Clinical significance of KRAS gene status in tumor

All patients with metastatic colorectal cancer should be detected KRAS gene statusOnly patients with wild-type KRAS is recommended for EGFR

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All patients with metastatic colorectal cancer should be detected KRAS gene status

Only patients with wild-type KRAS is recommended for EGFR inhibitors.

2008 is destined to be a brilliant year for KRAS. In June, CRYSTAL and OPUS in the American Society of Clinical Oncology (ASCO) annual meeting in the limelight, the status of KRAS gene and epidermal growth factor receptor (EGFR) inhibitor efficacy gradually clear; followed by various well-known journals continue to publish new evidence; in October, the latest version is written to the detection of KRAS gene (2008 third edition) "National Comprehensive Cancer Network (NCCN) in colorectal cancer clinical practice guidelines".

The new guidelines passed to the majority of physicians and patients that two important messages, one is that all patients with metastatic colorectal cancer should be detected KRAS gene, two is the only wild type KRAS patients suggested that EGFR inhibitors such as cetuximab and panitumumab (including receiving monotherapy or with chemotherapy and treatment).

So, how big is the impact of KRAS on clinical practice? Marshall, Marshall, in the United States: "in the treatment of colorectal cancer," KRAS changed everything (KRAS Changes Everything)!"

From now on"

KRAS gene is a wild type or mutant, so that the traditional sense of a disease is divided into two separate diseases. About 40% of patients with KRAS mutations in colorectal cancer, these patients can not benefit from anti EGFR therapy, but increase the risk of adverse reactions and treatment costs. The remaining 60% or so of KRAS wild type patients are likely to benefit from this type of drug therapy.

In fact, in the field of tumor therapy by molecular markers had physical phenomenon state divided subsets of patients "have, for example, in the treatment of breast cancer, HER2 receptor that also divided the patients into the can and cannot be from HER2 receptor antagonist (trastuzumab) treatment benefit two subgroups.

Primary or metastatic focus

According to the new guidelines, the KRAS gene can be detected in both primary and metastatic samples.

NCCN experts believe that KRAS mutation is an early event in the process of colorectal cancer, and there is a strong correlation between the primary and metastatic gene status. In view of this, the detection of KRAS gene can be carried out in the archived samples of the primary tumor, and can also be carried out on the archived samples of the metastatic foci. Moreover, as long as you can find one of these samples, there is no need to get fresh biopsy samples for testing.

EGFR gene detection is not worth

Detection of EGFR gene was not found to be predictive of the efficacy of EGFR inhibitors compared with KRAS gene detection. Therefore, it is not recommended to carry out routine EGFR gene testing, and should not be judged by the results of EGFR gene test to give EGFR inhibitor treatment.

Figure 1 EGFR signal transduction pathway

EGFR is activated by ligands such as TGF, EGF and so on, which can activate intracellular signal transduction, maintain cell survival, promote cell proliferation and metastasis, and promote angiogenesis in the presence of vascular endothelial growth factor (VEGF)

Figure 2 the mechanism of anti EGFR monoclonal antibody

Anti EGFR monoclonal antibodies inhibit the formation of EGFR two and inhibit the intracellular signal transduction, which can inhibit the survival, proliferation, metastasis and angiogenesis of tumor cells

Figure 3 KRAS gene mutation induced anti EGFR monoclonal antibody failure

Mutations in KRAS can bypass the activation of intracellular signal transduction, leading to the loss of antitumor activity of anti EGFR monoclonal antibodies

- Links - the story of KRAS (1916-2008)

1916196419751982

It was found that the first oncogenic virus was found in the RAS rat sarcoma virus to reveal the role of oncogenes in tumorigenesis. The mutant KRAS gene was detected in human tumors

1987 1993-4

Detection of mutant KRAS gene in biopsy samples of colorectal cancer confirmed that KRAS protein could activate Raf and PI3K protein

1999 to reveal the important role of KRAS gene in tumor progression: 2006 for the first time confirmed that the mutation of KRAS gene can influence the effect of anti EGFR therapy

2007 the first phase III clinical trial confirmed the efficacy of anti EGFR monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer in KRAS

2008KRAS gene detection was written into the NCCN Guide

1967 KRAS gene,, was isolated from rat sarcoma virus. The KRAS gene was found to be involved in EGFR signaling

1997 to reveal the important role of the KRAS gene in tumorigenesis, the first phase III clinical study confirmed that only KRAS of patients with wild-type colorectal cancer can benefit from first-line therapy with anti EGFR monoclonal antibodies and chemotherapy ()

- Links - ASCO hot research

CRYSTAL study

Analysis of 540 cases of metastatic colorectal cancer patients, for patients with wild-type KRAS, efficacy of cetuximab combined with FOLFIRI was significantly higher than that of FOLFIRI alone, efficiency of 59% to 43% (P=0.0025), median progression free survival (PFS) for a period of 9.9 to 8.7 months (P=0.0167), and in the mutant in the crowd, there were no significant differences between the two groups of PFS and the total effective rate, even the cetuximab group decreased, the total effective rate was 36% in 40% (P=0.46), the median PFS was 7.6 to 8.1 months (P=0.75).

OPUS study

Analysis of 233 cases of metastatic colorectal cancer patients showed that the total efficiency of the wild type KRAS patients treated with cetuximab plus FOLFOX treatment (61% vs. 37%, P=0.011) and PFS phase (7.7 to 7.2 months, P=0.02) are significantly increased, but the mutant with efficiency is on the contrary. The total cetuximab group (32.7% vs 48.9%, P=0.106) and PFS phase (5.5 to 8.6 months, P=0.0192) were decreased.

EVEREST study

Treated with cetuximab plus irinotecan treatment and rash 0~1 level in patients with metastatic colorectal cancer were randomly divided into cetuximab standard dose and dose escalation group. The results showed that, in either group, the benefit of KRAS wild-type patients was significantly better than that of the patients with the mutation, and the relationship between KRAS status and efficacy was stronger than that of the rash.

 

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