scholarly journals Biomarkers in Colorectal Cancer: Current Research and Future Prospects

2020 ◽  
Vol 21 (15) ◽  
pp. 5311 ◽  
Author(s):  
Olorunseun O. Ogunwobi ◽  
Fahad Mahmood ◽  
Akinfemi Akingboye
Keyword(s):  
Colorectal Cancer ◽  
Clinical Decision Making ◽  
Positive Impact ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Predictive Biomarkers ◽  
Clinical Decision ◽  
Dna And Rna ◽  
Increased Risk ◽  
Individualization Of Therapy

Colorectal cancer (CRC) is a leading cause of death worldwide, despite progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. Novel therapeutic agents have improved survival in both the adjuvant and advanced disease settings, albeit with an increased risk of toxicity and cost. However, metastatic disease continues to have a poor long-term prognosis and significant challenges remain due to late stage diagnosis and treatment failure. Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response. The past three decades have seen advances in genomics and molecular pathology of cancer biomarkers, allowing for greater individualization of therapy with a positive impact on survival outcomes. Clinically useful predictive biomarkers aid clinical decision making, such as the presence of KRAS gene mutations predicting benefit from epidermal growth factor receptor (EGFR) inhibiting antibodies. However, few biomarkers have been translated into clinical practice highlighting the need for further investigation. We review a range of protein, DNA and RNA-based biomarkers under investigation for diagnostic, predictive, and prognostic properties for CRC. In particular, long non-coding RNAs (lncRNA), have been investigated as biomarkers in a range of cancers including colorectal cancer. Specifically, we evaluate the potential role of lncRNA plasmacytoma variant translocation 1 (PVT1), an oncogene, as a diagnostic, prognostic, and therapeutic biomarker in colorectal cancer.

scholarly journals Choice of faecal immunochemical test matters: comparison of OC-Sensor and HM-JACKarc, in the assessment of patients at high risk of colorectal cancer

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Caroline J. Chapman ◽  
Ayan Banerjea ◽  
David J Humes ◽  
Jaren Allen ◽  
Simon Oliver ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Decision Making ◽  
Full Range ◽  
Clinical Decision ◽  
Detection Rates ◽  
Faecal Immunochemical Test ◽  
Specimen Collection ◽  
Increased Risk ◽  
Immunochemical Test

AbstractObjectivesCurrently, NICE recommends the use of faecal immunochemical test (FIT) at faecal haemoglobin concentrations (f-Hb) of 10 μg Hb/g faeces to stratify for colorectal cancer (CRC) risk in symptomatic populations. This f-Hb cut-off is advised across all analysers, despite the fact that a direct comparison of analyser performance, in a clinical setting, has not been performed.MethodsTwo specimen collection devices (OC-Sensor, OC-S; HM-JACKarc, HM-J) were sent to 914 consecutive individuals referred for follow up due to their increased risk of CRC. Agreement of f-Hb around cut-offs of 4, 10 and 150 µg Hb/g faeces and CRC detection rates were assessed. Two OC-S devices were sent to a further 114 individuals, for within test comparisons.ResultsA total of 732 (80.1%) individuals correctly completed and returned two different FIT devices, with 38 (5.2%) CRCs detected. Median f-Hb for individuals diagnosed with and without CRC were 258.5 and 1.8 µg Hb/g faeces for OC-S and 318.1 and 1.0 µg Hb/g faeces for HM-J respectively. Correlation of f-Hb results between OC-S/HM-J over the full range was rho=0.74, p<0.001. Using a f-Hb of 4 µg Hb/g faeces for both tests found an agreement of 88.1%, at 10 µg Hb/g faeces 91.7% and at 150 µg Hb/g faeces 96.3%. A total of 114 individuals completed and returned two OC-S devices; correlation across the full range was rho=0.98, p<0.001.ConclusionsWe found large variations in f-Hb when different FIT devices were used, but a smaller variation when the same FIT device was used. Our data suggest that analyser-specific f-Hb cut-offs are applied with regard to clinical decision making, especially at lower f-Hb.

scholarly journals Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3481
Author(s):  
Rebecca A. Shuford ◽  
Ashley L. Cairns ◽  
Omeed Moaven
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Clinical Decision Making ◽  
Growth Factor Receptor ◽  
Clinical Decision ◽  
Current Evidence ◽  
Therapeutic Modalities ◽  
Clinically Significant

The genetic and molecular underpinnings of metastatic colorectal cancer have been studied for decades, and the applicability of these findings in clinical decision making continues to evolve. Advancements in translating molecular studies have provided a basis for tailoring chemotherapeutic regimens in metastatic colorectal cancer (mCRC) treatment, which have informed multiple practice guidelines. Various genetic and molecular pathways have been identified as clinically significant in the pathogenesis of metastatic colorectal cancer. These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications. RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively. Furthermore, there are several emerging pathways and therapeutic modalities that have not entered mainstream use in mCRC treatment and are ripe for further investigation. The well-established data in the arena of targeted therapies provide evidence-based support for the use or avoidance of various therapeutic regimens in mCRC treatment, while the emerging pathways and platforms offer a glimpse into the future of transforming a precision approach into a personalized treatment.

Novel mutational and pathway signatures in relapsed/refractory colorectal cancer patients.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 591-591
Author(s):  
Benny Johnson ◽  
Laurence Cooke ◽  
Daruka Mahadevan
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Clinical Decision Making ◽  
Gene Mutations ◽  
Clinical Decision ◽  
Braf V600e ◽  
Driver Mutations ◽  
Common Mutation ◽  
Mutational Signatures ◽  
Pathway Networks

591 Background: In the management of metastatic colorectal cancer (mCRC), all RAS (KRAS, NRAS) and BRAF V600E mutation status guides therapeutic options and identify a unique cohort of patients (pts) with a more aggressive clinical course. We hypothesized that relapsed/refractory CRC pts develop unique mutational signatures that guide standard and targeted therapy but also predict for therapeutic response, identify novel driver mutations and highlight key signaling pathways for clinical decision making. Methods: Relapsed/refractory mCRC pts (N=31) were molecularly profiled by NGS Caris Molecular Intelligence (IHC, FISH/CISH, NGS) and/or Foundation One (NGS, copy number). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation, domain, topology, and mutation count. Web-based bioinformatics tools (Enrichr/IntAct) were utilized to analyze mutational profiles, identifying pathway-networks. Results: Pts included progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab. Most common histology was adenocarcinoma followed by squamous cell carcinoma (colon N=28; rectal N=3). TP53 was the most common mutation followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average >5 unique gene mutations. High mutational burden was not predictive for PD-1 (5 pts) or PD-L1 (1 pt) positivity. The most common activated signaling pathways were: ERRB2/HER2, FGFR, p38 activation through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant oncogene mutations do not always equate with oncogenic dependence, therefore understanding the pathologic interactome in each patient is important to both identification of clinically relevant targets and choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to 1). Evaluate functional investigation in the laboratory, 2). Predict response to drug therapy, and 3). Guide rational drug combinations in relapsed/refractory mCRC pts entering targeted and immune checkpoint trials.

scholarly journals Recent developments in the treatment of metastatic colorectal cancer

2017 ◽  
Vol 9 (8) ◽  
pp. 551-564 ◽  
Author(s):  
Jonathan M. Loree ◽  
Scott Kopetz
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Growth Factor Receptor ◽  
Low Frequency ◽  
Clinical Decision ◽  
Tumor Location ◽  
Targeted Agents ◽  
Braf Mutations ◽  
Exon 2

Over the past decade there have been significant advances in the molecular characterization of colorectal cancer (CRC) that are driving treatment decisions. Expanded RAS testing beyond KRAS exon 2 was established as crucial for identifying patients who will respond to anti-epidermal growth factor receptor (EGFR) therapies and low-frequency mutations in RAS/tumor heterogeneity are gaining recognition as potential mechanisms of resistance. Despite this progress, the fact that we do not understand why left-sided but not right-sided tumors have improved outcomes following anti-EGFR therapy highlights our superficial understanding of this disease. Even with few new targeted agents receiving approval in CRC, the incorporation of next-generation sequencing into clinical decision making represents an important step forward. Biomarkers such as BRAF mutations, microsatellite instability, and HER2 amplification represent promising molecular aberrations with therapies in various stages of development, and highlight the importance of companion diagnostics in supporting targeted agents. In this review, we will discuss the importance of incorporating biomarkers into clinical decision making and regimen selection in CRC. We will particularly focus on the recent evidence suggesting an important role for tumor location in selecting first-line therapy, the importance of recent advances in biomarker development and molecular subtyping, as well as recently approved agents (regorafenib and TAS-102) and promising targeted agents that have the potential to change the standard of care.

“Right Drug for the Right Patient”: Hurdles and the Path Forward in Colorectal Cancer

2013 ◽  
pp. e115-e120
Author(s):  
Scott Kopetz
Keyword(s):  
Colorectal Cancer ◽  
Drug Development ◽  
Current Model ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Predictive Biomarkers ◽  
Novel Therapy ◽  
Kras Mutations ◽  
Low Frequencies ◽  
The Right

Predictive biomarkers have been heralded as the way to develop the “right drug for the right patient.” However, despite many studies incorporating novel biomarkers with targeted therapies, there has been little progress over the 5 years since the identification of KRAS mutations' ability to predict resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies. Recently approved therapeutics (regorafenib, aflibercept) or label extensions for existing therapies (bevacizumab) lack companion biomarkers. The current model of biomarker development, “target-based biomarker” design, attempts to identify individual biomarkers that are closely tied to the activity of a particular treatment. There are several limitations to prospective utilization of predictive biomarkers in novel therapy development, including technical validation of the assay and the logistics of timely biomarker determination with available material that limit the options. Tumor heterogeneity, both between different regions in the tumor and as a result of changes induced over time and under the selective pressure of chemotherapy, can reduce the precision of biomarker determination. Biomarkers present in low frequencies are increasingly common in drug development and will require efficient screening infrastructure to be feasible. Although development efforts will continue in the current target-based biomarker model for the near future, it is increasingly apparent that a new model is needed. A “taxonomy-based biomarker” model has been proposed, which is less tied to novel drug development and instead attempts to classify individual tumors based on their intrinsic biology. This requires integrating multiple characteristics of the tumors, including gene mutations, amplifications, methylation, as well as RNA and protein expression. Identification of the taxonomy of colorectal cancer will then allow more efficient development of targeted agents that can leverage the distinct molecular vulnerabilities of the resulting subsets. A transition to a taxonomy-based biomarker model would provide the classification structure and biologic insights needed to advance the ultimate goal of the right drug for the right patient.

scholarly journals NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020

2020 ◽  
Vol 18 (10) ◽  
pp. 1312-1320
Author(s):  
Dawn Provenzale ◽  
Reid M. Ness ◽  
Xavier Llor ◽  
Jennifer M. Weiss ◽  
Benjamin Abbadessa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Average Risk ◽  
Genetic Syndromes ◽  
Nccn Guidelines ◽  
Crc Screening ◽  
Increased Risk ◽  
Colorectal Screening

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

scholarly journals Hemoglobin A1c and preoperative glycemia as a decision tool to help minimise sternal wound complications: a retrospective study in OPCAB patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jef Van den Eynde ◽  
Abel Van Vlasselaer ◽  
Annoushka Laenen ◽  
Delphine Szecel ◽  
Bart Meuris ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Hemoglobin A1c ◽  
Clinical Decision Making ◽  
Artery Bypass ◽  
Clinical Decision ◽  
Wound Complications ◽  
Minimal Risk ◽  
Off Pump ◽  
Increased Risk ◽  
Diabetes Patients

Abstract Background Poor glycemic control has been associated with an increased risk of wound complications after various types of operations. However, it remains unclear how hemoglobin A1c (HbA1c) and preoperative glycemia can be used in clinical decision-making to prevent sternal wound complications (SWC) following off-pump coronary artery bypass grafting (OPCAB). Methods We conducted a retrospective study of 1774 consecutive patients who underwent OPCAB surgery between January 2010 and November 2016. A new four-grade classification for SWC was used. The associations of HbA1c and preoperative glycemia with incidence and grade of SWC were analysed using logistic regression analysis and proportional odds models, respectively. Results During a median follow-up of 326 days (interquartile range (IQR) 21–1261 days), SWC occurred in 133/1316 (10%) of non-diabetes and 82/458 (18%) of diabetes patients (p < 0.001). Higher HbA1c was significantly associated with a higher incidence of SWC (odds ratio, OR 1.24 per 1% increase, 95% confidence interval, CI 1.04;1.48, p = 0.016) as well as a higher grade of SWC (OR 1.25, 95% CI 1.06;1.48, p = 0.010). There was no association between glycemia and incidence (p = 0.539) nor grade (p = 0.607) of SWC. Significant modifiers of these effects were found: HbA1c was associated with SWC in diabetes patients younger than 70 years (OR 1.41, 95% CI 1.17;1.71, p < 0.001), whereas it was not in those older than 70 years. Glycemia was associated with SWC in patients who underwent non-urgent surgery (OR 2.48, 95% CI 1.26;4.88, p = 0.009), in diabetes patients who received skeletonised grafts (OR 4.83, 95% CI 1.28;18.17, p = 0.020), and in diabetes patients with a BMI < 30 (OR 2.19, 95% CI 1.01;4.76, p = 0.047), whereas it was not in the counterparts of these groups. Conclusions Under certain conditions, HbA1c and glycemia are associated SWC following OPCAB. These findings are helpful in planning the procedure with minimal risk of SWC.

Highly specific detection of KRAS single nucleotide polymorphism by asymmetric PCR/SERS assay

The Analyst ◽  
2021 ◽  
Author(s):  
Nana Lyu ◽  
Vinoth Kumar Rajendran ◽  
Jun Li ◽  
Alexander Engel ◽  
Mark P. Molloy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Nucleotide Polymorphism ◽  
Asymmetric Pcr ◽  
Specific Detection ◽  
Kras Mutations ◽  
Single Nucleotide ◽  
The Common

The molecular diagnosis of KRAS mutations has become crucial for clinical decision-making in colorectal cancer (CRC) treatments. Currently, the common methods for detecting mutations are based on quantitative PCR, DNA...

scholarly journals The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

2020 ◽  
Vol 21 (19) ◽  
pp. 7040 ◽  
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Gaetano Luglio ◽  
Francesca Paola Tropeano ◽  
Gianluca Pagano ◽  
Maria D’Armiento ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Decision Making ◽  
Locally Advanced ◽  
Therapy Response ◽  
Predictive Biomarkers ◽  
Advanced Rectal Cancer ◽  
Clinical Decision ◽  
Locally Advanced Rectal Cancer ◽  
Specific Expression ◽  
Micro Rnas

The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients’ survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers.

scholarly journals A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3396
Author(s):  
Lorena Incorvaia ◽  
Daniele Fanale ◽  
Giuseppe Badalamenti ◽  
Chiara Brando ◽  
Marco Bono ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Clinical Decision ◽  
Mirna Expression Profile ◽  
Immune Checkpoints ◽  
Cancer Evolution ◽  
Specific Subset ◽  
Number Of Patients

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called “lymphocyte miRNA signature”, specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.

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