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Individualization of therapy for colorectal cancer based on clinical and molecular parameters.

ABSTRACT: To improve the treatment of patients with colorectal cancer, efforts must be directed toward the identification of patients likely to respond to a specific therapy, those who will experience severe toxicities, and those who will benefit from chemotherapy in the adjuvant setting. In recent years, studies on a global scale have attempted to define subsets of biochemical markers that may predict response to treatment (evaluated through clinical response, toxicity, and time to disease progression), and prognostic markers, which are equally important in determining how aggressive the disease is (generally evaluated in terms of overall survival), and the likelihood of disease recurrence after surgery. The science of pharmacogenomics is emerging as a useful molecular tool to investigate the disparity in drug efficacy by analyzing variations such as genetic polymorphisms in drug targets, metabolizing enzymes, transporters, and influential receptors. Consequently, the identification of accurate and validated predictive and prognostic markers combined with an increasing arsenal of therapeutic agents will improve the clinician's ability to tailor effective therapy to the molecular profile of the patient while minimizing life-threatening toxicities. This paper describes markers under study in the setting of colorectal cancer, including loss of heterozygosity of 18q and microsatellite instability, polymorphisms in thymidylate synthase, IL-8, CXCR-2, vascular endothelial growth factor, epidermal growth factor and their receptors, and K-ras mutations.

SUBMITTER: Pohl A

PROVIDER: S-EPMC2661548 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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Individualization of therapy for colorectal cancer based on clinical and molecular parameters.

Pohl Alexandra A Lenz Heinz-Josef HJ

Gastrointestinal cancer research : GCR 20080701 4 Suppl

To improve the treatment of patients with colorectal cancer, efforts must be directed toward the identification of patients likely to respond to a specific therapy, those who will experience severe toxicities, and those who will benefit from chemotherapy in the adjuvant setting. In recent years, studies on a global scale have attempted to define subsets of biochemical markers that may predict response to treatment (evaluated through clinical response, toxicity, and time to disease progression), ...[more]

PMID: 19343148

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Project description:Colonoscopy provides incomplete protection from colorectal cancer (CRC), but determinants of post-colonoscopy CRC are not well understood. We compared clinical features and molecular characteristics of CRCs diagnosed at different time intervals after a previous colonoscopy.We performed a population-based, cross-sectional study of incident CRC cases in Denmark (2007-2011), categorized as post-colonoscopy or detected during diagnostic colonoscopy (in patients with no prior colonoscopy). We compared prevalence of proximal location and DNA mismatch repair deficiency (dMMR) in CRC tumors, relative to time since previous colonoscopy, using logistic regression and cubic splines to assess temporal variation.Of 10,365 incident CRCs, 725 occurred after colonoscopy examinations (7.0%). These were more often located in the proximal colon (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.90-2.89) and were more likely to have dMMR (OR, 1.26; 95% CI, 1.00-1.59), but were less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89) compared with CRCs diagnosed in patients with no prior colonoscopy. The highest proportions of proximal and/or dMMR tumors were observed in CRCs diagnosed 3-6 years after colonoscopy, but these features were still more frequent among cancers diagnosed up to 10 years after colonoscopy. The relative excess of dMMR tumors was most pronounced in distal cancers. In an analysis of 85 cases detected after colonoscopy, we found BRAF mutations in 23% of tumors and that 7% of cases had features of Lynch syndrome. Colonoscopy exams were incomplete in a higher proportion of cases diagnosed within <1 year (in 38%) than in those diagnosed within 1-10 years after colonoscopy (16%).In a study of incident CRC cases in Denmark, we observed that tumors found in patients who have undergone colonoscopy are more often proximal and have dMMR compared to CRCs detected in patients without previous colonoscopies. The excess of right-sided tumors and the modest independent effects of dMMR reinforce the importance of proper colonoscopic examination of the proximal large bowel.

Project description:UnlabelledColorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance.SignificanceColorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.

Dataset Information

Individualization of therapy for colorectal cancer based on clinical and molecular parameters.

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Individualization of therapy for colorectal cancer based on clinical and molecular parameters.

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