Clinical Management Of Colon Cancer Research Articles

A novel angiogenesis-associated risk score predicts prognosis and characterizes the tumor microenvironment in colon cancer.

Angiogenesis of the tumor microenvironment (TME) can promote the proliferation and metastases of colon cancer (CC). However, there is a lack of bioinformatics analysis to comprehensively clarify the molecular characteristics, immune interaction characteristics and predictive values of angiogenesis characteristics in CC patients. This study aimed to perform a comprehensive elucidation of the correlation between angiogenesis and CC for the purpose of improving the clinical management of CC. Angiogenesis-associated genes (AAGs) were evaluated in the population of CC patients from the Cancer Genome Atlas database and Gene Expression Omnibus dataset. The expression, prognostic role, and immune cell infiltration of AAGs were assessed first. And then we established the AAGs score to further explore the prognosis and treatment response of angiogenesis characteristics in individual patient. Totally, we identified two different molecular subtypes of angiogenesis, and there was a significant difference in the background of genome, expression profiles, prognosis, and characteristics of TME between two subtypes. And the AAGs score was independently associated with over survival in CC patients, the prognostic value was significant and confirmed in the entire cohort. And we also constructed a nomogram based on the risk score and clinical parameters to maximize the predictive ability of the risk score. Additionally, the AAGs score was significantly correlated with the tumor mutation burden score, cancer stem cell score and drug sensitivity. Our study elucidated the role of angiogenesis characteristics in CC and the AAGs score could help clinicians plan for individual management with chemotherapy agents and promote the development of immunotherapy in CC. Prospective studies need to be conducted to further confirm our findings.

Characteristics of Prognostic Programmed Cell Death-Related Long Noncoding RNAs Associated With Immune Infiltration and Therapeutic Responses to Colon Cancer.

Programmed cell death (PCD) plays an important role in the onset and progression of various cancers. The molecular events surrounding the occurrence of abnormally expressed long noncoding RNAs (lncRNAs) leading to colon cancer (CC) have become a focus. We comprehensively evaluated the roles of PCD-related lncRNAs in the clinical management of CC and their immune responses. Therefore, we screened 41 prognostic PCD-related lncRNAs in The Cancer Genome Atlas database using co-expression analysis and assigned patients to groups according to the results of cluster analysis. The immune response and functions of cluster 2 were substantially suppressed, which might explain the poor prognosis in this group. A prognostic model comprising eight PCD-related lncRNAs was developed, and its effectiveness was verified using an external database. High-and low-risk groups had different epigenetic modifications and changes in immune cell infiltration. Patients in the high-risk group were resistant to immunotherapy and various chemotherapeutic drugs. Studies in vitro and in vivo further confirmed a carcinogenic role of the lncRNA U62317.4. Our findings of the prognostic value of PCD-related lncRNAs revealed their important roles in immune response disorders, thus providing valuable insights into the clinical management and molecular mechanisms of CC.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study

BackgroundIt is estimated that around 15–30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy.It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs.MethodsIn this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3–4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8–10 Dutch hospitals. The first patient was included in February 2020.DiscussionPatient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated.Trial registrationThis study has been registered in the Netherlands Trial Register (NL8177) at 11–26-2019, https://www.trialregister.nl/trial/8177. The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Immunoscore®: A Diagnostic Assay for Clinical Management of Colon Cancer.

Immunoscore® is an in vitro diagnostic assay that is designed to predict the risk of relapse in patients with early-stage colon cancer, thus helping to guide treatment strategies. Immunoscore has CE-IVD status in the EU, is CLIA certified in the USA, and is commercially available in many other countries worldwide. It is designed to be used in conjunction with TNM staging. Immunoscore uses digital images of tumour samples and advanced software to quantify the densities of CD3+ and CD8+ lymphocytes in defined regions of the tumour (i.e. core tumour and the invasive margin). A risk score is calculated, with a lower Immunoscore (i.e. lower densities) corresponding to a higher risk of recurrence. In an international, retrospective, validation study led by the Society for Immunotherapy of Cancer (SITC), Immunoscore was found to be robust, reproducible, quantitative and standardized, providing a reliable estimate of the risk of recurrence. The clinical utility of Immunoscore has been validated in the SITC-led study and in several supportive studies in which Immunoscore predicted survival, optimal treatment duration and relapse in patients with colon cancer.

Prognostic and predictive value of radiomics signatures in stage I-III colon cancer.

Accurate identification of patients with poor prognosis after radical surgery is essential for clinical management of colon cancer. Thus, we aimed to develop death and relapse specific radiomics signatures to individually estimate overall survival (OS) and relapse free survival (RFS) of colon cancer patients. In this study, 701 stage I‐III colon cancer patients were identified from Fudan University Shanghai Cancer Center. A total of 647 three‐dimensional features were extracted from computed tomography images. LASSO Cox was used to identify the significantly death‐ and relapse‐associated features and to build death and relapse specific radiomics signatures, respectively. A total of 13 death‐specific and 26 relapse‐specific features were identified from 647 screened radiomics features. The developed signatures can divide patients into two groups with significantly different death (Hazard Ratio (HR): 3.053; 95% CI, 1.78‐5.23; P < .001) or relapse risk (HR: 2.794; 95% CI, 1.87‐4.16; P < .001). Time‐dependent Relative operating characteristic curve showed that the signatures performed better than any other clinicopathological factors in predicting OS (AUC: 0.768; 95% CI, 0.745‐0.791) and RFS (AUC: 0.744; 95% CI, 0.687‐0.801). Further, survival decision curve analyses confirmed the good clinical utility of the two radiomics signatures. In conclusion, we successfully developed death‐ and relapse‐specific radiomics signatures that can accurately predict OS and RFS, which may facilitate personalized treatment.

Assessment of Fascin by immunohistochemistry in colorectal carcinoma

Background: The increased incidence of colon cancer may be attributed to an increase in the awareness of the disease, accessible screening modalities through widespread availability of preventive health check-ups & affordable newer imaging techniques. One of the essential components of clinical management of colon cancer is histopathological diagnosis and the role of Fascin-1 expression in colon cancers remains unexplored. This study was carried out to evaluate the fascin-1 expression in colon cancer specimens. Methods: This retrospective study was carried out on 60 paraffin blocks of colorectal carcinoma specimens received for a period of four years. IHC for Fascin was done on the sections along with controls. Clinical data regarding the participant’s demographics and medical history were captured from the hospital medical records. Gross findings were recorded from the blocks. Blocks with section containing normal epithelium and tumour were chosen for immunohistochemistry. Results: There was a significant association between pT1/pT2 staging and grade 0 fascin expression (80%) compared to those with pT3/pT4 staging (50%) (p<0.05). Similarly, grade 1 had strong positive correlation with fascin expression (70%) compared to other grades of the tumor (p<0.05). Conclusion: Presence of fascin expression significantly indicates the metastatic potential of colon carcinomas. Further research is required to delineate the mechanism of fascin expression at the cellular level in determining the prognosis of colon cancers.

P-TNM staging system for colon cancer: combination of P-stage and AJCC TNM staging system for improving prognostic prediction and clinical management.

AimThis study focused on improving the American Joint Committee on Cancer TNM staging system and demonstrated an improvement in prognostic accuracy and clinical management of colon cancer using the P–TNM staging system.Patients and methodsEligible patients (N=56,800) were identified from the Surveillance, Epidemiology, and End Results database between January 1, 2010, and December 31, 2014. The P-stage (P0 or P1) was assigned to each patient based on age at diagnosis, tumor grade, and tumor size. The outcome of interest was cancer-specific survival (CSS). The Cox proportional hazards regression analyses were used to identify independent prognostic factors and analyze the CSS probabilities of patients with colon cancer having different P–TNM stages, respectively.ResultsA total of 29,627 patients were assigned to P0-stage and 27,173 patients were assigned to P1-stage. The P1-stage was associated with a 98.1% increased risk of cancer-specific mortality (hazard ratio =1.981, 95% confidence interval =1.891–2.076, P<0.001), which was higher in patients with nonmetastatic colon cancer. The P1-stage patients had improvement in CSS compared with those in P0-stage in respective stages (P<0.001). Moreover, CSS decreased in stage I–P1 compared with stage IIA–P0 or IIIA–P0 (P<0.001), stage IIIA–P1 compared with stage IIA–P0 (P<0.001), stage IIB–P1 compared with stage IIIB–P0 or IIC–P0 (P<0.001), stage IIIB–P1 compared with stage IIC–P0 (P<0.001), and stage IIC–P1 compared with stage IIIC–P0 (P<0.001).ConclusionP-stage was an independent prognostic factor for colon cancer. This study strongly supported the incorporation of P-stage into the American Joint Committee on Cancer TNM staging system for a better approach to prognostication and, thus, more individualized risk-adaptive therapies in colon cancer.

MiR-195 suppresses colon cancer proliferation and metastasis by targeting WNT3A.

MicroRNAs (miRNAs) are a novel class of diagnostic and therapeutic target in cancer. Here, we aimed to explore the effects and mechanism of miR-195 regulation in colon cancer. The expressions of several putative miRNAs in colon tumors, compared to those in normal tissues, were investigated by bioinformatical analysis of a Gene Expression Omnibus database. Quantitative real-time PCR analysis (qRT-PCR) was used to validate the identified changes in normal tissues, primary tumors, and metastatic tumors. MTT, soft agar colony formation, and transwell assays were used to evaluate the effects of miR-195 overexpression or inhibition on cell viability, proliferation, migration, and invasion. Targets of miR-195 were identified by TargetScan, and subsequently verified by qRT-PCR and Western blot. The role of miR-195 in the β-catenin pathway was also studied using RT-PCR and Western blot. MiR-195 expression was downregulated in colon carcinoma tissues and negatively correlated with the metastatic potential. While transfecting miR-195 mimics decreased the proliferation, migration, and invasion of colon cancer cells, miR-195 inhibition exerted opposing effects. WNT3A was identified as a direct target of miR-195. β-catenin was also downregulated by miR-195 in colon cancers. MiR-195 downregulation is associated with the enhanced proliferation, migration, and invasion of colon cancer. MiR-195 directly downregulates WNT3A. Our results indicate that miR-195 is a potential diagnostic marker and therapeutic target for improving the clinical management of colon cancer.

Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes.

Although clinical management of colon cancer generally has not accounted for the primary tumor site, left-sided and right-sided colon cancers harbor different clinical and biologic characteristics. Right-sided colon cancers are more likely to have genome-wide hypermethylation via the CpG island methylator phenotype (CIMP), hypermutated state via microsatellite instability, and BRAF mutation. There are also differential exposures to potential carcinogenic toxins and microbiota in the right and left colon. Gene expression analyses further shed light on distinct biologic subtypes of colorectal cancers (CRCs), with 4 consensus molecular subtypes (CMSs) identified. Importantly, these subtypes are differentially distributed between right- and left-sided CRCs, with greater proportions of the "microsatellite unstable/immune" CMS1 and the "metabolic" CMS3 subtypes found in right-sided colon cancers. This review summarizes important biologic distinctions between right- and left-sided CRCs that likely impact prognosis and may predict for differential responses to biologic therapy. Given the inferior prognosis of stage III-IV right-sided CRCs and emerging data suggesting that anti-epidermal growth factor receptor antibody therapy is associated with worse survival in right-sided stage IV CRCs compared with left-sided cancers, these biologic differences between right- and left-sided CRCs provide critical context and may provide opportunities to personalize therapy.

A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI.

Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5‐fluorouracil (5‐FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5‐FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5‐FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5‐FU response signature. We refined this signature using a clinically relevant DNA microarray‐based dataset of 359 formalin‐fixed and paraffin‐embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray‐based dataset of 316 stage III FFPE samples from the PETACC‐3 (Pan‐European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5‐FU resistant patients using our signature. We confirmed using the PETACC‐3 dataset that the overall survival of subjects responding well to 5‐FU did not improve with the addition of irinotecan (FOLFIRI; two‐sided log‐rank test p = 0.795). Conversely, patients who responded poorly to 5‐FU based on our 12‐gene signature were associated with better survival on FOLFIRI therapy (one‐sided log‐rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5‐FU treatment alone.

Changes in pathologic characteristics and clinical management of colon cancer with increasing patient age

Akmal, Yasir M. MD; Yamamoto, Maki MD; Mailey, Brian MD; Artinyan, Avo MD; Hurria, Arti MD; Bhatia, Smita MD, MPH; Pigazzi, Alessio MD, PhD, FACS; Garcia-Aguilar, Julio MD, Phd, FACS; Kim, Joseph MD, FACS Author Information

Efficacy of a nitric oxide–releasing nonsteroidal anti-inflammatory drug and cytotoxic drugs in human colon cancer cell linesin vitroand xenografts

We previously showed that NCX 4040 inhibits in vitro and in vivo tumor growth and induces apoptosis in human colon cancer cell lines. On the basis of these results, NCX 4040 antitumor activity in combination with 5-fluorouracil (5-FU) or oxaliplatin was evaluated in vitro and in vivo in human colon cancer models. The cytotoxicity of different NCX 4040 and 5-FU or oxaliplatin combination schemes was evaluated on a panel of colon cancer lines (LoVo, LoVo Dx, WiDr, and LRWZ) by the sulforhodamine B assay, and apoptosis was assessed by flow cytometry. NCX 4040 and 5-FU combination was always additive in vitro regardless of the scheme used. Sequential NCX 4040-->oxaliplatin treatment produced a strong synergism in three cell lines, with a ratio index ranging from 3.7 to 4. The synergistic effect was accompanied by apoptosis induction (up to 40%). In the in vivo experiments, xenografted mice were treated with the sequential combination of NCX 4040 and oxaliplatin, and apoptosis was evaluated immunohistochemically in excised tumors. Furthermore, in WiDr xenografts, this sequence caused a significantly higher reduction ( approximately 60%) in tumor growth compared with single-drug treatments and produced extensive apoptotic cell death (15.3%), significantly higher (P < 0.01) than that observed in untreated tumors (2.7%) or in tumors treated with NCX 4040 (5.1%) or oxaliplatin (5.7%) alone. These data show that NCX 4040 sensitizes colon cancer cell lines to the effect of antitumor drugs and suggests that their combination could be useful for the clinical management of colon cancer.

Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.

The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.

Effects of 1,25-dihydroxyvitamin D 3 and its analogs on butyrate-induced differentiation of HT-29 human colonic carcinoma cells and on the reversal of the differentiated phenotype

1,25-Dihydroxyvitamin D 3 (1,25-(OH) 2D 3) greatly enhances sodium butyrate (NaB)-induced enterocyte differentiation of HT-29 human colonic carcinoma cells while 1,25-(OH) 2D 3 alone induces growth restriction without associated differentiation. In the present study, the efficacies of various analogs of 1,25-(OH) 2D 3 to enhance NaB-induced HT-29 differentiation and to prolong the reversal of the differentiated phenotype under NaB-free growth conditions were subsequently examined. Extent of HT-29 differentiation was assessed by measurement of alkaline phosphatase (AP) activity, appearance of mucin-producing cells, changes in morphological characteristics, and expression of differentiation-associated cytokeratin proteins. Among active analogs of 1,25-(OH) 2D 3, 26,26,26,27,27,27-hexafluoro-1,25-(OH) 2D 3 (F 6-1,25-(OH) 2D 3), 24,24-difluoro-24-homo-1,5-(OH) 2D 3, and 26,27-dimethyl-1,25-(OH) 2D 3 were 100-, 10-, and 5-fold, respectively, more effective than 1,25-(OH) 2D 3 in enhancing NaB-induced mucin production. Combined use of NaB and F 6-1,25-(OH) 2D 3 (10 −9 m) also induced HT-29 cells to form highly differentiated goblet-like enterocytes, and increased both cellular AP enzymatic activity and tissuetype cytokeratin content. This differentiated state was qualitatively more advanced than that achieved by a combination of NaB and 10 −7 m 1,25-(OH) 2D 3. NaB-mediated HT-29 differentiation (in short-term inductions) was found to be reversible following a return to NaB-free medium. HT-29 cells differentiated by combined use of NaB and 1,25-(OH) 2D 3 or its analogs exhibited a significant prolonged reversal time relative to cells differentiated with NaB alone. The most prominent effect was achieved using cells differentiated with NaB and 10 −9 mF 6-1,25-(OH) 2D 3 which exhibited a 7-fold prolonged reversal time over colonocytes differentiated by NaB alone. Our data suggest that a combined use of NaB and 1,25-(OH) 2D 3 or its derivatives may provide a convenient in vitro model system to probe molecular events associated with steroid-target tissue interactions in a differentiating cell system as commonly occurs in vivo. Such an analysis might lend itself to design of a rational combination differentiation-based therapy for the clinical management of colon cancer.