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      Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

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          Abstract

          Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research.

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          Most cited references106

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          Systematic review of microsatellite instability and colorectal cancer prognosis.

          A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies. Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques. Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14). CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.
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            Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.

            Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
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              Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                30 January 2020
                February 2020
                : 12
                : 2
                : 319
                Affiliations
                [1 ]Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, L-4367 Esch-sur-Alzette, Luxembourg; eric.koncina@ 123456ext.uni.lu (E.K.); Serge.haan@ 123456uni.lu (S.H.)
                [2 ]Centre Hospitalier Emile Mayrisch, Department of Oncology, L-4240 Esch-sur-Alzette, Luxembourg; stefan.rauh@ 123456chem.lu
                Author notes
                [* ]Correspondence: elisabeth.letellier@ 123456uni.lu ; Tel.: +352-4666446954
                Author information
                https://orcid.org/0000-0001-8242-9393
                Article
                cancers-12-00319
                10.3390/cancers12020319
                7072488
                32019056
                4137be01-217c-4740-8439-f6a14d3dbe4f
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 December 2019
                : 22 January 2020
                Categories
                Review

                colorectal cancer,biomarkers,molecular markers,early stage crc,gene signature,clinical transition,clinical test,challenges

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