Risk Of Colorectal Cancer Recurrence Research Articles

Coffee consumption is associated with a reduced risk of colorectal cancer recurrence and all-cause mortality.

Coffee consumption has been associated with a reduced risk of developing colorectal cancer (CRC). However, it is not clear whether coffee consumption is related to CRC progression. Hence, we assessed the association of coffee consumption with CRC recurrence and all-cause mortality using data from a prospective cohort study of 1719 stage I-III CRC patients in the Netherlands. Coffee consumption and other lifestyle characteristics were self-reported using questionnaires at the time of diagnosis. We retrieved recurrence and all-cause mortality data from the Netherlands Cancer Registry and the Personal Records Database, respectively. Cox proportional hazard regression models with and without restricted cubic splines were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, education, smoking status, cancer stage and tumor location. We observed 257 recurrences during a 6.2-year median follow-up and 309 deaths during a 6.6-year median follow-up. Consuming more than 4 cups/d of coffee compared to an intake of <2 cups/d was associated with a 32% lower risk of CRC recurrence (95% CI: 0.49, 0.94,). The association between coffee consumption and all-cause mortality was U-shaped; coffee intake seemed optimal at 3-5 cups/d with the lowest risk at 4 cups/d (HR: 0.68, 95% CI: 0.53, 0.88). Our results suggest that coffee consumption may be associated with a lower risk of CRC recurrence and all-cause mortality. The association between coffee consumption and all-cause mortality appeared nonlinear. More studies are needed to understand the mechanism by which coffee consumption might improve CRC prognosis.

The association between surgical site infection and postoperative colorectal cancer recurrence and the effect of laparoscopic surgery on prognosis.

Studies have shown that surgical site infection (SSI) incidence is lower in patients undergoing laparoscopic surgery. Therefore, we reported the SSI countermeasures adopted by our institution and aimed to evaluate the association between SSI occurrence and postoperative colorectal cancer recurrence and the usefulness of laparoscopic surgery for prognosis. Among the patients with colorectal cancer who underwent radical surgery at our hospital between January 2015 and December 2017, 197 with stage I-III cancer without distant metastases were included. We retrospectively analyzed patients' electronic medical records and classified them into the non-SSI (without SSI, n = 159) and SSI (with SSI, n = 38) groups. We calculated and compared the 5-year relapse-free survival (RFS) and overall survival (OS) rates. Additionally, we assessed the relationship between prognosis in the non-SSI, incisional SSI, and organ/space SSI groups and the usefulness of laparoscopic surgery. The 5-year RFS and OS were 80.5% versus 63.2% (P = 0.024; hazard ratio [HR], 2.065; 95% confidence interval [CI], 1.099-3.883) and 88.7% versus 84.2% (P = 0.443; HR, 1.436; 95% CI, 0.570-3.617), respectively. The SSI group had a significantly worse 5-year RFS prognosis. Regarding the relationship with laparoscopic surgery, the SSI incidence was 45.0% (9/20 cases) and 16.4% (29/177 cases) with laparotomy and laparoscopic surgery, respectively, indicating a significantly reduced SSI occurrence with laparoscopic surgery (P = 0.005). Patients with SSI were at high risk for colorectal cancer recurrence, and laparoscopic surgery may be useful for reducing SSI.

Abstract 4206: The impact of two decades of multidisciplinary efforts to reduce the risk of recurrence from colorectal cancer - a Danish population-based registry-study

Abstract Purpose: Over the last two decades, several initiatives have aimed at reducing risk of recurrence in patients operated for non-metastatic colorectal cancer (CRC). The focus has been on improving treatment in a multidisciplinary setting and implementing a population-based screening program. However, the combined impact of these initiatives on the risk of recurrence is not well described. Therefore, the primary aim of this study was to determine and compare recurrence rates for three calendar periods 2004-2008, 2009-2013, and 2014-2019 (after implementation of screening) in CRC. Material and Methods: Patients undergoing surgery for UICC TNM stage I-III CRC in the period 2004 to 2019 were included. All patients were identified using the nationwide clinical quality database DCCG, and hereafter linked with data from the Danish Cancer Registry, the Danish National Registry of Patients, and the Danish Pathology Registry. Recurrence status was determined using a validated algorithm defining recurrence based on diagnosis codes of local recurrence or metastases, the receipt of chemotherapy, or a pathological tissue assessment code of recurrence. The algorithm has shown a positive predictive value of 94% and a negative predictive value of 99%. Cumulative risk of recurrence and relapse-free survival (RFS) was reported by grouping the patients in calendar periods. Results: Of 33,470 stage I-III patients, 7,002 developed recurrence within 5 years after primary surgery (incidence rate = 60.4 per 1,000 person years, 95% CI: 59-61.8) with highest incidence among rectal cancer patients. The 5-year cumulative incidence of recurrence decreased for both colon cancers (2004-2009: 26% (95% CI: 25-27%); 2009-2013: 21% (95% CI: 20-22%); 2014-2019: 15% (95% CI: 14-16%)) and rectal cancers (2004-2009: 30% (95% CI: 29-32%); 2009-2013: 25% (95% CI: 24-27%); 2014-2019: 19% (95% CI: 18-20%)). The same pattern was found within each of stages I, II and III when stratifying by the three calendar periods. Screening-detected (SD) patients had lower risk of recurrence when compared to non-screening detected patients. The 5-year cumulative incidence of recurrence remained lower for 2014-2019 compared to previous calendar periods when excluding SD patients. Adjusted RFS improved significantly from 2004-2008 (reference) to 2014-2019 for colon cancer patients across all UICC stages; I) HR=0.49 (95%CI: 0.42-0.57), II) HR=0.56 (0.51-0.62) and III) HR=0.67 (0.62-0.73). The same pattern was seen for rectal cancer patients with HR=0.50 (0.42-0.60), HR=0.60 (0.52-0.69) and HR=0.67 (0.60-0.75) for stage I, II and III, respectively. Conclusion: The national multidisciplinary initiatives to improve the outcome of CRC within the past two decades have borne fruit, as reflected by significant reductions in CRC recurrence risk and prolonged RFS observed for Danish stage I-III CRC patients. Citation Format: Jesper Nors, Kaare A. Gotschalck, Rune Erichsen, Lene H. Iversen, Claus L. Andersen. The impact of two decades of multidisciplinary efforts to reduce the risk of recurrence from colorectal cancer - a Danish population-based registry-study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4206.

Locally performed postoperative circulating tumour DNA testing performed during routine clinical care to predict recurrence of colorectal cancer.

Identifying patients at high risk for colorectal cancer recurrence is essential for improving prognosis. In the postoperative period, circulating tumour DNA (ctDNA) has been demonstrated as a significant prognostic indicator of recurrence. These results have been obtained under the strict rigours of clinical trials, but not validated in a real-world setting using in-house testing. We report the outcomes of locally performed postoperative ctDNA testing conducted during routine clinical care and the association with the recurrence of colorectal cancer. We recruited 36 consecutive patients with newly diagnosed colorectal cancer between 2018 and 2020. Postoperative plasma samples were collected at the first outpatient review following resection. Tumour-informed ctDNA analysis was performed using droplet digital polymerase chain reaction or targeted next-generation sequencing. At the time of surgery, there were 24 patients (66.7%) with localized cancer, nine (25%) with nodal spread, and three (8.3%) with metastatic disease. The median time from surgery to plasma sample donation was 22 days (IQR 20-28 days). At least one somatic mutation was identified in primary tumour tissue for 28 (77.8%) patients. Postoperative ctDNA was detected in five patients (13.9%). The median duration of follow-up was 32.0months (IQR 27.2-38.1months). Two patients (5.56%) developed metastatic recurrence. However, neither had detectable postoperative ctDNA. There were no instances of loco-regional recurrence. Analysis of postoperative ctDNA testing can be performed locally, however this study did not reproduce the adverse association between detectable postoperative ctDNA and the development of colorectal cancer recurrence seen in clinical trials.

Post-treatment detection of circulating methylated BCAT1 and IKZF1 as prognostic indicators for recurrence in patients with colorectal cancer.

3575 Background: Patient risk for recurrence after completion of initial treatment of colorectal cancer (CRC) is difficult to predict. Post-treatment circulating tumor DNA (ctDNA) analysis is a promising approach for stratifying such patients but the value of using tumor-uninformed biomarkers, such as methylated BCAT1 and IKZF1, is unknown. This study aimed to determine whether detection of circulating methylated BCAT1 and IKZF1 DNA following completed initial treatment with curative intent, identified patients at elevated risk of CRC recurrence. Methods: CRC stage I-III cases were eligible for study inclusion if a BCAT1/IKZF1 methylation test result was available at least 2 weeks after, but within 12mo, of completing initial treatment, and had had at least 2y follow-up unless recurrence was evident sooner (n = 142). Surveillance included regular clinical assessments and radiographic imaging. Level of methylation was reported as the total methylated BCAT1/ IKZF1 expressed as percent of cell-free DNA; levels ≥0.07% were considered positive. Primary outcome measure was recurrence-free survival. Mantel-Cox (logrank) method was used to assess the association between BCAT1/IKZF1 results and recurrence-free survival. Multivariable survival analysis by Cox proportional hazards modelling assessed the impact of covariates, including: BCAT1/IKZF1 result, age, gender, T-stage (T1-2 vs T3-4), N-stage (N0 vs N1-2), extra- and/or intra-mural vascular invasion (EMVI/IMVI) and nature of treatment. Time to recurrence was measured from the date of treatment completion to first evidence of recurrence and data were censored to last date of follow-up. Results: 33/142 (23.2%) cases had recurrence detected at a median 1.6y (IQR: 0.8-2.4). Follow-up time for those who remained recurrence free was 5.3y (IQR: 3.7-6.9). The time between completing treatment and BCAT1/IKZF1 testing was not different between these groups (median 2.4 vs 3.1mo, p = 0.530). 13 (9.2%) cases were positive for methylated BCAT1/IKZF1 after completing treatment and a positive result was associated with a significant risk of recurrence (hazard ratio [HR], 10.0 (95%CI 2.6-39.3), p &lt; 0.001). In the multivariable survival analysis, only a positive BCAT1/IKZF1 methylation result following treatment (HR 2.6, 95%CI: 1.0-6.0, p = 0.041) and evidence of EMVI or IMVI (HR 2.3, 95%CI: 1.0-5.1, p = 0.044) were significant predictors of survival. Conclusions: This study shows that post-treatment BCAT1/IKZF1 methylation testing, which does not need personalization using tumor genotyping, is a promising independent prognostic indicator for CRC recurrence. Such cases are at high risk of recurrence compared to those who had no detectable ctDNA post treatment. These patients warrant enhanced and/or extended surveillance for recurrence. Clinical trial information: 12611000318987.

A systematic review of the literature assessing operative blood loss and postoperative outcomes after colorectal surgery.

There is no consensus in the literature regarding the association between operative blood loss and postoperative outcomes in colorectal surgery, despite evidence suggesting a link. Therefore, this systematic review assesses the association between operative blood loss, perioperative and long-term outcomes after colorectal surgery. A literature search of MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane was performed to identify studies reporting on operative blood loss in colorectal surgery. The review included forty-nine studies reporting on 61,312 participants, with a mean age ranging from 53.4 to 78.1years. The included studies demonstrated that major operative blood loss was found to be a risk factor for mortality, anastomotic leak, presacral abscess, and postoperative ileus, leading to an increased duration of hospital stay. In the long term, the studies suggest that significant blood loss was an independent risk factor for future small bowel obstruction due to colorectal cancer recurrence and adhesions. Studies found that survival was significantly reduced, whilst the risk of colorectal cancer recurrence was increased. Reoperation and cancer-specific survival were not associated with major blood loss. The results of this systematic review suggest that major operative blood loss increases the risk of perioperative adverse events and has short and long-term repercussions on postoperative outcomes. Laparoscopic and robotic surgery, vessel ligation technology and anaesthetic considerations are essential for reducing blood loss and improving outcomes. This review highlights the need for further high quality, prospective, multicentre trials with a greater number of participants, and accurate and standardised methods of measuring operative blood loss.

Lipopolysaccharides increase the risk of colorectal cancer recurrence and metastasis due to the induction of neutrophil extracellular traps after curative resection.

Intra-abdominal infection after curative surgery for colorectal cancer is a serious complication associated with an increased risk of recurrence. Lipopolysaccharides (LPS)-an essential component of the cell wall of Gram-negative bacteria-were found to exert a protumorigenic effect by stimulating the inflammatory pathology and formation of neutrophil extracellular traps (NETs). This study was conducted to test whether LPS-induced formation of NETs promotes the development of cancer and metastasis. The clinical characteristics, incidence of relapse, and serum myeloperoxidase-DNA complexes of 40 patients with infection and 40 patients without infection after curative surgery were analyzed. The effects of LPS on the induction of NETs were evaluated in a mouse model of colorectal cancer and liver metastasis. The toll-like receptor 9 (TLR9)-a DNA receptor-was knocked down to assess its effect on the mitogen-activated protein kinase pathway and activities implicated in the formation of NETs. Analysis of the clinical data obtained from these patients showed the significant relation of the formation of NETs and incidence of metastasis and survival rates. Subsequent in vitro experiments revealed an increased level of citrullinated-histone H3 and myeloperoxidase-DNA in LPS-injected mice with colorectal cancer. In the mimic metastatic model, injection of LPS enhanced the metastatic capacity, which was then attenuated by DNase I. This suggested that the formation of NETs was activated by LPS. Injection of TLR9-knockdown HCT116 cells in mice, followed by induction through LPS, mitigated the level of citrullinated-histone H3 and myeloperoxidase-DNA. This finding implied that the formation of NETs was suppressed. These findings shed light on the mechanism underlying the relationship between the elevated rate of colorectal cancer recurrence in patients who underwent surgery and the incidence of infection. This mechanism involves the protumorigenic activities of LPS-induced formation of NETs. The NETs which could be mediated by the TLR9 and the mitogen-activated protein kinase signaling pathway.

Lifestyle after colorectal cancer diagnosis in relation to recurrence and all-cause mortality

ABSTRACTBackgroundAn unhealthy lifestyle is associated with the risk of colorectal cancer (CRC), but it is unclear whether overall lifestyle after a CRC diagnosis is associated with risks of recurrence and mortality.ObjectivesTo examine associations between postdiagnosis lifestyle and changes in lifestyle after a CRC diagnosis with risks of CRC recurrence and all-cause mortality.MethodsThe study population included 1425 newly diagnosed, stage I–III CRC patients from 2 prospective cohort studies enrolled between 2010 and 2016. Lifestyle, including BMI, physical activity, diet, and alcohol intake, was assessed at diagnosis and at 6 months postdiagnosis. We assigned lifestyle scores based on concordance with 2 sets of cancer prevention guidelines—from the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and the American Cancer Society (ACS)—and national disease prevention guidelines. Higher scores indicate healthier lifestyles. We computed adjusted HRs and 95% CIs using Cox regression.ResultsWe observed 164 recurrences during a 2.8-year median follow-up and 171 deaths during a 4.4-year median follow-up. No associations were observed for CRC recurrence. A lifestyle more consistent with the ACS recommendations was associated with a lower all-cause mortality risk (HR per +1 SD, 0.85; 95% CI: 0.73–0.995). The same tendency was observed for higher WCRF/AICR (HR, 0.92; 95% CI: 0.78–1.08) and national (HR, 0.90; 95% CI: 0.77–1.05) lifestyle scores, although these associations were statistically nonsignificant. Generally, no statistically significant associations were observed for BMI, physical activity, diet, or alcohol. Improving one's lifestyle after diagnosis (+1 SD) was associated with a lower all-cause mortality risk for the ACS (HR, 0.80; 95% CI: 0.67–0.96) and national (HR, 0.84; 95% CI: 0.70–0.999) scores, yet was statistically nonsignificant for the WCRF/AICR score (HR, 0.94; 95% CI: 0.78–1.13).ConclusionsA healthy lifestyle after CRC diagnosis and improvements therein were not associated with the risk of CRC recurrence, but were associated with a decreased all-cause mortality risk.

Plasma and Urine Metabolite Profiles Impacted by Increased Dietary Navy Bean Intake in Colorectal Cancer Survivors: A Randomized-Controlled Trial.

Navy beans contain bioactive phytochemicals with colon cancer prevention properties as demonstrated in carcinogen-induced animal models. Human studies support that dietary navy bean intake modulates metabolism by the gut microbiome. This study investigated the effect of navy bean ingestion on plasma and urine metabolite profiles of overweight and obese colorectal cancer survivors. Twenty participants completed a single-blinded, randomized-controlled dietary intervention with precooked navy beans (35 g bean powder/day) or control (0 g/day) for 4 weeks. Plasma and urine were collected at baseline, 2 weeks, and 4 weeks following consumption. Nontargeted metabolomics was applied to study meals and snacks, navy beans, plasma, and urine. Increased navy bean consumption was hypothesized to (i) delineate dietary biomarkers and (ii) promote metabolic shifts relevant for cancer protection in the plasma and urine metabolome. At 4 weeks, 16 plasma and 16 urine metabolites were significantly different in the navy bean intervention group compared with placebo control (P < 0.05). Increased plasma 2,3-dihydroxy-2-methylbutyrate (1.34-fold), S-methylcysteine (1.92-fold), and pipecolate (3.89-fold), and urine S-adenosylhomocysteine (2.09-fold) and cysteine (1.60-fold) represent metabolites with cancer-protective actions following navy bean consumption. Diet-derived metabolites were detected in plasma or urine and confirmed for presence in the navy bean intervention meals and snacks. These included 3-(4-hydroxyphenyl)propionate, betaine, pipecolate, S-methylcysteine, choline, eicosapentaenoate (20:5n3), benzoate, S-adenosylhomocysteine, N-delta-acetylornithine, cysteine, 3-(4-hydroxyphenyl)lactate, gentisate, hippurate, 4-hydroxyhippurate, and salicylate. The navy bean dietary intervention for 4 weeks showed changes to pathways of metabolic importance to colorectal cancer prevention and merit continued attention for dietary modulation in future high-risk cohort investigations. PREVENTION RELEVANCE: This clinical study suggests that increased consumption of navy beans would deliver bioactive metabolites to individuals at high risk for colorectal cancer recurrence and produce metabolic shifts in plasma and urine profiles.

Spatial domain analysis predicts risk of colorectal cancer recurrence and infers associated tumor microenvironment networks

An unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. Here, we develop a transformational spatial analytics computational and systems biology platform (SpAn) that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. We apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naïve colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of 55 fluorescently tagged antibodies. We show that SpAn predicts the 5-year risk of CRC recurrence with a mean AUROC of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. Additionally, SpAn infers the emergent network biology of tumor microenvironment spatial domains revealing a spatially-mediated role of CRC consensus molecular subtype features with the potential to inform precision medicine.

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

BackgroundFolates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.MethodsCirculating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.ResultsNo statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.ConclusionsCirculating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

Impact of antibiotics (ATB) on the recurrence of resected colorectal cancer (CRC): Results of EVADER-1 a nation-wide pharmacoepidemiologic study.

4106 Background: Recent studies suggest that ATB increase the overall risk of CRC incidence through disruption of gut microbiota. Impact of ATB on the risk of CRC recurrence after curative resection remains unknown. Methods: Using the French nation-wide Institut National du Cancer (INCa – Système National des Données de Santé) database of cancer patients, all newly diagnozed localized CRC patients resected between 01/2012 and 12/2014 were involved. The perioperative ATB intake (6 month before until 1 year after surgery) was classified according to the spectrum, doses and period of use. The primary endpoint was 3-year Disease-Free Survival (3-DFS), stratified on chemotherapy (chemo) administration (yes/no), and assessed using multivariate Cox models. Results: Out of 219,884 CRC patients, the present study included 36,640 patients: male 53%, age≥75 years 39%, left colon/rectal 59%, exposure to chemo 44%, at least one ATB intake 74%. At 3-years, 29% of patients had recurred and 18% had died. In multivariate analysis, in patients not receiving chemo, ATB intake as an out-patient was significantly associated with better 3-DFS [HR (one ATB only) = 0.88 (0.82-0.94)]. This effect remained in the same range whatever the number of ATB or cumulative exposure to ATB. In patients receiving chemo, ATB intake as an out-patient had a significant detrimental effect on 3-DFS [HR (one ATB only) = 1.15 (1.08-1.23)], increasing with the number of ATB [HR (≥5 ATB) = 1.54 (1.39-1.71)] and longer exposure [HR ( &gt; 30 days) = 1.39 (1.31-1.48)]. Penicillin A, quinolones and ATB combinations were associated with worse 3-DFS. The timing of ATB intake related to chemo revealed that the strongest deleterious effect was observed when ATB were taken during chemo [HR = 1.64 (1.53-1.75)]. No difference in the mean number of chemo cycle was observed comparing patients receiving ATB or not. Conclusions: This nation-wide study is the first to suggest that ATB modulate 3-DFS in resected CRC with a differential impact according to chemo exposure. Importantly, ATB intake with chemo is detrimental in a dose- and time-dependent manner suggesting that dysbiosis of gut microbiota during adjuvant chemo might increase risk of recurrence.

Abstract 1642: Spatial proteomics with hyperplexed fluorescence imaging predicts risk of colorectal cancer recurrence and infers recurrence-specific protein-protein networks

Abstract Introduction: Colorectal cancer (CRC) is the third leading cause of cancer related deaths in United States with recurrence after resection-with-a-curative-intent being frequently implicated in these deaths. The basis for CRC recurrence is not completely understood, is multifactorial, and involves dysregulation of heterocellular signaling among tumor cells and their microenvironment. Based on hyperplexed immunofluorescence imaging and novel computational analyses, we have developed a recurrence-risk prediction method that samples these signaling networks within the epithelial and stromal domains of the tumor microenvironment and provides improved performance over current state-of-the-art recurrence-risk prediction assays. Data: In the retrospective study presented here, we used 52 hyperplexed immunofluorescence biomarkers associated with either canonical oncogenic pathways, immune response, or colon cancer per se to spatially profile tissue microarrays obtained from resected tissue samples from 432 chemo-naïve CRC patients. Results: Using epithelial- and stromal-domain expression and co-expression diversity of the biomarkers, our preliminary results predicted the risk of CRC recurrence with a concordance index of 0.91. We also generated training and validation sets from the CRC patient cohort and demonstrated that the area under the curve (AUC) of the prediction receiver operating characteristic (ROC) was 0.90. We utilized stratified bootstrapping to show that the AUC was stable with a standard deviation of 0.02. Significantly, the penalized model selection used within our method allowed us to infer epithelial and stromal-domain protein networks specific to the risk-of-recurrence from the underlying signaling networks. Despite the limited sampling intrinsic to tissue microarrays we were able to capture immune cell infiltration and the differential modulation of these outcome specific protein-protein networks. Conclusions: Our CRC recurrence-risk prediction method exploits our spatial proteomics computational pathology platform involving hyperplexed immunofluorescence imaging. This study demonstrates the potential of this paradigm to not only accurately predict risk of CRC recurrence but also to reveal the underlying systems pathophysiology. Inferring outcome- and domain-specific CRC protein networks will enable biomarkers mechanistically linked to disease progression to be determined and their causality corroborated. In turn, this knowledge can be used to inform optimal therapeutic strategies for individual patients. Citation Format: Shikhar Uttam, Andrew M. Stern, Samantha A. Furman, Filippo Pullara, Fiona Ginty, D. Lansing Taylor, S. Chakra Chennubhotla. Spatial proteomics with hyperplexed fluorescence imaging predicts risk of colorectal cancer recurrence and infers recurrence-specific protein-protein networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1642.

Self-monitoring and reminder text messages to increase physical activity in colorectal cancer survivors (Smart Pace): a pilot randomized controlled trial

BackgroundOver 1.3 million people live with colorectal cancer in the United States. Physical activity is associated with lower risk of colorectal cancer recurrence and mortality. Interventions are needed to increase physical activity in colorectal cancer survivors.MethodsWe conducted a 2-arm non-blinded pilot randomized controlled trial at the University of California, San Francisco among 42 individuals who had completed curative-intent treatment for colorectal cancer to determine the feasibility and acceptability of a 12-week (84 days) physical activity intervention using a Fitbit Flex™ and daily text messages. Participants were randomized 1:1 to receive the intervention with print educational materials or print educational materials alone. We explored the impact of the intervention versus usual care on physical activity using ActiGraph GT3X+ accelerometers pre−/post-intervention.ResultsWe screened 406 individuals and randomized 42 to intervention (n = 21) or control (n = 21) groups. During the 12-week study, the intervention arm wore their Fitbits a median of 74 days [88% of days in study period, interquartile range: 23–83 days] and responded to a median of 34 (out of 46) text messages that asked for a reply (interquartile range: 13–38 text messages). Among the 16 intervention participants who completed the feedback survey, the majority (88%) reported that the intervention motivated them to exercise and that they were satisfied with their experience. No statistically significant difference in change in moderate-to-vigorous physical activity was found from baseline to 12 weeks between arms.ConclusionA 12-week physical activity intervention with a Fitbit and text messages was feasible and acceptable among colorectal cancer patients after curative treatment. Larger studies are needed to determine whether the intervention increases physical activity.Trial registrationClinicaltrials.gov Identifier NCT02966054. Registered 17 November 2016, retrospectively registered.

Modulation of plasma and urine metabolome in colorectal cancer survivors consuming rice bran.

Rice bran has bioactive phytochemicals with cancer protective actions that involve metabolism by the host and the gut microbiome. Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and the increased incidence is largely attributed to poor dietary patterns, including low daily fiber intake. A dietary intervention trial was performed to investigate the impact of rice bran consumption on the plasma and urine metabolome of CRC survivors. Nineteen CRC survivors participated in a randomized-controlled trial that included consumption of heat-stabilized rice bran (30 g/day) or a control diet without rice bran for 4 weeks. A fasting plasma and first void of the morning urine sample were analyzed by non-targeted metabolomics using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After 4 weeks of either rice bran or control diets, 12 plasma and 16 urine metabolites were significantly different between the groups (p≤0.05). Rice bran intake increased relative abundance of plasma mannose (1.373-fold) and beta-citrylglutamate (BCG) (1.593-fold), as well as increased urine N-formylphenylalanine (2.191-fold) and dehydroisoandrosterone sulfate (DHEA-S) (4.488-fold). Diet affected metabolites, such as benzoate, mannose, eicosapentaenoate (20:5n3) (EPA), and N-formylphenylalanine have been previously reported for cancer protection and were identified from the rice bran food metabolome. Nutritional metabolome changes following increased consumption of whole grains such as rice bran warrants continued investigation for colon cancer control and prevention attributes as dietary biomarkers for positive effects are needed to reduce high risk for colorectal cancer recurrence.

Abstract LB-166: Antibiotic prescriptions and colorectal cancer recurrence risk: A Danish nationwide prospective cohort study

Abstract The large number of colorectal cancer survivors, coupled with the financial burden of colorectal cancer, makes it critical to identify factors associated with cancer recurrence. The human gut microbiome is one of the most densely populated bacterial communities known to exist. It plays a vital role in the host's gut physiology and potentially contributes to colorectal cancer progression. Given the prevalence and often overuse of antibiotics in the population, and their effects on the gut microbiome, the potential influence of antibiotics on the clinical course of colorectal cancer is of great public health importance. Using data from Danish medical registries, we followed 21,152 patients (5,036 with recurrences) diagnosed with stage I-III colorectal cancer from 2001 to 2011. We examined the association between pre- and post-diagnostic antibiotic use and cancer recurrence. After adjustment for potential confounders (age at diagnosis, sex, year of diagnosis, stage, tumor location, cancer treatment, comorbidities, inflammatory bowel disease, and use of statins, non-steroidal anti-inflammatory drugs and aspirin), any antibiotic prescription 90 days prior to colorectal cancer diagnosis was not associated with recurrence [adjusted hazard ratio (aHR) = 1.06, 95% confidence interval (CI): 0.98, 1.14]. However, antibiotic use after cancer diagnosis was associated with a higher risk of recurrence (aHR = 1.23, 95% CI: 1.16, 1.31). Additional ongoing analyses address cancer-specific and all-cause mortality and different time-lag periods. Their results also will be presented at the meeting. Our preliminary findings support further investigation into the possible roles of the gut microbiome and agents that alter its composition and diversity in colorectal cancer progression. Citation Format: Veronika Fedirko, Deirdre Cronin-Fenton, Anders Hammerich Riis, Henrik Toft Sørensen, Claus Lindbjerg Andersen, Ole Thorlacius-Ussing, Timothy Lash. Antibiotic prescriptions and colorectal cancer recurrence risk: A Danish nationwide prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-166.

The prognostic value of lymph node yield in the earliest stage of colorectal cancer: a multicenter cohort study

BackgroundIn patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10–12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice.MethodsPatients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation).ResultsIn total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6–81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06–0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39–3.69; P = 0.001).ConclusionsIn this retrospective observational study, retrieving < 10 LNs was associated with an increased risk of CRC recurrence, advocating the importance to perform an appropriate oncologic resection of the draining LNs and diligent LN search when patients with T1 CRC at high-risk for LNM are referred for surgical resection. Given that both gastroenterologists, surgeons and pathologists will encounter T1 CRCs with increasing frequency due to the introduction of national screening programs, awareness on the consequences of an inadequate LN retrieval is of utmost importance.

Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Follow Up, Lifestyle and Survivorship.

Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Follow Up, Lifestyle and Survivorship.

Descriptive characteristics of colon and rectal cancer recurrence in a Danish population-based study

Background: Recurrence is a common outcome among patients that have undergone an intended curative resection for colorectal cancer. However, data on factors that influence colorectal cancer recurrence are sparse. We report descriptive characteristics of both colon and rectal cancer recurrence in an unselected population.Material and methods: We identified 21,152 patients with colorectal cancer diagnosed between May 2001 and December 2011 and registered with the Danish Colorectal Cancer Group. Recurrences were identified in 3198 colon and 1838 rectal cancer patients during follow-up. We calculated the frequency, proportion, and incidence rates of colon and rectal cancer recurrence within descriptive categories, and the cumulative five- and ten-year incidences of recurrence, treating death as a competing risk. We used a Cox proportional hazard model to calculate hazard ratios (HR) and 95% confidence intervals (CI).Results: Recurrence risk was highest in the first three years of follow-up. Patients <55 years old at initial diagnosis (incidence rate for colon: 7.2 per 100 person-years; 95% CI: 6.5–7.9; rectum: 8.1 per 100 person-years; 95% CI: 7.2–9.0) and patients diagnosed with stage III cancer (colon HR: 5.70; 95% CI: 4.61–7.06; rectal HR: 7.02; 95% CI: 5.58–8.82) had increased risk of recurrence. Patients diagnosed with stage III cancer from 2009 to 2011 had a lower incidence of recurrence than those diagnosed with stage III cancer in the years before. Cumulative incidences of colon and rectal cancer recurrence were similar for both cancer types among each descriptive category.Conclusions: In this population, increases in colorectal cancer recurrence risk were associated with younger age and increasing stage at diagnosis. Cumulative incidence of recurrence did not differ by cancer type. Descriptive characteristics of colon and rectal cancer recurrence may help to inform patient–physician decision-making, and could be used to determine adjuvant therapies or tailor surveillance strategies so that recurrence may be identified early, particularly within the first 3 years of follow-up.

Abstract 507: Prediction of colorectal cancer recurrence with plasma miRNAs in the ColoCare Study

Abstract Background Colorectal cancer is the third most common cancer and third most common cause of cancer-related death in the US. Recurrence of primary tumors occurs in 10-40% of patients depending on tumor stage. Early detection of recurrence can increase the treatment options for those eligible for curative therapy, which may lead to better survival. We determined the levels of multiple different plasma miRNAs and assessed their association with clinical outcomes to identify specific miRNAs that may serve as predictors of CRC recurrence. Methods Colorectal cancer patients (age 18-80, newly diagnosed, stage I-IV) were recruited as part of the ColoCare Study in Seattle, Washington, between 2007 and 2011. Patients who had a blood sample taken &amp;gt;30 and &amp;lt;365 days after surgery and prior to any recurrence were included in the study (n = 83). Candidate miRNAs (miRNA 31, 141, 200b, 203, 16, 17-3p, 29a, 92a, 125b) were quantified using pre-designed TaqMan microRNA assays in triplicate assays. Plasma miRNA expression was normalized and expressed as copy number. Cox proportional hazards regression with robust standard errors was used to estimate hazard ratios of recurrence associated with level of each miRNA, adjusted for age, sex and tumor site and stratified by stage. No recurrences were observed in stage I patients. Statistical analyses were conducted separately for stages II-III and II-IV colorectal cancer. Results During a median of 1,067 days (33-2,254 days) follow-up after surgery, 20 recurrences were observed. In stage II-III patients, the presence of detectable circulating levels of miR-141 (HR = 4.30 [1.10-16.84]) or miR-203 (HR = 8.04 [1.39-46.4]) were associated with risk of recurrence. In stage II-IV patients, detectable miR-203 (HR = 3.52 [1.13-10.96]) was associated with recurrence, and elevated miR-29a levels were associated with greater risk of recurrence (HR: 1.80 per natural log unit, 95% CI: 1.06-3.04). Conclusion The present study identified multiple plasma miRNAs that may help to predict those patients at greatest risk of colorectal cancer recurrence. Our results require validation in order to determine the role for such plasma markers in clinical practice. Citation Format: Brandon Dickinson, Scott V. Adams, Cornelia Ulrich, Kathy Vickers, Michelle Wurscher, William M. Grady, Karen W. Makar. Prediction of colorectal cancer recurrence with plasma miRNAs in the ColoCare Study. [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 507.