High-risk Colorectal Cancer Patients Research Articles

Effect of Adjuvant Chemotherapy on Elderly Stage II High-Risk Colorectal Cancer Patients.

PurposeAdjuvant chemotherapy (AC) is recommended for patients with stage II colorectal cancer with adverse features. However, the effect of adjuvant treatment in elderly patients with high-risk stage II colorectal cancer remains controversial. This study aimed to investigate the oncologic outcomes in elderly high-risk stage II colorectal cancer patients who underwent curative resection with or without AC.MethodsPatients aged over 70 years having stage II colorectal adenocarcinoma with at least 1 adverse feature who underwent radical surgery between 2008 and 2017 at a single center were included. We compared recurrence-free survival (RFS) and overall survival (OS) between patients who received more than 80% of the planned AC cycle (the AC+ group) and those who did not receive it (the AC− group).ResultsThe AC+ and AC– group contained 46 patients and 50 patients, respectively. The log-rank test revealed no significant intergroup differences in RFS (P=0.083) and OS (P=0.122). In the subgroup of 27 patients with more than 2 adverse features, the AC+ group (n=16) showed better RFS (P=0.006) and OS (P=0.025) than the AC− group. In this subgroup, AC was the only significant factor affecting RFS in the multivariate analysis (P=0.023). AC was significantly associated with OS (P=0.033) in the univariate analysis, but not in the multivariate analysis (P=0.332).ConclusionAmong elderly patients with stage II high-risk colorectal cancer, the AC+ group did not show better RFS or OS than the AC− group. However, selected patients with more than 2 adverse features might benefit from AC.

A multimodal prehabilitation program in high-risk patients undergoing elective resection for colorectal cancer: A retrospective cohort study

AimUp to 50% of the patients experience complications after colorectal cancer (CRC) surgery. Improved preoperative physical and nutritional status can enhance clinical outcomes and reduce postoperative complications. This retrospective, single-center, observational cohort study assessed the impact of a four-week multimodal prehabilitation program on postoperative complications, unplanned readmissions, length of stay, and mortality in elective high-risk CRC patients. MethodElective high-risk CRC patients, defined as ASA ≥3 or ≥65yr, who attended the multimodal prehabilitation program (prehabilitation-group) were compared to a historical cohort receiving standard care (control-group). Differences in outcomes between these groups were tested using Fisher's Exact and Mann-Whitney U test. To adjust for confounding, multivariate logistic regression analysis was performed. The main study outcome was the occurrence of postoperative complications. Secondary outcomes included unplanned readmissions, length of hospital stay, and mortality. Results351 patients were included (n = 275 control-group, n = 76 prehabilitation-group). The complication rate was lower in the prehabilitation group compared to the control group, 26.3% (n = 20) versus 40% (n = 110) (p = .032). There were fewer unplanned readmissions in the prehabilitation group compared to the control group, 5.3% (n = 4) versus 16.4% (n = 45), p = .014. Median hospital days of stay was 1 day shorter for the prehabilitation-group (p = .004), mortality did not significantly differ between the groups. ConclusionThis study shows that the used multimodal prehabilitation program leads to a reduction of medical postoperative complications, unplanned readmissions, and shortens the median hospital stay compared with standard care in high-risk CRC patients undergoing elective CRC surgery.

Endoscopic Resection Before Surgery Does Not Affect the Recurrence Rate in Patients With High-Risk T1 Colorectal Cancer.

INTRODUCTION:Patients with high-risk T1 colorectal cancer (CRC) after endoscopic resection (ER) should undergo surgery in view of the risk of lymph node metastasis. Although additional surgery can potentially prevent recurrence, there is a paucity of data and longitudinal studies exploring this potential. Hence, this study aimed to evaluate the prolonged influence of ER before additional surgery on recurrence in T1 CRC.METHODS:Between January 2004 and October 2015, 162 patients who underwent secondary surgery (SS) after ER ([ER + SS] group) and 392 consecutive patients with T1 CRC who underwent primary surgery at our institution were retrospectively analyzed. Recurrence was analyzed in these 2 groups. High-risk CRC patients were histologically defined according to the Japanese Society for Cancer of the Colon and Rectum guidelines (2016) for the treatment of CRC. Data were analyzed based on clinical and histological features, including lymph node metastasis, and the number of lymph nodes evaluated.RESULTS:The recurrence rate was comparable between the ER + SS and primary surgery groups, with no significant difference (P = 0.625, log-rank test). There was no significant difference in the recurrence in patients receiving adjuvant chemotherapy in both groups (7.4% vs 10.4%, P = 0.27). The difference in the mean number of lymph nodes dissected between both groups was also not significant (24.3 vs 25.3, P = 0.43).DISCUSSION:There was no significant difference in recurrence rates between patients undergoing ER before surgery and those undergoing primary surgery for high-risk T1 CRC. Hence, ER may be acceptable for high-risk T1 CRC.

ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

A protease-activated, near-infrared fluorescent probe for early endoscopic detection of premalignant gastrointestinal lesions

Fluorescence imaging is currently being actively developed for surgical guidance; however, it remains underutilized for diagnostic and endoscopic surveillance of incipient colorectal cancer in high-risk patients. Here we demonstrate the utility and potential for clinical translation of a fluorescently labeled cathepsin-activated chemical probe to highlight gastrointestinal lesions. This probe stays optically dark until it is activated by proteases produced by tumor-associated macrophages and accumulates within the lesions, enabling their detection using an endoscope outfitted with a fluorescence detector. We evaluated the probe in multiple murine models and a human-scale porcine model of gastrointestinal carcinogenesis. The probe provides fluorescence-guided surveillance of gastrointestinal lesions and augments histopathological analysis by highlighting areas of dysplasia as small as 400 µm, which were visibly discernible with significant tumor-to-background ratios, even in tissues with a background of severe inflammation and ulceration. Given these results, we anticipate that this probe will enable sensitive fluorescence-guided biopsies, even in the presence of highly inflamed colorectal tissue, which will improve early diagnosis to prevent gastrointestinal cancers.

PCN99 Economic Evaluation of Artificial Intelligence-Assisted Colonoscopy for Routine Screening of High-Risk Colorectal Cancer Patients in Spain

An increase in adenoma detection rates (ADRs) in routine colonoscopy screening has been shown to decrease the incidence and subsequent mortality rates of colorectal cancer (CRC). The application of artificial intelligence (AI)-assisted colonoscopy in recent clinical trials has demonstrated significant increases in ADRs compared to standard colonoscopy (SC). Thus, this study evaluates the long-term clinical- and cost-effectiveness of using AI-assisted colonoscopy versus SC A Markov model simulating the natural history of high-risk CRC patients (N=1000) was developed from the Spanish healthcare perspective. The model tracked patients from the age of 50 years through screening, stages of CRC at diagnosis, disease progression, remission, and death. Clinical efficacy inputs were obtained from literature sources. Cost were obtained from reference sources and adjusted using purchasing power parity where necessary. Model outcomes included life-years gained, CRCs prevented, costs, averted healthcare resource use, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). A discount rate of 3.0% was used in the calculations. A range of sensitivity analyses were conducted to test the robustness of the model. Price sensitivity analysis was conducted to provide value-based pricing ranges of AI-assisted colonoscopy at different willingness-to-pay (WTP) thresholds. The adoption of AI-assisted colonoscopy compared to SC was expected to reduce long-term risks of interval CRC by 0.27%. The average life-years and QALYs gained were 0.033 and 0.155, respectively. Price sensitivity analysis demonstrated AI software to be cost-effective at a WTP threshold of €20,000–€30,000/QALY. Parameters with the largest impact on the ICER were the cost of AI software, transition probabilities for disease progression and ADRs. This is the first published economic analysis of AI-assisted colonoscopy in Spain. These results suggest that AI-assisted colonoscopy could be cost-effective. However, there is value in reducing the uncertainty around these cost-effectiveness estimates to better inform future screening policy.

PCN115 Economic Evaluation of Artificial Intelligence-Assisted Colonoscopy for Routine Screening of Low- to High-Risk Colorectal Cancer Patients in the United Kingdom

An increase in adenoma detection rates (ADRs) in routine colonoscopy screening has been shown to decrease the incidence and subsequent mortality rates of colorectal cancer (CRC). The application of artificial intelligence (AI)-assisted colonoscopy in recent clinical trials has demonstrated significant increase in ADRs compared to standard colonoscopy (SC). Thus, this study evaluates the long-term clinical- and cost-effectiveness of using AI-assisted colonoscopy versus SC. A Markov model simulating the natural history for low- to high-risk CRC patients (N=1,000) was developed from the UK healthcare perspective. The model tracked patients from the age of 50 years through screening, stages of CRC at diagnosis, disease progression, remission, and death. Clinical efficacy and cost inputs were obtained from NHS Reference Costs and literature sources. Outcomes included life-years gained, CRCs prevented, costs and health care resources adverted, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). A discount rate of 3.5% was used in the calculations. A range of sensitivity analyses were conducted to test the robustness of the economic model. Price sensitivity analysis was also conducted to provide value-based pricing ranges of AI-assisted colonoscopy at different willingness-to-pay (WTP) thresholds. The adoption of AI-assisted colonoscopy compared to SC was expected to reduce long-term risks of interval CRC by 0.27%. The average life-years and QALYs gained were 0.004 and 0.008, respectively. Price sensitivity analysis demonstrated AI software to be cost-effective at a WTP threshold of £20,000–£30,000/QALY. The parameters with the largest impact on the ICER were the cost of AI software, transition probabilities for disease progression and ADRs. This is the first published economic analysis of AI-assisted colonoscopy in the UK. These results suggest that AI-assisted colonoscopy could be cost-effective. However, there is value in reducing the uncertainty around these cost-effectiveness estimates to better inform future screening policy.

Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.

Inherited pathogenic variants account for 5% to 10% of all breast cancer (BC) and colorectal cancer (CRC) cases. Here, we sought to profile the pathogenic variants in 25 cancer susceptibility genes in Turkish population. Germline pathogenic variants were screened in 732 BC patients, 189 CRC patients and 490 cancer-free elderly controls, using next-generation sequencing-based multigene panel testing and multiplex ligation-dependent probe amplification testing. Pathogenic variants were detected in 17.2% of high-risk BC patients and 26.4% of high-risk CRC patients. More than 95% of these variants were clinically actionable. BRCA1/2 and mismatch repair genes (MLH1, MSH2 and MSH6) accounted for two-thirds of all pathogenic variants detected in high-risk BC and CRC patients, respectively. Pathogenic variants in PALB2, CHEK2, ATM and TP53 were also prevalent in high-risk BC patients (4.5%). BRCA1 exons 17-18 deletion and CHEK2 c.592+3A>T were the most common variants predisposing to BC, and they are likely to be founder variants. Three frequent MUTYH pathogenic variants (c.884C>T, c.1437_1439delGGA and c.1187G>A) were responsible for all MUTYH biallelic cases (4.4% of high-risk CRC patients). The total pathogenic variant frequency was very low in controls (2.4%) and in low-risk BC (3.9%) and CRC (6.1%) patients. Our study depicts the pathogenic variant spectrum and prevalence in Turkish BC and CRC patients, guiding clinicians and health authorities for genetic testing applications and variant classification in Turkish population.

A novel mesenchymal-associated transcriptomic signature for risk-stratification and therapeutic response prediction in colorectal cancer.

Risk stratification in Stage II and III colorectal cancer (CRC) patients is critical, as it allows patient selection for adjuvant chemotherapy. In view of the inadequacy of current clinicopathological features for risk-stratification, we undertook a systematic and comprehensive biomarker discovery effort to develop a risk-assessment signature in CRC patients. The biomarker discovery phase examined 853 CRC patients, and identified a gene signature for predicting recurrence-free survival (RFS). This signature was validated in a meta-analysis of 1212 patients from nine independent datasets, and its performance was compared against established prognostic signatures and consensus molecular subtypes (CMS). In addition, a risk-prediction model was trained (n = 142), and subsequently validated in an independent clinical cohort (n = 286). As a result, this mesenchymal-associated transcriptomic signature (MATS) identified high-risk CRC patients with poor RFS in the discovery (hazard ratio [HR]: 1.79), and nine validation cohorts (HR: 1.86). In multivariate analysis, MATS was the most significant predictor of RFS compared to established prognostic signatures and CMS subtypes. Intriguingly, MATS robustly identified CMS4-subtype in multiple CRC cohorts (AUC = 0.92-0.99). In the two clinical cohorts, MATS stratified low and high-risk groups with a 5-year RFS in the training (HR: 4.11) and validation cohorts (HR: 2.55), as well as predicted response to adjuvant therapy in Stage II and III CRC patients. We report a novel prognostic and predictive biomarker signature in CRC, which is superior to currently used approaches and have the potential for clinical translation in near future.

The Ability of Polymorphisms in DNA Repair Enzymes to Predict Clinical Outcome in Colorectal Cancer Patients

Background: Genomic polymorphisms of DNA repair enzymes/excision repair cross complementation group 1 (ERCC1), excision repair cross complementation group 2 (ERCC2), and X-ray repair cross complementation group 1 (XRCC1) correlate with survival and therapeutic responses in colorectal cancer (CRC) patients. Therefore, the present study examined the frequency of ERCC1 C118T, ERCC2 Lys751Gln, and XRCC1 Arg399Gln polymorphisms and their prognostic and predictive values in CRC patients. Method: In this retrospective study, a total of 143 CRC patients were evaluated for these polymorphisms by PCR-RFLP. Results: The majority of the patients showed heterozygous C/T (56%) compared to wild type C/C (29%) and variant T/T (15%) genotypes for ERCC1 C118T polymorphism. ERCC2 Lys751Gln polymorphism showed wild type A/A (44%), heterozygous A/C (40%), and variant C/C genotypes (16%). The frequency of XRCC1 Arg399Gln polymorphism was 48% (wild type G/G), 42% (heterozygous G/A), and 10% (variant A/A). The relapse-free survival (RFS) significantly decreased in patients with ERCC1 118 C/C wild type genotype in the subgroups of patients with advanced stage and colon cancer; however, variant T/T genotype correlated with reduced overall survival (OS) in patients treated with combined drug 5-FU/Oxaliplatin. Taken together, in CRC patients and patients treated with 5-FU/Oxaliplatin, ERCC2 Lys751Gln A/A wild type genotype led to significantly unfavorable clinical outcomes. However, XRCC1 Arg399Gln polymorphism did not show any significant association with prognosis. Additionally, on analyzing combined effect of ERCC1 and ERCC2 polymorphisms, a significant reduced OS in patients with both unfavorable genotypes (ERCC1: C/C and ERCC2: A/A) was found. Furthermore, in the subgroup of patients treated with 5-FU/Oxaliplatin, RFS and OS significantly decreased in patients with both unfavorable genotypes (ERCC1: T/T and ERCC2: A/A). Conclusion: The significant relationship of ERCC1 C118T and ERCC2 Lys751Gln polymorphisms with prognosis and treatment response reflects the vital role of these molecules as prognostic and predictive markers in patients with CRC. Additionally, the combined evaluation of ERCC1 and ERCC2 polymorphisms might identify high risk CRC patients with poor prognosis.

TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients

BackgroundColorectal cancer is one of most common tumors in developed countries and, despite improvements in treatment and diagnosis, mortality rate of patients remains high, evidencing the urgent need of novel biomarkers to properly identify colorectal cancer high-risk patients that would benefit of specific treatments. Recent works have demonstrated that the telomeric protein TRF2 is over-expressed in colorectal cancer and it promotes tumor formation and progression through extra-telomeric functions. Moreover, we and other groups evidenced, both in vitro on established cell lines and in vivo on tumor bearing mice, that TRF2 regulates the vascularization mediated by VEGF-A. In the present paper, our data evidence a tight correlation between TRF2 and VEGF-A with prognostic relevance in colorectal cancer patients.MethodsFor this study we sampled 185 colorectal cancer patients surgically treated and diagnosed at the Regina Elena National Cancer Institute of Rome and investigated the association between the survival outcome and the levels of VEGF-A and TRF2.ResultsTissue microarray immunohistochemical analyses revealed that TRF2 positively correlates with VEGF-A expression in our cohort of patients. Moreover, analysis of patients’ survival, confirmed in a larger dataset of patients from TCGA, demonstrated that co-expression of TRF2 and VEGF-A correlate with a poor clinical outcome in stage I-III colorectal cancer patients, regardless the mutational state of driver oncogenes.ConclusionsOur results permitted to identify the positive correlation between high levels of TRF2 and VEGF-A as a novel prognostic biomarker for identifying the subset of high-risk colorectal cancer patients that could benefit of specific therapeutic regimens.

Prognostic value of a hypoxia-related microRNA signature in patients with colorectal cancer.

Hypoxia has been particularly associated with poor prognosis in cancer patients. Recent studies have suggested that hypoxia-related miRNAs play a critical role in various cancers, including colorectal cancer (CRC). In the present study, we found 52 differentially expressed miRNAs in HT-29 cells under hypoxic conditions versus normoxic conditions by analyzing the profiles of miRNAs. Using Cox model, we developed a hypoxia-related miRNA signature consisting of four miRNAs, which could successfully discriminate high-risk patients in the Cancer Genome Atlas (TCGA) training cohort (n=381). The prognostic value of this signature was further confirmed in the TCGA testing cohort (n=190) and an independent validation cohort composed of formalin-fixed paraffin-embedded clinical CRC samples (n=220), respectively. Multivariable Cox regression and stratified survival analysis revealed this signature was an independent prognostic factor for CRC patients. Time-dependent receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of this signature was significantly larger than that of any other clinical risk factors or single miRNA alone. A nomogram was constructed for clinical use, which incorporated both the miRNA signature and clinical risk factors and performed well in the calibration plots. Collectively, this novel hypoxia-related miRNA signature was an independent prognostic factor, and it possessed a stronger predictive power in identifying high-risk CRC patients than currently used clinicopathological features.

Silencing PSME3 induces colorectal cancer radiosensitivity by downregulating the expression of cyclin B1 and CKD1.

Resistance to radiotherapy remains a severe obstacle in the treatment of high-risk colorectal cancer patients. Recent studies have indicated that proteasome activator complex subunit 3 (PSME3) participates in the development and progression of various human malignancies and is proposed to play a role in tumor radioresistance. However, the impact of PSME3 on radioresistance of colorectal cancer has been largely unknown. In the present study, the enhanced expression of PSME3 was observed in colorectal cancer cells and tissue. Upregulation of PSME3 was significantly implicated in lymph node state, lymphovascular invasion, and Dukes' stage. Furthermore, high PSME3 expression was closely linked to poorer overall and progression-free survival in patients with colorectal cancer. The study further demonstrated that the proliferative, invasive and migratory potential of colorectal cancer cells was effectively inhibited in vitro after silencing PSME3. Our results verified that knockdown of PSME3 probably triggered cell cycle arrest at the G2/M phase by downregulation of cyclinB1 and CDK1, thereby enhancing the radiosensitivity of colorectal cancer cells. These data illustrated that PSME3 is a promising biomarker predictive of colorectal cancer prognosis and silencing of PSME3 may provide with a new approach for sensitizing the radiotherapy in colorectal cancer. Impact statement It is reported that colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related death. At present, the main treatment method of colorectal cancer is surgery, supplemented by radiotherapy and chemotherapy. Among them, radiotherapy plays an important role in the treatment of locally advanced colorectal cancer, surgery, and chemotherapy. Our study found that down-regulation of PSME3 may enhance the radiosensitivity of CRC cells by triggering cell cycle arrest, which suggests that silence PSME3 may provide a new method for improving the radiosensitivity of CRC. What’more, our research also demonstrated that PSME3 may promote proliferation, invasive and migratory potential of CRC cells, which implies that PSME3 might be a biomarker of CRC for early diagnosis and treatment.

Prognostic value of estrogen receptor-\u03b1 and progesterone receptor in curatively resected colorectal cancer: a retrospective analysis with independent validations

BackgroundPrognostic assessment is crucial for optimal treatment. The aim of our study was to investigate the potential impact of estrogen receptor-α (ER-α) and progesterone receptor (PR) on the prognosis of colorectal cancer (CRC) patients who received curative resection.MethodsRetrospective evaluation of two independent cohorts of CRC patients maintained prospectively in 2009–2010 (training set) (n = 148) and 2007–2009 (internal validation set) (n = 485). Furthermore, we used an external independent CRC cohort from The Cancer Genome Atlas (TCGA) (n = 511) for further validation. ER-α and PR expression as well as other potential prognostic factors were retrospectively evaluated in training set with respect to overall survival (OS), local relapse free survival (LRFS) and distant metastasis free survival (DMFS). The prognostic factors found in training set will be validated in two validation cohorts.ResultsOn univariate analysis for the training set, OS, LRFS and DMFS were not associated with PR expression. While patients with ER-αexpression were found to have poor prognosis. In addition, multivariate analysis showed that ER-αexpression maintained significance with respect to OS (HR, 5.06; p = 0.002), LRFS (HR, 8.81; p = 0.002) and DMFS (HR, 8.07; p = 0.004). Similarly, ER-α expression showed prognostic significance with respect to OS with hazard ratios (HRs) of 1.572 (95% CI: 1.001–2.467, p = 0.049) and 1.624 (95% CI: 1.047–2.520, p = 0.031) for the internal and external validation cohort, respectively.ConclusionER-α expression was a biomarker of poor prognosis and it might inform treatment decision for high risk CRC patients. However, PR expression was not associated with survival outcomes.

A prognostic index based on an eleven gene signature to predict systemic recurrences in colorectal cancer

Approximately half of colorectal cancer (CRC) patients experience disease recurrence and metastasis, and these individuals frequently fail to respond to treatment due to their clinical and biological diversity. Here, we aimed to identify a prognostic signature consisting of a small gene group for precisely predicting CRC heterogeneity. We performed transcriptomic profiling using RNA-seq data generated from the primary tissue samples of 130 CRC patients. A prognostic index (PI) based on recurrence-associated genes was developed and validated in two larger independent CRC patient cohorts (n = 795). The association between the PI and prognosis of CRC patients was evaluated using Kaplan–Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR analysis. Transcriptomic profiling in 130 CRC patients identified two distinct subtypes associated with systemic recurrence. Pathway enrichment and RT-PCR analyses revealed an eleven gene signature incorporated into the PI system, which was a significant prognostic indicator of CRC. Multivariate and subset analyses showed that PI was an independent risk factor (HR = 1.812, 95% CI = 1.342–2.448, P < 0.001) with predictive value to identify low-risk stage II patients who responded the worst to adjuvant chemotherapy. Finally, a comparative analysis with previously reported Consensus Molecular Subgroup (CMS), high-risk patients classified by the PI revealed a distinct molecular property similar to CMS4, associated with a poor prognosis. This novel PI predictor based on an eleven gene signature likely represents a surrogate diagnostic tool for identifying high-risk CRC patients and for predicting the worst responding patients for adjuvant chemotherapy.

Prediction of risk scores for colorectal cancer patients from the concentration of proteins involved in mitochondrial apoptotic pathway.

One of the major challenges in managing the treatment of colorectal cancer (CRC) patients is to predict risk scores or level of risk for CRC patients. In past, several biomarkers, based on concentration of proteins involved in type-2/intrinsic/mitochondrial apoptotic pathway, have been identified for prognosis of colorectal cancer patients. Recently, a prognostic tool DR_MOMP has been developed that can discriminate high and low risk CRC patients with reasonably high accuracy (Hazard Ratio, HR = 5.24 and p-value = 0.0031). This prognostic tool showed an accuracy of 59.7% when used to predict favorable/unfavorable survival outcomes. In this study, we developed knowledge based models for predicting risk scores of CRC patients. Models were trained and evaluated on 134 stage III CRC patients. Firstly, we developed multiple linear regression based models using different techniques and achieved a maximum HR value of 6.34 with p-value = 0.0032 for a model developed using LassoLars technique. Secondly, models were developed using a parameter optimization technique and achieved a maximum HR value of 38.13 with p-value 0.0006. We also predicted favorable/unfavorable survival outcomes and achieved maximum prediction accuracy value of 71.64%. A further enhancement in the performance was observed if clinical factors are added to this model. Addition of age as a variable to the model improved the HR to 40.11 with p-value as 0.0003 and also boosted the accuracy to 73.13%. The performance of our models were evaluated using five-fold cross-validation technique. For providing service to the community we also developed a web server ‘CRCRpred’, to predict risk scores of CRC patients, which is freely available at https://webs.iiitd.edu.in/raghava/crcrpred.

Development and Validation of an Autophagy Score Signature for the Prediction of Post-operative Survival in Colorectal Cancer.

Background: Survival rates for Colorectal cancer (CRC) patients who experienced early relapse have usually been relatively low. Our study aims at developing an autophagy signature that could help to detect early relapse cases in CRC.Methods: Propensity score matching analysis was carried out between patients from the early relapse group and the long-term survival group from GSE39582. For both groups, respectively, global autophagy expression changes were then analyzed to identify the differentially expressed prognostic autophagy related genes by conducting Linear Models for Microarray data method analysis. Then, the multi-gene signature was validated in TCGA and Fudan University Shanghai Cancer Center (FUSCC) cohorts. Time-dependent ROC were used to test the efficiency of this signature feature in predicting the prognosis of CRC patients.Results: 5 autophagy genes were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into low- or high-risk group. Time-dependent ROC analyses proved its prognostic accuracy, with AUC 0.841 and 0.803 at 1 and 3 years, respectively. Then, we validated its prognostic value in two external validation series (GSE17538 and GSE33113) and proved that the result is indeed significant irrespective of datasets in two external independent validation cohorts (TCGA and FUSCC cohorts). A nomogram was constructed to guide individualized treatment of patients with CRC.Conclusions: The identification of robust autophagy-related features can effectively classify CRC patients into groups with low and high risk of early relapse. This signature may be used to help select high-risk CRC patients who require more aggressive treatment interventions.

Abstract 3148: Identification and establishment of an 18-gene redox signature for recurrence prediction in colorectal cancer

Abstract Purpose: Colorectal cancer (CRC) is the third most common cancers worldwide. The immediate clinical challenge is the identification of high-risk CRC patients, particularly stage II and III, who are genuine candidates for adjuvant chemotherapy, while sparing the low-risk patients from the toxicity and expense of such treatment modalities. According to ASCO guidelines, the high-risk stage II CRC patients are currently defined by specific clinicopathological risk factors. However, the prognosis of patients, even with similar clinicopathological features varies significantly; highlighting their inadequacy in identifying true high-risk CRC patients. Accumulating evidence shows that redox adaptation provides survival benefit to cancer cells and enhances resistance to conventional chemotherapy. Therefore, in this study we performed a comprehensive evaluation of the clinical potential of redox-related genes as recurrence prediction biomarkers in CRC patients. Experimental Design: We undertook a rigorous biomarker discovery effort (GSE33113, n=90), followed by validation of a redox gene signature for recurrence prediction in two datasets (GSE39582, n=461 and GSE14333, n=185) of stage II and III CRC patients. The 18-gene signature discovered from the genome wide discovery effort was subsequently validated in an independent in-house clinical cohort (n=128) by qRT-PCR assays. Univariate and multivariate analyses were performed using CoxPH regression by including various clinicopathological features. Results: A systematic analysis of 312 redox-related genes in three public datasets of 736 CRC patients led to the identification of an 18-gene panel for predicting recurrence free survival (RFS) in stage II and III CRC patients. This gene signature could successfully discriminate high vs. low risk patients in the discovery cohort (AUC=0.88, HR=17.0, p&amp;lt;0.0001), as well as two validation cohorts (GSE39582: AUC=0.70; HR=3.1, p&amp;lt;0.0001; GSE14333: AUC=0.63; HR=3.8, p&amp;lt;0.0001). Subsequent validation in an independent CRC clinical cohort (n=128) confirmed that this gene signature was significantly associated with RFS (AUC=0.81; HR=9.3, CI=3.8 to 22.5, p&amp;lt;0.0001). Univariate analysis identified tumor stage, tumor infiltration, and TNM stage as significant predictors of RFS, and multivariate analysis further confirmed that our gene signature was a significant predictor of RFS in stage II/III CRC patients (p&amp;lt;0.0001). A risk-assessment model by combining the 18-gene signature and the three clinical factors exhibited an even superior prediction for RFS (AUC = 0.877; HR=10.34, CI=4.2 to 25.6, p&amp;lt;0.0001). Conclusions: We identified and established a novel 18-gene redox signature for the prediction of tumor recurrence in high-risk stage II/III CRC patients, which has the potential for translation into the clinic for improved risk-assessment and stratification in CRC patients. Citation Format: Priyanka Sharma, Jasjit K. Banwait, Luis Bujanda, Ajay Goel. Identification and establishment of an 18-gene redox signature for recurrence prediction in colorectal cancer [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 3148.

Abstract 4012: Small RNA-sequencing identifies a microRNA signature predictive of response to FOLFOX-based adjuvant therapy in stage II and III colorectal cancer

Abstract Purpose: Current NCCN guidelines for identifying high-risk stage II/III colorectal cancer (CRC) who may benefit from FOLFOX-based adjuvant chemotherapy remain inadequate. While stage III CRC patients often receive six months of oxaliplatin-based therapy following radical surgery, such treatments are frequently toxic and do not benefit all patients. The use of adjuvant chemotherapy in stage II CRC patients is even more controversial. Hence, identification of high-risk CRC patients with the highest likelihood to benefit from such treatments is of paramount clinical importance. Since microRNAs (miRNAs) have emerged as key functional players and important disease biomarkers, using genomewide miRNA expression profiling, we explored their potential as predictive biomarkers of therapeutic response in CRC. Experimental design: Small RNA-sequencing was performed in a cohort of stage II/III CRC patients who received, at least 6 months of FOLFOX-based therapy (n=71; 30 with recurrence, and 41 without recurrence). Identification of differentially expressed miRNAs was done using DESeq2, and biomarker prioritization using LASSO-Cox's proportional hazards model and AUC (area under the curve) analysis, using recurrence-free survival (RFS) as an outcome. The miRNA-signature was validated by using miRCURY LNA miRNA assays in three, independent patient cohorts of tissue (fresh frozen and FFPE) and serum specimens obtained from stage II/III CRC patients (n=91, 77 and 82, respectively). Univariate and multivariate Cox proportional hazard models were used to evaluate the performance of the miRNA classifier, in conjunction with known clinicopathological risk factors and the microsatellite instability (MSI) status. Results: The small RNA-expression profiling led to the identification of a 13-gene miRNA classifier that significantly predicted recurrence free survival (HR: 2.72, 95% CI: 1.96-3.76, p&amp;lt;0.0001) with an AUC of 0.90 (95% CI: 0.83-0.97). This classifier was successfully validated in two tissue cohorts, with impressive AUCs of 0.78 (95% CI: 0.64-0.90, fresh frozen cohort) and 0.86 (95% CI: 0.69-1.00, FFPE cohort), respectively. Importantly, our miRNA signature yielded an impressive AUC of 0.73 (95% CI: 0.60-0.88), even in the preoperative serum specimens from CRC patients. Multivariate analyses revealed that our miRNA classifier was the only independent predictor of response to FOLFOX-based treatment in stage II and III CRC patients. Conclusions: We report a novel miRNA-based classifier, which robustly predicts response to FOLFOX-based adjuvant chemotherapy in stage II/III CRC patients. Validation of this classifier in pre-operative serum provides an attractive opportunity to explore its potential for disease monitoring during the longitudinal follow-up in CRC patients. Citation Format: Raju Kandimalla, Uthra Balaji, Jinghua Gu, Marta Mendiola, Francesc Balaguer, Luis Bujanda, Joan Maurel, Jaime Feliu, Ajay Goel. Small RNA-sequencing identifies a microRNA signature predictive of response to FOLFOX-based adjuvant therapy in stage II and III colorectal cancer [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 4012.

Lifestyle in patients at increased risk of colorectal cancer

The present study aimed to assess modifiable risk factors in patients at high risk for colorectal cancer (CRC) and their experience of lifestyle advice. A questionnaire study was conducted in high-risk CRC patients attending for surveillance colonoscopy. Current lifestyle behaviours [smoking, alcohol, diet (fruit and vegetables, wholegrains, red meat, processed meat), physical activity and bodyweight] related to CRC were ascertained, and experience on receiving, seeking and desire for advice was queried. In total, 385 study invitations were sent and 208 (54%) questionnaires were returned. The majority of participants (72%) were estimated to have a body mass index beyond the healthy range, 89% achieved a fibre score indicative of a low plant-based diet and 91% reported eating processed meat. Overall, 36% were achieving at least four recommendations and 2% were adhering to all recommendations examined. The main area in which participants reported receiving advice on was body weight (33%) and 31% reported that they had personally sought information on this topic, although the data suggest that 72% of people may benefit from such guidance. Fewer participants reported receiving (18-26%) and seeking (15-17%) dietary advice on fruits, vegetables and wholegrains. Many participants said they would find lifestyle information useful, notably in relation to body fatness (43%) and physical activity (38%). The development of a process for supporting lifestyle change in this patient group, comprising individuals who are already engaging in positive health practices (regular colonoscopy surveillance), could usefully be identified and tested.