Predictive Factors In Colorectal Cancer Research Articles

PAIP 2020: Microsatellite instability prediction in colorectal cancer.

Microsatellite instability (MSI) refers to alterations in the length of simple repetitive genomic sequences. MSI status serves as a prognostic and predictive factor in colorectal cancer. The MSI-high status is a good prognostic factor in stage II/III cancer, and predicts a lack of benefit to adjuvant fluorouracil chemotherapy in stage II cancer but a good response to immunotherapy in stage IV cancer. Therefore, determining MSI status in patients with colorectal cancer is important for identifying the appropriate treatment protocol. In the Pathology Artificial Intelligence Platform (PAIP) 2020 challenge, artificial intelligence researchers were invited to predict MSI status based on colorectal cancer slide images. Participants were required to perform two tasks. The primary task was to classify a given slide image as belonging to either the MSI-high or the microsatellite-stable group. The second task was tumor area segmentation to avoid ties with the main task. A total of 210 of the 495 participants enrolled in the challenge downloaded the images, and 23 teams submitted their final results. Seven teams from the top 10 participants agreed to disclose their algorithms, most of which were convolutional neural network-based deep learning models, such as EfficientNet and UNet. The top-ranked system achieved the highest F1 score (0.9231). This paper summarizes the various methods used in the PAIP 2020 challenge. This paper supports the effectiveness of digital pathology for identifying the relationship between colorectal cancer and the MSI characteristics.

Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer

BackgroundTissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103+ Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm.MethodsImmunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan–Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC.ResultsThe number of CD103+/CD8+ tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683+ Trm cells.ConclusionsThe number of CD103+/CD8+ TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation.

The correlation of immunoscore and frailty in colorectal cancer.

The Immunoscore is a useful prognostic and predictive factor for colorectal cancer. Frailty predicts overall and recurrence-free survival following resection of colorectal cancer, and the immunosuppressive state of frailty might affect tumor progression. This study investigated the relationship between the Immunoscore and frailty in colorectal cancer. This retrospective study included patients who underwent radical surgery for stage II and III colorectal cancer (n = 108). Patients were divided into frail (n = 11) and non-frail (n = 97) groups, and low (IS0-2) (n = 70) and high (IS3-4) Immunoscore groups (n = 38), for comparison. American Society of Anesthesiologists physical status was higher, tumor diameter was larger, number of well-differentiated tumors was higher, albumin was lower, 5-year overall survival (OS) was lower (frail group: 50.0%, non-frail group: 90.5%, p < 0.001) and 5-year disease-free survival (DFS) was lower (frail group: 36.4%, non-frail group: 75.2%, p = 0.024) in the frail than in the non-frail group. Left colon cancer was more, 5-year OS was lower (IS0-2 group: 82.0%, IS3-4 group: 96.7%, p = 0.040) and 5-year DFS was lower (IS0-2 group: 66.3%, IS3-4 group: 83.3%, p = 0.043) in the IS0-2 than in the IS3-4 group. The Immunoscore was lower in the frail than in the non-frail group. Immunoscore and frailty are prognostic and predictive factors in colorectal cancer, and they are correlated with each other. The immunosuppressive state from frailty might affect this correlation.

Microsatellite instability in Costa Rican patients with colorectal adenocarcinoma and its association with overall survival and response to fluoropyrimidine-based chemotherapy

BackgroundMicrosatellite instability (MSI) is a prognostic and predictive factor in colorectal cancer (CRC). Previous trials have acknowledged that MSI prevalence varies according to ethnicity. The aim of this study was to determine the prevalence of MSI among CRC patients from Costa Rica and to analyze its influence on overall survival (OS) and response to fluoropyrimidine-based chemotherapy. MethodsWe conducted a retrospective cohort study with all diagnosed CRC cases from 2010 to 2015 in a referral center in San José, Costa Rica. MSI was determined by immunohistochemical analysis. Clinical and epidemiological variables were retrieved from medical records. An univariate and multivariate COX regression analysis was performed to evaluate the association between MSI and mortality in the overall population and in those patients treated or not with fluoropyrimidine-based chemotherapy. Results553 CRC patients were identified during the study timeframe, and 165 of them were diagnosed with MSI (29.84 %; 95 % Confidence Interval CI: 26.02–33.65%). MSI was associated with M1 disease, and right-sided tumor location. After adjusting for potential confounders, MSI was an independent prognostic factor for OS (Hazard Ratio (HR): 0.56; 95 %CI: 0.43-0.67; Log-rankp = 0.03). MSI status did not modify the response to fluoropyrimidine-based chemotherapy (HR: 0.56; 95 %CI: 0.18–1.80; Log-rank: p = 0.33). ConclusionsMSI was detected in a higher proportion of CRC patients than previously reported for other non-Hispanic populations. MSI was an independent prognostic factor for OS, but did not predict the efficacy of cytotoxic treatment with Fluoropyrimidine-based chemotherapy.

Evaluation the Possibility of Using of miRNA-21 as a Prognostic and Predictive Factor in Colorectal Cancer (South Egypt Experience)

Background: Micro RNA 21 (miRNA-21) is overexpressed in numerous solid types of tumors, indicating that its biology is relevant to numerous types of cancer. However, in Colorectal Cancer (CRC) there is a lot of studies confirmed its use as diagnostic marker, other studies suggested it could be used as a predictive marker for 5 Fu sensitivity so this study was conducted to verified the significance of using miRNA-21 as a prognostic and predictive factor in CRC. Patients and Methods: It is a prospective study that included 45 patients with stage I-IV CRC who attended at South Egypt Cancer Institute from April 2017 to October 2018. miRNA-21 was measured by (q PCR) from peripheral blood. Response to 5-FU containing regimens was assessed using RECIST criteria and its levels of expression were correlated to the clincopathological data, response and survival of the patients. Results: High expression of the miRNA21 was significantly associated with advanced stage of CRC p 0.001, Lymph Node (LN) invasion p 0.001,distant metastasis p 0.01 lymphovascular (LVI) invasion p 0.01 and pre-treatment level of Carcino Embryonic Antigen (CEA) p 0.031. Also we found that high expression level significantly badly affected the response to 5-Fu containing regimen p 0.001, DFS p 0.01. Conclusion: miRNA-21 could be used as non-invasive prognostic and predictive marker in CRC.

Diagnostic value of inflammatory cell infiltrates, tumor stroma percentage and disease-free survival in patients with colorectal cancer.

The anticancer immune defense mechanism involves humoral and cellular responses. The main effector mechanisms of antitumor responses involve the following: the activity of cytotoxic T cells; the activation of macrophages and neutrophils; the activity of cytokines secreted by T cells; and natural killer cell activity. Selected cell populations are responsible for the stimulation or suppression of the immune system against tumor cells. Therefore, the aim of the present study was to evaluate the location, extent and composition of the cellular inflammatory infiltration of tumors in patients with colorectal cancer (CRC). In addition, the correlation between cellular inflammatory infiltration, and anatomoclinical and histopathological features of patients was evaluated. The study involved 160 patients diagnosed with primary operable CRC. The local inflammatory infiltrate was assessed in the invasive front and center of the tumor using light microscopy with hematoxylin and eosin (H&E) staining, according to the Klintrup-Makinen criteria, tumor stroma percentage, and Glasgow microenvironment score. The inflammatory infiltrate in the invasive front of the tumor was correlated with gender (P=0.018), the invasion of blood vessels (P=0.020) and lymph vessels (P=0.038), the presence of tumor-infiltrating lymphocytes in the invasive front (P=0.033) and center (P<0.001) of the tumor, fibrosis (P<0.001), and the degree of desmoplasmic stroma (P=0.004). In contrast, inflammatory infiltration in the center of the tumor was associated with the tumor node metastasis stage (P=0.012), Dukes' stage (P=0.009), primary tumor stage (P=0.036), lymph node status (P=0.005), number of lymph nodes (P=0.006), invasion of lymph node pouches (P=0.021), size of lymph node metastasis (P=0.025) and the degree of desmoplasmic stroma (P=0.002). The low-group, who demonstrated an absent or weak inflammatory cell infiltrate in the invasive front of the tumor, had a statistically significant shorter disease-free survival (DFS) time (P=0.004). Inflammatory cell infiltrate in the invasive front was identified as an independent predictive factor in CRC (P=0.041). In conclusion, the degree of inflammatory cell infiltration in the invasive front of the primary tumor significantly affects various variables that determine disease progression and DFS rates of patients with CRC. Furthermore, the routine histopathological assessment of this parameter in tissue stained with H&E may have potential prognostic value.

The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab

Background:The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting.Methods:We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months.Results:Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001).Conclusions:In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.

Neutrophil-lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: A systematic review and meta-analysis.

There is a growing body of evidence showing the functional relationship between inflammation index like netrophil.lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts. There is a growing body of evidence showing the functional relationship between inflammation index like netrophil-lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts. We systemically searched PubMed, Embase, and SciVerse Scopus databases, and performed a meta.analysis by Review Manager 5.2 software. (The Cochrane Collaboration, Software Update, Oxford). Two reviewers selected studies, assessed risk of bias, and extracted data independently. Newcastle.Ottawa Scale was applied to assess the quality of included studies. Fifteen studies involving 7741 patients with CRC were analyzed. Patients with an NLR < 5 before treatment were significantly more likely to have 5-year overall survival (odds ratio [OR] = 2.03; 95% confidence interval [CI] = 1.56-2.63) and 5-year disease-free survival (OR = 1.67; 95% CI = 1.19-2.35). Pretreatment CEA level < 5 were significantly associated with complete tumor response and tumor downstaging after neoadjuvant treatment. The result also showed that patients with NLR > 5 were expected to have a larger tumor, poorer tumor differentiation, and higher CEA level. NLR and CEA are valuable tools for the prediction of prognosis in CRC and adjusting the treatment strategy.

Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon.

Colorectal cancer is a heterogeneous disease with a wide range of long-term outcomes and responses to treatment. Recent advances in the genetic and molecular characterization of tumors has yielded a set of prognostic and predictive biomarkers that aid the identification of patients at higher risk for disease recurrence and progression, and in some cases indicate the likelihood of response to a specific treatment. Increasingly, these biomarkers have become integral to the treatment algorithm for managing patients with colorectal cancer. Prognostic and predictive factors in colorectal cancer can broadly be categorized into treatment impact, clinicopathologic factors, and molecular markers. This review will focus primarily on molecular markers, which are foundational to the paradigmatic shift toward personalized cancer therapy.

Functions and Regulation of the PTEN Gene in Colorectal Cancer

Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene located at chromosome 10q23.31, encoding for a 403-amino acid protein that possesses both lipid and protein phosphatase activities. The main function of PTEN is to block the PI3K pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. PTEN inactivation is a frequent event in many cancer types and can occur through various genetic alterations including point mutations, large chromosomal deletions, and epigenetic mechanisms. In colorectal cancer (CRC) PTEN is altered through mixed genetic/epigenetic mechanisms (typically: mutations and promoter hypermethylation or 10q23 LOH and promoter hypermethylation), which lead to the biallelic inactivation of the protein in 20–30% of cases. The role of PTEN as a prognostic and predictive factor in CRC has been addressed by relatively few works. This review is focused on the report and on the discussion of the studies investigating these aspects. Overall, at the moment, there are conflicting results and, therefore it has not been clarified whether PTEN might play a prognostic role in CRC. The same is valid also for the predictive role, leading to the fact that PTEN evaluation cannot be used in routinely diagnosis for the early identification of patients who might be addressed to the treatment with EGFR-targeted therapies, at odds with other genetic alterations belonging to EGFR-downstream pathways. The reason of discordant results may be attributable to several issues: (1) the size of the analyzed cohort, (2) patients inclusion criteria, (3) the methods of assessing PTEN alteration. In particular, there are no standardized methods to evaluate this marker, especially for immunohistochemistry, a technique suffering of intra and inter-observer variability due to the semi-quantitative character of such an analysis. In conclusion, much work, especially in large and homogeneous cohorts of cases from different laboratories, has to be done before the establishment of PTEN as prognostic or predictive marker in CRC.

Oncogenic mutations as predictive factors in colorectal cancer

The anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies cetuximab and panitumumab have been demonstrated to be new therapeutic options for metastatic colorectal cancer (mCRC). Oncogenic activation of intracellular signalling pathways downstream of EGFR has a major role in colorectal carcinogenesis but has also been reported to be an important mechanism of resistance to anti-EGFR antibodies. Among the activating mutations found in colorectal cancers, tumour KRAS mutations, which are found in approximately 40% of the cases, have been widely demonstrated as a major predictive marker of resistance to cetuximab or panitumumab, therefore, opening the way to individualized treatment for patients with mCRC. Other oncogenic mutations, such as BRAF or PIK3CA mutations or loss of PTEN expression, may also be additional interesting predictive markers of response to anti-EGFR monoclonal antibodies but required further evaluation before being incorporated in clinical practice. The identification of these molecular markers involved in the resistance of anti-EGFR antibodies will allow the development of new therapies that should target 'escape mechanisms' used by tumours to circumvent a pathway that has been pharmacologically blocked by anti-EGFR.

Sensitive Detection of KRAS Mutations in Archived Formalin-Fixed Paraffin-Embedded Tissue Using Mutant-Enriched PCR and Reverse-Hybridization

Recently, evidence has emerged indicating that assessment of KRAS mutations before anti-epidermal growth factor receptor therapy improves outcome in patients with metastatic colorectal cancer (CRC). We report here a novel reverse-hybridization (RH) assay to screen for KRAS mutations in formalin-fixed paraffin-embedded colorectal tissue samples. We combined mutant-enriched PCR based on peptide nucleic acid clamping and RH of amplification products to nitrocellulose test strips that contained a parallel array of oligonucleotide probes targeting 10 frequent mutations in codons 12 and 13 of the KRAS gene. DNA mixing experiments, which included eight different tumor cell lines with known KRAS mutations, were performed to examine the sensitivity of mutation detection. All KRAS mutations present in tumor cell lines were unambiguously identified by the RH assay with 1% of each cell line DNA diluted in normal DNA. RH was then used to screen for KRAS mutations in 74 colorectal tumor and 4 normal control samples. Twenty-six (35%) of the 74 tumor samples showed KRAS mutations. No mutation was found in the four samples of normal colorectal tissue. DNA sequencing without previous mutant enrichment, however, failed to detect four (15%) out of 26 KRAS-positive formalin-fixed paraffin-embedded samples (FFPE). This finding suggests that even after microdissection, mutant sequences in a given DNA isolate can be rare and more sensitive methods are needed for mutation analysis.

Prognostic and predictive factors in colorectal cancer

Prognostication of newly diagnosed colorectal cancer (CRC) predominantly relies on stage as defined by the UICC-TNM and American Joint Committee on Cancer classifications. Tumour extent, lymph node status, tumour grade...

Pathology of Colorectal Cancer

Colorectal cancer is an excellent example of a cancer where outcome can be, and has been, improved by the co-operation of clinicians and pathologists. This article summarises the basics of the pathology of colorectal cancer, with an emphasis on practical issues in clinical practice. The histopathology of colorectal cancer, staging and genetics are discussed, as are more recent developments such as the pathology of neoadjuvant therapy and colorectal cancer screening, and molecular prognostic and predictive factors in colorectal cancer.

Predictive markers for colorectal cancer: current status and future prospects.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Although there is clear evidence of the benefit of chemotherapy in adjuvant and metastatic settings, its use continues to be suboptimal because of intrinsic or acquired drug resistance. 5-Fluorouracil continues to be the mainstay of CRC therapy, and combinations with newer chemotherapeutic agents such as irinotecan and oxaliplatin have resulted in improved response rates and survival. The role of other agents including cyclooxygenase-2 inhibitors, epidermal growth factor receptor, and farnsyl transferase inhibitors remains to be elucidated. Despite these improvements, many patients undergo chemotherapy without benefit. Increased understanding of the biology of CRC has led to the identification of prognostic markers that may help identify patients who will benefit from chemotherapy. Furthermore, studies have also begun to identify markers that predict whether a tumor will respond to a particular chemotherapy. The ultimate goal of this research is to prospectively identify patients who should receive chemotherapy and, thus, to tailor treatment to the molecular profile of the tumor and patient. Such an approach has the potential to dramatically improve response rates. This review highlights potentially important prognostic and predictive factors in CRC and discusses the potential for their use in the treatment of this disease.

New prognostic and predictive factors in colorectal cancer

New prognostic and predictive factors in colorectal cancer