Colorectal Cancer in Clinical Practice

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Alves, I.

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Colorectal Cancer in Clinical Practice: Prevention, Early Detection and Management, Second Edition

Fuks, D. Goere, M. Karoui, J. Lefevre, P.

Molecular Biomarkers For Colorectal Cancer

Pessaux, G. Schmidt, O. Turrini, E. Vibert, J-C. Previous Article Management of esophageal adenocarcinoma D. Tougeron, J. Richer, C. Journal page Archives Contents list. Sa Cunha. Article Article Outline. Access to the text HTML. Access to the PDF text. Recommend this article. Results were consistent with previous data and confirmed that the benefit from regorafenib on survival and treatment outcomes was irrespective of KRAS and PIK3CA mutational status [ ].

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Additionally, Tabernero et al. Over the last decade, evidence on the role of the epigenome in CRC has been largely explored and it is now recognized that among thousands of epigenetic alterations which can be present in each tumor, a small subgroup may be considered a driver event in CRC development [ ]. Different epigenetic mechanisms, in fact, can play a key role in carcinogenesis, such as DNA methylation, nucleosome positioning, histone modifications and non-coding RNAs expression [ ]. Technological advances have considerably increased our ability to detect a wide number of epigenetic alterations which can eventually have a role as clinical biomarkers for early detection, prognostic stratification and treatment efficacy prediction in CRC patients.

Key Insights: Updates in Colorectal Cancer

Of note, recently the availability of more refined genome-wide mapping technologies, highlighted that the function of DNA methylation can vary depending on its context, underlining a deep complexity that warrants further evaluations [ ]. Long interspersed nucleotide element-1 LINE-1 methylation measured by pyrosequencing has been shown to correlate with global DNA methylation levels [ ].

LINE-1 methylation levels have been reported to impact CRC prognosis with hypomethylation conferring poor prognosis in terms of overall mortality OM and colorectal cancer-specific mortality [ ]. These data suggest that DNA demethylation may play, as well, a crucial role in CRC development, prognosis and response to treatment. Although promising, however, these findings need further validation. This gene encodes a DNA repair protein which removes alkylating groups from O6-guanine and is involved in protecting cells against damages from alkylating agents.

The loss of MGMT gene expression impairs the ability of DNA repair mechanisms to remove alkyl groups, potentially enhancing the cytotoxic effects of alkylating drugs, such as dacarbazine and temozolomide. On these bases, several phase II clinical trials [ ] evaluating the efficacy of alkylating agents in mCRC have been conducted with promising results.

In an era in which immuno-oncology is revolutionizing cancer treatment strategies, novel possible relevant implications of aberrant DNA methylation come from its tight connection with the immune cells system. To date, immune-checkpoint inhibitors ICI have shown striking results in selected cancer types, although only a minority of patients are sensitive to these drugs. De novo DNA methylation has been recently reported to have a central role in maintaining a T cell exhaustion status that contributes to resistance to ICI treatment [ ].

Moreover, treatment of epithelial cancer cell lines including CRC cell lines with demethylating agents, i. As a possible explanation, cryptic transcription of thousands of treatment-induced non-annotated transcriptional start sites TINATs may contribute to cancer immunogenicity through the translation of novel potential antigenic proteins, as recently shown by Brocks and colleagues in their work exploring DNA methyltransferases inhibitors DNMTi treatment consequences on epigenetic and genome-wide transcription [ ].

Overall, this growing evidence supports a strong immunomodulatory effect of DNA demethylating agents in cancer cells, and the rationale to combine these drugs with immunotherapy in cancer patients. Based on these premises, a deeper understanding of the interplay between epigenetic modifications, cancer cells and immune cells could reveal novel potential strategies to enhance ICI treatment efficacy and overcome primary and acquired resistance mechanisms to immunotherapy.

On the other hand, Khambata-Ford et al.

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These data have been confirmed by Jacobs et al. Additionally, the authors reported that treatment with hypomethylating agents i.

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DNA methylation may, then, partially account for primary anti-EGFRs resistance, supporting the rationale to explore the possible synergistic treatment effect of demethylating agents in combination with anti-EGFR drugs. Despite promising evidence, the complexity and heterogeneity of epigenetic alterations in CRC still represent a considerable challenge, which needs to be further addressed in order to identify reliable biomarkers and translate current knowledge into actionable therapeutic strategies.

In recent years, great advances have been made in understanding the complexity of tumor biology and genetic landscape underlying tumor development and response to treatment. In an international consortium developed the Consensus Molecular Subtypes, which classifies CRC into four distinct biological groups, based on gene expression signatures and correlated with distinct genetic, epigenomic, transcriptomic, microenvironmental, prognostic and clinical features [ ].

CMS subgroups show a strong prognostic value independent of tumor stage, with CMS4 associated with worse survival. Moreover, retrospective analyses of clinical trials have suggested a potential predictive value for CMS subtypes, including a better outcome following bevacizumab treatment for CMS1 [ ] , and a lack of benefit from oxaliplatin [ ] and anti-EGFRs irrespective of RAS mutational status [ ] for the mesenchymal-like phenotype.

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Although not yet implemented in clinical practice, this classification system has the potential to better inform clinicians of prognosis and therapeutic response, and to guide novel therapeutic strategies with subtype-based targeted interventions [ 6 ]. Results from these studies show interesting initial findings highlighting subtype-dependent response profiles, with a different sensitivity to chemotherapy either 5-FU or oxaliplatin -induced apoptosis between CMS2 and CMS4, which relates to the in vivo efficacy of chemotherapy in PDX models where a delay in outgrowth of CMS2, but not CMS4 xenografts, was observed.

Indeed, a deeper understanding of the unique drug-sensitivity profile of each CMS subtype and the possibility of performing high-throughput in vitro and in vivo drug screening using PDX technology have the potential to greatly advance precision medicine in CRC. Another field of major interest is the rapid development of liquid biopsies technology and the analysis of ctDNA as a more comprehensive and less invasive approach to pharmacogenomic profiling in CRC patients [ , ].

Allowing large-scale genomic profiling and being able to capture the molecular heterogeneity of different tumor sub-clones coexisting in the same patients, these techniques are expected to play a pivotal role in improving patients stratification and selection for targeted treatments. Moreover, the possibility to perform seriated testing over time represents a valid opportunity to guide treatment strategies through an early detection of the emergence of treatment resistance and a dynamic tumor molecular profiling [ ].

Recently, a large study on genomic profiling through liquid biopsy analyzing next generation sequencing data from cell-free DNA of CRC patients, confirmed the reliability of this methodology in detecting genomic alterations when compared with corresponding tissue-based sequencing. Additionally, results of this study highlighted the possibility of detecting the development of multiple distinct concomitant mechanisms of resistance after targeted treatment with anti-EGFRs in the same subject, proving that ctDNA sequencing can generate a valuable insight into tumor heterogeneity and therapeutic resistance [ ].

Although still needing extensive investigations and prospective validation, liquid biopsy approaches to profile tumor dynamics and response to treatment and to guide rechallenge strategies based on detection of circulating genomic alterations are currently under investigation in several clinical trials.

Finally, noncoding RNAs represent an evolving field in cancer diagnosis and prognosis, and several studies have suggested their possible role as treatment target in different diseases [ , ]. The role of several miRNAs has been implied in CRC evolution and progression, moreover different miRNAs have been identified as predictive of treatment response to standard chemotherapy i. Although promising these findings still need validation; nevertheless, the possible clinical application of miRNAs as biomarkers or as a potential target of treatment in CRC deserves further investigation.

Of note, new strategies are currently under study to develop miRNA based inference methods to extensively infer drug-disease causal relationship miRDDCR to assist in experimental design for drug discovery and disease treatment [ ]. The field of pharmacogenomics is constantly growing, and with the availability of new technologies it has been moving beyond candidate gene approaches and genome-wide association studies towards a comprehensive evaluation of genomic and epigenomic markers to drive treatment choices and optimize targeted therapies.

Several biomarkers have entered clinical practice so far, and many more are currently being tested in clinical trials. Biomarker discovery and validation however still encounter many issues, due often to the small subsets of patients bearing selected alterations, the retrospective nature of most studies and the difficulty in proving the cost-effectiveness of a specific novel marker.

Implementing biomarker-driven clinical trials and prospective pharmacogenomic profiling in clinical research, possibly integrating companion diagnostic tests since the early stages of novel drug development, is thus a priority for future research. Finally, dynamic profiling of tumor genomics under treatment pressure will play a critical role in uncovering acquired mechanism of resistance and directing personalized treatment strategies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Martin D. Ryuma Tokunaga received a grant from the Uehara Memorial Foundation. Cancer statistics, CA Cancer J Clin ; Lancet Oncol ; Genomics and the continuum of cancer care. N Engl J Med ; J Mol Diagn ; Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer ; Liquid biopsies come of age: towards implementation of circulating tumour DNA. ERBB receptors and cancer: the complexity of targeted inhibitors. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol ; National Comprehensive Cancer Network.

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Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Br J Cancer ; Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Clin Cancer Res ; Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.