Chemotherapy In Colorectal Cancer Patients Research Articles

Prediction of colorectal cancer chemotherapy efficacy using machine learning applied to gene expression data.

e15548 Background: FOLFOX and FOLFIRI chemotherapy are considered standard first-line treatment options for colorectal cancer (CRC). However, the criteria for selecting the appropriate treatments have not been thoroughly analyzed. Here, we aim to use machine learning and genetic profiles to identify precise multi-gene panels that can predict the response to 5-Fluorouracil-based chemotherapy in colorectal cancer patients. Methods: The genetic profiling data, including drug response profiles, were retrieved from the Gene Expression Omnibus (GEO) database. These datasets were used to train and validate machine learning models. Feature selection methods, such as least absolute shrinkage and selection operator (LASSO) and variable selection from random forests (varSelRF) and various algorithms, such as Random Forest and Support Vector Machines, were applied to develop predictive models. Functional enrichment and network analyses were performed using Ingenuity Pathway Analysis (IPA). Results: This study identified relevant gene signatures at two stages of colorectal cancer: primary and metastasis using two different chemotherapy regimens, FOLFOX and FOLFIRI. The predictive models achieved an average prediction accuracy of 93% in identifying drug response outcomes across multiple chemotherapy regimens. The application of the machine learning model suggested that 28.6% of patients who failed the treatment therapy they received would benefit from the alternative treatment. Conclusions: The developed machine learning models demonstrate potential for guiding clinicians in selecting the most effective treatment options based on individual genetic profiles. With additional clinical validation, this approach could lead to improvements in treatment outcomes for patients with CRC and other cancers.

PTOV1-AS1 desensitizes colorectal cancer cells to 5-FU through depressing miR-149-5p to activate the positive feedback loop with Wnt/β-catenin pathway.

5-Fluorouracil is a commonly used chemotherapy drug for colorectal cancer. Resistance to 5-Fluorouracil remains a challenge. This research aimed to explore the mechanism of 5-Fluorouracil resistance in colorectal cancer. RT-qPCR and Western blot were used to determine the RNA and protein expression in both cells and exosome. Assays in vitro and in vivo were performed to measure the role of miR-149-5p in colorectal cancer cells. RIP, luciferase activity report, and RNA pulldown assay were applied to detect the association of PTOV1-AS1, SUV39H1, miR-149-5p, and FOXM1. MiR-149-5p was down-expressed in 5-Fluorouracil-resistant cells. MiR-149-5p enhanced the effectiveness of 5-Fluorouracil both in vitro and in vivo. Sensitive colorectal cancer cells released exosomal miR-149-5p to sensitize resistant cells to chemotherapy. Mechanistically, miR-149-5p targeted the FOXM1 to inactivate Wnt/β-catenin pathway, and PTOV1-AS1 recruited SUV39H1 to suppress miR-149-5p transcription, in turn activating Wnt/β-catenin pathway, and forming a positive feedback loop with FOXM1. PTOV1-AS1 inhibits miR-149-5p by a positive feedback loop with FOXM1-mediated Wnt/β-catenin pathway, which provides insights into a potential novel target for enhancing the effectiveness of chemotherapy in colorectal cancer patients.

Correlation of gut microbiota with leukopenia after chemotherapy in patients with colorectal cancer

BackgroundThe most common toxic side effect after chemotherapy, one of the main treatments for colorectal cancer (CRC), is myelosuppression.ObjectiveTo analyze the correlation between gut microbiota and leukopenia after chemotherapy in CRC patients.MethodsStool samples were collected from 56 healthy individuals and 55 CRC patients. According to the leukocytes levels in peripheral blood, the CRC patients were divided into hypoleukocytes group (n = 13) and normal leukocytes group (n = 42). Shannon index, Simpson index, Ace index, Chao index and Coverage index were used to analyze the diversity of gut microbiota. LDA and Student's t-test(St test) were used for analysis of differences. Six machine learning algorithms, including logistic regression (LR) algorithm, random forest (RF) algorithm, neural network (NN) algorithm, support vector machine (SVM) algorithm, catboost algorithm and gradient boosting tree algorithm, were used to construct the prediction model of gut microbiota with leukopenia after chemotherapy for CRC.ResultsCompared with healthy group, the microbiota alpha diversity of CRC patients was significantly decreased (p < 0.05). After analyzing the gut microbiota differences of the two groups, 15 differential bacteria, such as Bacteroides, Faecalibacterium and Streptococcus, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Peptostreptococcus, Faecalibacterium, and norank_f__Ruminococcaceae, respectively. Compared with normal leukocytes group, the microbiota alpha diversity of hypoleukocytes group was significantly decreased (p < 0.05). The proportion of Escherichia-Shigella was significantly decreased in the hypoleukocytes group. After analyzing the gut microbiota differences of the two groups, 9 differential bacteria, such as Escherichia-Shigella, Fusicatenibacter and Cetobacterium, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Fusicatenibacte, Cetobacterium, and Paraeggerthella.ConclusionGut microbiota is related to leukopenia after chemotherapy. The gut microbiota may provide a novel method for predicting myelosuppression after chemotherapy in CRC patients.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

The Value of Prolactin, a Panel of Cytokines, and the Soluble Human Epidermal Growth Factor Receptor 2 in the Prediction of Rapid Progression and Shorter Survival during Palliative Chemotherapy of Colorectal Cancer Patients.

The prediction of colorectal cancer (CRC) response to palliative chemotherapy (CTH) is still difficult. Patients at a higher risk of progression may benefit from more aggressive treatment. This study assessed the predictive value of prolactin (PRL) and a panel of cytokines, chemokines, and growth factors for the risk of rapid progression in CRC patients starting palliative CTH. This study included 51 CRC patients initiating palliative CTH with up to 5-year follow-up, divided into rapid and non-rapid progressors. Serum samples were collected before CTH for assessment of a large panel of cytokines, chemokines, growth factors, and PRL via a multiplex method. Rapid progressors (N = 19) were characterized by increased baseline values of IL-8 and IP10 but decreased PRL levels. In addition, PRL below 18.2 ng/mL was a strong predictor of weight loss during CTH. Grade 3 (HR = 2.97; 95%CI: 1.48-5.98) and PRL level (HR = 0.96; 95%CI: 0.91-1.01) were independent risk factors of progression. We showed that CRC rapid progressors are characterized by decreased baseline PRL levels. In addition, increased baseline levels of IP-10, sHER-2, IL-6, and IL-8 may be associated with longer survival; however, larger studies are needed to confirm their predictive role in CRC patients.

Combined expression of HIF1α, VEGF and HER2 predicts metastasis, relapse and response to combination chemotherapy in colorectal cancer patients

Addressing a single target is the frequent development of drug resistance followed by cancer relapse and treatment failure. Therefore, assessment of simultaneous expression of target molecules is essential to choose the optimal combination therapy for each colorectal cancer patient.This study aims to evaluate the immunohistochemical expression of HIF1α, HER2 and VEGF and to clarify their clinical significance as prognostic factors and predictive markers of FOLFOX (combination chemotherapy inclusive of Leucovorin calcium, Fluorouracil and Oxaliplatin response).Marker expression was retrospectively evaluated by immunohistochemistry in 111 patients with colorectal adenocarcinomas from south Tunisia, followed by statistical analysis.The immunohistochemical staining revealed that 45 %, 80.2 %, 86.5 % and 25.5 % of specimen were positive for nuclear, cytoplasmic HIF1α expression, VEGF and HER2 respectively. Nuclear HIF1α and VEGF were associated with worst prognosis while cytoplasmic HIF1α and HER2 were correlated with favourable prognosis. Multivariate analysis confirms the association between nuclear HIF1α, distant metastasis, relapse, FOLFOX response and 5 years overall survival. HIF1α positivity and HER2 negativity were significantly associated to short survival. Combined immunoprofiles HIF1α+/VEGF+, HIF1α+/HER2-, HIF1α+/VEGF+/HER2- were associated to distant metastasis, cancer relapse and short survival. Interestingly, our findings confirmed that patients bearing a HIF1α positive tumor were significantly more resistant to FOLFOX compared to negative ones (p = 0.002, p ≤ 0.001). Positive expression of HIF1α and VEGF, or decreased expression of HER2 was each associated with poor prognosis and short overall survival. In summary, we found that expression of nuclear HIF1α, alone or combined with VEGF and HER2 serves as a predictive marker of poor prognosis and FOLFOX response in colorectal cancer from south Tunisia.

Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells

BackgroundTumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy.MethodsImmunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The “one-two punch” sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines and murine models.ResultsWe found a significant correlation between CLDN1 expression level and histologic response to chemotherapy, CLDN1 expression being the highest in resistant metastatic residual cells of patients showing minor responses. Moreover, in both murine xenograft model and CRC cell lines, CLDN1 expression was upregulated after exposure to conventional chemotherapies used in CRC treatment. CLDN1 overexpression was, at least in part, functionally related to the activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway. Overexpression of CLDN1 was also observed in oxaliplatin-resistant CRC cell lines and was associated with resistance to apoptosis, suggesting an anti-apoptotic role for CLDN1. Finally, we demonstrated that the sequential treatment with oxaliplatin followed by an anti-CLDN1 ADC displayed a synergistic effect in vitro and in in vivo.ConclusionOur study identifies CLDN1 as a new biomarker of acquired resistance to chemotherapy in CRC patients and suggests that a “one-two punch” approach targeting chemotherapy-induced CLDN1 expression may represent a therapeutic opportunity to circumvent resistance and to improve the outcome of patients with advanced CRC.

Influence of Single-Nucleotide Polymorphisms on Clinical Outcomes of Capecitabine-Based Chemotherapy in Colorectal Cancer Patients: A Systematic Review.

The aim of this systematic review was to provide a comprehensive overview of the literature published in the last decade on the association of single-nucleotide polymorphisms in genes involved in the pharmacodynamic and pharmacokinetic pathways of capecitabine with treatment outcomes among colorectal cancer patients. A systematic search of the literature published in the last 10 years was carried out in two databases (Medline and Scopus) using keywords related to the objective. Quality assessment of the studies included was performed using an assessment tool derived from the Strengthening the Reporting of Genetic Association (STREGA) statement. Thirteen studies were included in this systematic review. Genes involved in bioactivation, metabolism, transport, mechanism of action of capecitabine, DNA repair, and folate cycle were associated with toxicity. Meanwhile, genes related to DNA repair were associated with therapy effectiveness. This systematic review reveals that several SNPs other than the four DPYD variants that are screened in clinical practice could have an impact on treatment outcomes. These findings suggest the identification of future predictive biomarkers of effectiveness and toxicity in colorectal cancer patients treated with capecitabine. However, the evidence is sparse and requires further validation.

Emerging glyco-risk prediction model to forecast response to immune checkpoint inhibitors in colorectal cancer.

Aberrant glycosylation is one of the most common post-translational modifications leading to heterogeneity in colorectal cancer (CRC). This study aims to construct a risk prediction model based on glycosyltransferase to forecast the response to immune checkpoint inhibitors in CRC patients. Based on the TCGA dataset and glycosyltransferase genes, the NMF algorithm and WGCNA were used to identify molecular subtypes and co-expressed genes, respectively. Lasso and multivariate COX regression were used to identify prognostic glycosyltransferase genes and construct a glyco-risk prediction model in CRC patients. Univariate and multivariate Cox regression, Kaplan-Meier, and ROC curves were applied to further verify the prognostic performance of the model in CRC patients in the training and validation sets. We compared the responsiveness of immunotherapy and chemotherapy between the two groups. In vitro experiments and clinical specimens verified the specific function of the key glycosyltransferase genes in CRC. The CRC cohort was divided into two subtypes with prominent differences in survival based on the well-robust seven-gene glyco-risk prediction model (composed of ALG1L2, HAS1, PYGL, COLGALT2, B3GNT4, POFUT2, and GALNT7). The nomograms based on the risk model could predict the prognosis of CRC patients independently of other clinicopathologic characteristics. Our prediction model showed a better overall prediction performance than other models. Compared with the low-risk group, the high-risk CRC patients showed a lower immune infiltration state, but a higher TMB and a lower response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapy. Clinical specimen validation showed an obvious difference in the expression of seven glycosyltransferase genes between the low- and high-risk groups. Significant reduction in POFUT2 expression in high-risk groups was associated with reduced N-glycans production. Our study constructed a robust glyco-risk prediction model that could provide direction for immunotherapy and chemotherapy in CRC patients, which could help clinicians make personalized treatment decisions.

Postoperative Probiotics Administration Attenuates Gastrointestinal Complications and Gut Microbiota Dysbiosis Caused by Chemotherapy in Colorectal Cancer Patients.

The current study aims to evaluate the potential roles of taking probiotics postoperatively in attenuating the gastrointestinal complications and disturbed gut microbiota in colorectal cancer (CRC) patients undergoing chemotherapy. One hundred eligible CRC patients who were treated with radical surgery and needed to receive chemotherapy were recruited. Half of them were randomly assigned to the Probio group to take a probiotic combination from post-operation to the end of the first chemotherapeutic course. The other half of patients taking placebo instead were classified as the Placebo group. Gastrointestinal complications such as nausea, acid reflux, abdominal pain, abdominal distention, constipation, and diarrhea were recorded during chemotherapy. Fecal samples were collected preoperatively and after the first cycle of postoperative chemotherapy for 16S rRNA high-throughput sequencing and short-chain fatty acids (SCFAs) analysis. Results showed that probiotics administration could effectively reduce chemotherapy-induced gastrointestinal complications, particularly in diarrhea (p &lt; 0.01). Additionally, chemotherapy also reduced the bacterial diversity indexes of the gut microbiota in CRC patients, which could be significantly increased by taking probiotics. Moreover, this chemotherapy caused significant changes in the composition of the gut microbiota, as indicated by decreased phylum levels of Firmicutes and increased Bacteroidetes, Proteobacteria, and Verrucomicrobia. In particular, several bacterial genera such as Akkermansia and Clostridium were significantly increased, while Prevotella, Lactobacillus, and Roseburia were decreased (p &lt; 0.05). However, probiotic administration could effectively restore these taxa changes both at the phylum and genus levels, and mildly increase the genus levels of Bifidobacterium, Streptococcus, and Blautia. Furthermore, probiotics could also promote the production of SCFAs, particularly increasing acetate, butyrate, and propionate (p &lt; 0.0001). These results support the beneficial effects of the probiotic interventions as novel alternative or complementary strategies in chemoprevention.

Short-term outcomes of neoadjuvant chemotherapy in colorectal cancer patients with isolated liver metastasis

The purpose of the study was to assess the short-term effcacy and tolerability of neoadjuvant chemotherapy (NAC) in colorectal cancer (CRC) patients with isolated liver metastasis.Material and Methods. Since 2020, a pilot study including 23 CRC patients with liver metastasis has been conducted at the Abdominal Cancer Department of the Cancer Research Institute (Tomsk, Russia). The combined treatment modality included 3 cycles of NAC according to FOLFOXIRI + cetuximab (20 patients with wtKRAS) and FOLFOXIRI + bevacizumab (3 patients with mtKRAS) regimens followed by simultaneous laparoscopic colorectal resection and open liver resection.Results. For liver metastases, the objective response rate reached 100 % (complete response: 8.7 %, partial response: 91.3 %). For the primary tumor, the objective response rate was 100 % (partial response). The overall NAC toxicity rate was 53.6 %. The major I–II grade toxicities included nausea/vomiting (27.5 %), polyneuropathy (10.1 %), skin reaction (10.1 %), hepatotoxicity (5.8 %), and corresponded to I–II grade. R0 resection was performed in all patients. Postoperative complications were observed in 19 (82.6 %) patients; of them 18 (78.3 %) had a febrile temperature (grade 1, according to the Clavien–Dindo classifcation) due to the use of bipolar coagulation during liver surgery, and 1 (4.4 %) patient developed a biliary fstula (3 A/B grade according to Clavien–Dindo). No postoperative death occurred. For liver metastasis, pathological complete response rate was 4.4 % (TRG1 according to Mandard); for the primary tumor, in most cases was TRG 3 – 87 %.Conclusion. Combined treatment modality, including NAC with FOLFOXIRI regimen and targeted therapy for CRC with liver metastases, is well tolerated, has a signifcant damaging effect on the tumor, and does not affect the course of the postoperative period. Further studies are required to assess the long-term treatment outcomes.

HUBUNGAN DUKUNGAN KELUARGA DAN PERAWAT DENGAN MOTIVASI PASIEN KANKER KOLOREKTAL DALAM MENJALANI KEMOTERAPI

ABSTRACT&#x0D; Chemotherapy can cause physiological and psychological impacts that cause some patients to feel afraid to do chemotherapy, for this reason, family support and nurse support are needed so that colorectal cancer patients remain motivated to undergo chemotherapy. The purpose of this study was to determine the relationship between family support and nurse support on patient motivation to undergo chemotherapy in colorectal cancer patients at Dr. Saiful Anwar Hospital Malang. The design used is a correlation study to study the relationship between the independent variables of family support and nurse support, the dependent variable is the motivation of patients undergoing chemotherapy. Data collection is a cross sectional study using an instrument in the form of a questionnaire. By using the purposive sampling technique, a sample of 40 people was obtained. The research was conducted at Dr. Saiful Anwar Hospital, Malang. The results of the Rank Spearman correlation test show that there is a relationship between family support and motivation in colorectal cancer patients of 0.347 (p=0.028), the relationship is positive/unidirectional with moderate strength, the better the family support, the better the motivation of colorectal cancer patients undergoing chemotherapy. With family support helps cancer patients to increase their confidence that they are accepted by their families, thus providing motivation to do chemotherapy regularly in order to recover. The results of the Rank Spearman correlation test showed that there was a relationship between nurse support and motivation in colorectal cancer patients of 0.490 (p=0.000), the relationship was positive/unidirectional with moderate strength, the better the nurse support, the better the motivation of colorectal cancer patients undergoing chemotherapy. Because with the support of nurses, it will increase the patient's knowledge about chemotherapy and healing, thereby increasing the patient's motivation to undergo chemotherapy.&#x0D; &#x0D; Keywords: Colorectal cancer, chemotherapy, family support, nurse support, motivation

Construction and Validation of an Oxaliplatin-Resistant Gene Signature in Colorectal Cancer Patients Who Underwent Chemotherapy.

Aberrant expression of genes contributes to the chemoresistance of colorectal cancer (CRC) treatment. This study aimed to identify genes associated with the chemoresistance of oxaliplatin-based chemotherapy in CRC patients and to construct a signature. Oxaliplatin resistance-related genes were screened by analyzing the gene profiles of cell lines and tissue samples that underwent oxaliplatin-based treatment. Oxaliplatin resistance-related genes were used to establish a signature. The association of the signature had clinical significance, so the prognostic value of the signature was analyzed. Independent cohorts and CRC cell lines were used to validate the value of the gene signature and the oxaliplatin-resistant genes. There were 64 oxaliplatin resistance-related genes identified after overlapping the genes from the dataset of oxaliplatin-treated CRC cells and the dataset of patients treated with oxaliplatin-based chemotherapy. A gene signature based on five oxaliplatin resistance-related genes was established. This gene signature effectively predicted the prognosis of CRC patients who underwent chemotherapy. No significant associations were found between the gene mutations and survival of the patients; however, two genes were associated with microsatellite instability status. Two external independent cohorts and CRC cell line experiments validated the prognostic values of the signature and expression of the genes after oxaliplatin treatment. In conclusion, the oxaliplatin resistance-related gene signature involving five genes was a novel biomarker for the prediction of the chemotherapy response and prognosis of CRC patients who underwent oxaliplatin-based chemotherapy.

Clinical efficacy of chemotherapy in colorectal cancer patients over 80 years old

PurposeColorectal cancer (CRC) is a common and aggressive gastrointestinal cancer, and the prognostic impact associated with chemotherapy in super elderly (over 80 years old) patients remains poorly defined. We aimed to define the effect of chemotherapy on the prognosis of patients with CRC over 80 years old.Patients and methodsA retrospective study including CRC patients over 80 years old was conducted. The patients were screened from the Surveillance Epidemiology and End Results (SEER) database from 2010 to 2015. Overall survival (OS) and cancer-specific survival (CSS) were applied as the primary and secondary outcome. Cox proportional hazards regression models were used to evaluate factors associated with OS and CSS. Survival curves of OS and CSS were estimated by Kaplan–Meier method and compared by log-rank test.ResultsIn total, 14,748 CRC patients over 80 years old were included in this study. The median patient age was 85 (IQR: 82–87). All patients were divided into surgical group and non-surgical group. The OS and CSS of the surgical group were significantly better than those of the non-surgical group (P < 0.001). Chemotherapy can improve OS and CSS for patients with stage III and IV (P < 0.001) in surgical group. For the super elderly patients with CRC, chemotherapy significantly improved OS and CSS in all TNM stages in non-surgical group.ConclusionFor super elderly patients with colorectal cancer, tumor treatment should not be abandoned because of their age. It is necessary to carry out clinical trials in super elderly patients.

Abstract 5717: Novel evidence for FTO as an oncogenic player and mediator of chemoresistance in colorectal cancer

Abstract Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Although, 5-flurouracil (5FU) based chemotherapy and surgical resection are considered most effective treatments for CRC patients, the 5-year survival rates remain poor primarily due to distant metastasis, local recurrence and acquired drug resistance. Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine demethylase, has recently been reported to be upregulated in various cancers, including CRC. However, thus far, the molecular mechanism underlying the role of FTO in CRC and/or acquisition of 5FU resistance remains unclear. Methods: To study the relevance of FTO overexpression in CRC, we adopted various approaches: a) lentiviral-mediated stable depletion of FTO or (b) CS1-mediated pharmacological inhibition in CRC cells, c) lentiviral-mediated FTO overexpression in normal colonic epithelial cells (NCM460), and thereafter analyzed the effect on cell viability, cell cycle, wound healing, invasion, epithelial-mesenchymal transition (EMT), cancer stemness, 5FU drug response and tumor forming capability in nude mice. Expression of markers of cell proliferation and apoptosis in the tumor extracts were analyzed by western blotting. To augment the clinical relevance, we evaluated the effect of CS1 on the growth and response to 5FU in patient-derived organoids (PDOs). Kaplan Meier analysis was performed to correlate the significance of FTO overexpression with survival in CRC patient cohorts. Results: A significant upregulation of both mRNA and protein expression of FTO was found in various CRC cells compared to NCM460 cells. Notably, FTO inhibition hampered the proliferative, migratory and invasive capabilities of CRC cells whilst, ectopic overexpression of FTO in the NCM460 cells promoted oncogenic phenotype. Furthermore, FTO depletion in CRC cells led to EMT reversal, impaired tumor-sphere formation and stemness traits, which in turn was reflected in the sensitization towards 5FU in otherwise resistant cells. Moreover, xenograft tumor forming capabilities of CRC cells was severely hindered in FTO depleted cells. Besides, FTO-depleted xenografts displayed a significant decrease in the expression of markers of cell survival and proliferation (p-AKT and PCNA), while there was an increment in the apoptotic marker, Caspase 9. The relevance of our in vitro and in vivo findings was further strengthened as CS1-mediated inhibition not only decrease the number and size of PDO, but also sensitized them towards 5FU. In addition, we unambiguously demonstrate a significant correlation between FTO upregulation and poor overall and recurrence-free-survival of CRC patients. Conclusions: Our study establishes the functional importance of FTO in CRC and provides novel evidence for the potential use of FTO inhibitor as an adjunctive treatment to 5FU based chemotherapy for CRC patients. Citation Format: Rachana Garg, Laleh Melstorm, Jianjun Chen, Chuan He, Ajay Goel. Novel evidence for FTO as an oncogenic player and mediator of chemoresistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5717.

Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy.

Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear. Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment. Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher. Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.

Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients.

BackgroundAddition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients.MethodsA living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs) in vitro and in PDO-xenografted tumors in mice. Based on in vitro oxaliplatin IC50 values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance.ResultsOxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs.ConclusionsPDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.

Translation and Validation of the Indonesian Version of the Adverse Drug Reaction Severity Level Instruments in Colorectal Cancer Patients.

IntroductionAssessment of the severity of adverse drug reaction (ADR) is very rare in Indonesia. The severity of ADR can describe how serious this affects the clinical condition of the patient. In Indonesia, there are no instruments used to measure the severity of ADR.PurposeThis study aims to translate, pilot test, and validate Hartwig instruments for measuring the severity of ADR in colorectal cancer patients in Indonesia.Patients and MethodsThe translation method was used forward-backward technique from English to Indonesian, then being retranslated from Indonesia to English. The instrument of Indonesian version was used to assess the severity of ADR as the effect of chemotherapy. The assessment was conducted to 10 colorectal cancer patients by 30 health workers. The test validity was done based on content validity ratio (CVR) and content validity index (CVI); meanwhile, the test reliability was based on intraclass coefficient correlation (ICC).ResultsAll of the results of CVR present a value of >0.33, while the range of CVI moves between 0.8 to 1.0, which declares that the instrument is valid. The satisfactory alpha value for reliability is 0.996 with signification of 0.197 (p > 0.05) based on ANOVA analysis. Meanwhile, the ICC value of 0.896 indicates a good reliability among raters.ConclusionIndonesian version of Hartwig Instrument can be applied in measuring the severity of ADR caused by chemotherapy in colorectal cancer patients.

Comparison of follow-up treatment regimens for colorectal cancer liver metastases without objective response to neoadjuvant chemotherapy: direct surgery or surgery after second-line chemotherapy

Objective: To compare the effect of direct surgery or surgery after second-line chemotherapy for colorectal cancer patients with liver metastases who did not achieve objective remission after neoadjuvant chemotherapy. Methods: A retrospective case cohort study was used. The clinical and pathological data of 107 patients with colorectal cancer liver metastases who did not achieve objective response to neoadjuvant chemotherapy at Department of Hepatobiliary Surgery,Cancer Hospital,Chinese Academy of Medical Sciences from December 2008 to December 2016 were retrospectively collected. There were 71 males and 36 females, median age was 57 years (range: 28 to 79 years). According to the different treatment regimens after neoadjuvant chemotherapy,107 cases were divided into a direct surgery group (direct group,n=65) and an operation after receiving second-line chemotherapy group (second-line group,n=42). The propensity score matching(PSM) of the Logistic regression model was used to match the bilobar distribution of liver metastases and the number of first-line chemotherapy cycles in the two groups of patients. The caliper value was set to 0.10 and the matching ratio was 1∶2. T test, Mann-Whitney U test, χ2 test or Fisher's exat test was used to analyzed the data between the tuo groups, respectively. Survival analysis design was used to investigate the difference in prognosis between the two groups of patients. Results: The follow-up time(M(IQR)) was 56.3(34.3) months (range: 2.1 to 95.0 months),and all patients were followed up. After PSM,there were 28 cases in the direct group and 42 cases in the second-line group, there were no significant differences in whether R0 resection was feasible,blood loss,blood transfusion,postoperative complications and postoperative hospital stay between the two groups (all P>0.05). The 1,3,and 5-year progression-free survival(PFS) rates of the direct group were 40.0%,16.5%,and 11.0%,and the 1,3,and 5-year overall survival(OS) rates were 98.5%,61.2%,and 41.4%,respectively, the second-line group 1,3,5 years PFS rates were 35.7%,14.3%,14.3%,1,3,5-year OS rate were 95.2%,55.1%,44.4%,respectively. The median PFS time of the direct group and the second-line group was 8.5 months and 7.5 months,respectively,and the difference was not statistically significant (P=0.826). The median OS time of the direct group and the second-line group were 33.8 months and 46.9 months,respectively. The difference was not statistically significant(P=0.646).The median PFS time of the direct group and second-line chemotherapy complete remission and partial remission group(CR/PR group) was 10.2 months and 9.1 months,respectively,and the difference was not statistically significant(P=0.669). The median OS time of the direct group and the second-line CR/PR group was 51.0 months and 46.9 months,respectively,and the difference was not statistically significant(P=0.427). The results of survival analysis suggested that major liver resection was an independent prognosis factor for PFS (HR=1.809,95%CI: 1.067 to 3.067,P=0.028) and OS(HR=2.751,95%CI: 1.317 to 5.747,P=0.007). Second-line chemotherapy was not an independent prognostic factor for PFS (HR=0.945, 95%CI:0.570 to 1.567,P=0.828) and OS (HR=0.866,95%CI: 0.468 to 1.602,P=0.646). Conclusions: There is no significant difference in the short-term outcome and long-term prognosis between direct surgery patients and second-line chemotherapy followed by surgery. Second-line chemotherapy is not an independent prognostic factor for colorectal cancer liver metastases patients who fail to achieve objective response after neoadjuvant chemotherapy.

Is CA19-9 effective in predicting chemotherapeutic response in patients with synchronous liver metastases with colorectal cancer?

Evaluation of response to chemotherapy in colorectal cancer patients with synchronous liver metastases is important in terms of treatment management. In this Letter to the Editor, several issues in the article are discussed. For the comparison of carbohydrate antigen 19-9 (CA19-9) values referenced in the study, the patient group was not matched for cancer stage. Therefore, it may be more appropriate to select and compare CA19-9 values in patients with same-stage cancer.