictors of metachronous adenoma after CRC removal while neoadjuvant therapy (HR = 0.25, p = 0.02), active smoke (HR = 1.54, p = 0.04), and presence of synchronous polyps (HR = 1.86, p = 0.02) resulted independent predictors of metachronous lesions after CRC removal.Conclusions: This study demonstrated a high rate of metachronous lesions in the early follow-up after curative CRC resection. The negative effects of synchronous polyps should be carefully evaluated when planning patients’ follow-up.

Circulating microRNAs as Prognostic and Predictive Biomarkers in Patients with Colorectal Cancer.

MiRNAs are suggested as promising cancer biomarkers. They are stable and extractable from a variety of clinical tissue specimens (fresh frozen or formalin fixed paraffin embedded tissue) and a variety of body fluids (e.g., blood, urine, saliva). However, there are several challenges that need to be solved, considering their potential as biomarkers in cancer, such as lack of consistency between biomarker panels in independent studies due to lack of standardized sample handling and processing, use of inconsistent normalization approaches, and differences in patients populations. Focusing on colorectal cancer (CRC), divergent results regarding circulating miRNAs as prognostic or predictive biomarkers are reported in the literature. In the present review, we summarize the current data on circulating miRNAs as prognostic/predictive biomarkers in patients with localized and metastatic CRC (mCRC).

Increased Incidence of Second Primary Pancreatic Cancer in Patients with Prior Colorectal Cancer: A Population-Based US Study.

Identifying high-risk groups for pancreatic cancer (PC) may lead to earlier detection. We determined the risk of subsequent PC among survivors of sporadic colorectal cancer (CRC). We evaluated data from the US Surveillance, Epidemiology, and End Results registry to identify individuals with primary CRC between the years 1973-2006. Standardized incidence ratios (SIRs) and 95% confidence interval (95% CI) were calculated to compare the risk of subsequent primary PC in the study cohort to that of the standard population. Analysis was stratified by age at diagnosis of CRC and sex. CRC characteristics were compared among CRC survivors with and without PC. Multivariate sub-hazard ratios were calculated to identify factors associated with subsequent primary PC, using death from non-PC causes as a competing event. Of the 273,144 patients with first primary CRC, 657 (0.24%) developed subsequent PC. CRC survivors were more likely to develop PC (SIR 1.22; 95% CI 1.09-1.35). Mean latency period (time between CRC and PC diagnosis) was 1, 3, and 5years from index age of CRC 20-49, 50-64, and >65years, respectively. Multivariate analysis showed CRC survivors >50years had 3.5-fold, those with right-sided CRC had 1.2-fold, and those with localized and regional CRCs had sixfold and fivefold increased risk of PC, respectively. This study suggests that CRC survivors have an increased risk of developing subsequent PC within 1-5years. CRC survivors age >50 with localized/regional stage, and right-sided CRC have higher predisposition to PC.

What happens when we do not operate? Survival following conservative bowel cancer management.

Introduction While surgery is the cornerstone of bowel cancer treatment, it comes with significant risks. Among patients aged over 80 years, 30-day mortality is 13%-15%, and additionally 12% will not return home and go on to live in supportive care. The question for patients and clinicians is whether operative surgery benefits elderly, frail patients. Methods Multidisciplinary team outcomes between October 2010 and April 2012 were searched to conduct a retrospective analysis of patients with known localised colorectal cancer who did not undergo surgery due to being deemed unfit. Results Twenty six patients survived for more than a few weeks following surgery, of whom 20% survived for at least 36 months. The average life expectancy following diagnosis was 1 year and 176 days, with a mean age at diagnosis of 87 years (range 77-93 years). One patient survived for 3 years and 240 days after diagnosis. Conclusions Although surgeons are naturally focused on surgical outcomes, non-operative outcomes are equally as important for patients. Elderly, frail patients benefit less from surgery for bowel cancer and have higher risks than younger cohorts, and this needs to be carefully discussed when jointly making the decision whether or not to operate.

Pre- and Post-Diagnostic Non-Steroidal Anti-Inflammatory Drug Use and Colorectal Cancer Survival in Seattle Colon Cancer Family Registry

Abstract Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the general population, and regular NSAID use is associated with improved survival among colorectal cancer (CRC) patients. We examined the association of NSAID use prior to, and after, diagnosis in relation to CRC-specific and overall survival. Methods: Study subjects were incident, invasive CRC cases from the population-based Seattle Colon Cancer Family Registry. Eligible cases were 20–74 years of age, diagnosed from 1997 to 2008, and identified from the Puget Sound Surveillance, Epidemiology and End Results (SEER) Registry. NSAID use two years prior to the interview date (“pre-diagnosis period”) was collected by telephone interview at study enrollment an average of eight months after diagnosis. A follow-up questionnaire was administered approximately five years after the cases' CRC diagnosis (“post-diagnosis period”). Regular NSAID use was defined as having taken aspirin or ibuprofen at least twice per week for more than a month. Follow-up for survival and cause of death was completed through linkage to the National Death Index. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of pre- and post-diagnostic NSAID use, and initiation, continuation and discontinuation of NSAIDs between pre- and post-diagnostic periods with survival after CRC diagnosis. Results: Compared to never users, regular NSAID use after diagnosis was associated with better overall survival (HR = 0.69, 95% CI, 0.54–0.89) and CRC-specific survival (HR = 0.48, 95% CI, 0.29–0.80). Among people who survived five years after diagnosis, both overall and CRC-specific survival were better for patients who initiated NSAID use post-diagnosis compared to never users, with HRs (95% CI) of 0.70 (0.51–0.95) and 0.43 (0.23–0.82), respectively. HR estimates were stronger for CRC-specific survival among those with non-advanced (local and regional) CRC (HR = 0.38, 95% CI, 0.18–0.77). Conclusion: Our results suggest that among long-term CRC survivors, regular use of NSAID after CRC diagnosis, including when initiated after diagnosis, is significantly associated with longer CRC-specific survival. This association is more pronounced for patients with non-advanced CRC.