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Colorectal cancer Introduction

Colorectal cancer is a cancer that starts in the colon or the rectum. These cancers can also be named colon cancer or rectal cancer, depending on where they start. Colon cancer and rectal cancer are often grouped together because they have many features in common. Colorectal cancer (CRC) is one of the most common cancers either in males or in females. It was predicted that there were approximately 133,000 newly diagnosed CRC cases in the United States along with 49,700 associated deaths in 2015 . Even though an increasing number of potentially curative treatments including operation, chemotherapy agents, and molecular targeting therapies have been developed for CRC, the clinical prognosis still remains unsatisfactory, especially as CRC patients with lymph node metastases. It is well known that the response to treatments are variable among patients, even when they are clinically diagnosed at the same stage. There is a barrier to optimize therapies for each individual due to the presence of clinical diversities. The most plausible explanations for these clinical diversities may root in the tumour heterogeneity both between and inside of tumours. Furthermore,

tumour heterogeneity leads to an important consequence of resistant responses to targeted therapies . Growing evidence indicate heterogeneity is critical since it has robust effects on targeted therapies and especially states of therapeutic resistance that threat the outcome of targeted therapies for CRC .


Targeted Drugs screening

The curative effect of EGFR–specific monoclonal antibodies such as cetuximab and panitumumab, the agent to anti-EGFR to treat patients with mCRC, has been established in massive studies . Those monoclonal antibodies binding to the extra-cellular domain of EGFR block the ligand-induced EGFR tyrosine kinase activation by competing with EGF . Even though anti-EGFR therapies are approved to treat patients with wild-type KRAS mCRC, some clinical observations suggested that a substantial proportion of patients seem to be far less efficacious from the use of anti-EGFR targeted antibodies treatments. Intertumour and intratumour heterogeneity may be one of the most important causes for resistant response to the therapy.
RAS testing was widely accepted in prior to use anti-EGFR treatment for patients with CRC. The National Comprehensive Cancer Network(NCCN) guidelines recommended that KRAS and NRAS mutation status genotyping for tumour tissue at diagnosis of mCRC, the CRC patients with KRAS or NRAS mutations should not be treated with anti-EGFR agents.
Another biomarker, BRAF, has gained more attention in recent years as it was proved that BRAF mutation was more likely to be a poor prognostic biomarker . However, several studies illustrated that it also impacted the efficacy to anti-EGFR agents in KRAS wild-type CRC patients, these evidences further supported that the BRAF mutation should be tested prior to the treatment with anti-EGFR antibodies . Since an increasing number of evidences indicated that CRC patients with BRAF mutation was highly unlikely to response to either cetuximab or panitumumab therapies, the NCCN guideline shows that BRAF mutation test is recommended to patients with mCRC.

Evaluation of the efficacy and side effects of chemotherapy drugs


The development of pharmacogenomics theory and technology has provided us with more information.  Genetics may account for much of the variability in the patients’ responses to drug therapies. Polymorphisms that affect the pharmacokinetics and

pharmacodynamics of specific drugs are common. Testing for certain polymorphisms before prescribing certain drugs could help avoid adverse drug effects and improve efficacy. Pharmacogenomic testing has only recently begun to enter clinical practice, and routine testing is currently limited to a few clinical scenarios. However, additional applications may be just around the corner.



Reference

1.Bureau of Medical Administration, National Health and Family Planning Commission of the PRC, Oncology Branch of Chinese Medical Association .  Standardization of Diagnosis and Treatment for Colorectal Cancer in China (2015 edition). Chin J Dig Surg, 2015,14(10):783-799.
2.Liu Jia-yun, Li Wei-su, Liu Fu-kun, Research Progress of Drug Sensitive Gene Test and Therapy for Colorectal Cancer. Medical Recapitulate, 2014,20(5):810-813.
3.Chinese Cancer Association Professional Committee of colorectal cancer. Consensus of Diagnosis and Treatment for Local Advanced Rectal Cancer in China . China Oncology, 2017,27(1):41-80.
4.NCCN Clinical Practice Guidelines in Oncology. Colon Cancer.2017. V2
5.NCCN Clinical Practice Guidelines in Oncology. Colorectal Cancer Screening.