Wild-Type <i>KRAS</i> Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Amado, Rafael G.; Wolf, Michael; Peeters, Marc; Cutsem, Éric Van; Siena, Salvatore; Freeman, Daniel J.; Juan, Todd; Sikorski, Robert; Suggs, Sid; Radinsky, Robert; Patterson, Scott D.; Chang, David D.

doi:10.1200/jco.2007.14.7116

Cited by 2,956 publications

(2,120 citation statements)

References 36 publications

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“…Cetuximab, a human-mouse chimeric IgG1 monoclonal antibody, was the first EGFR-targeted agent approved for the treatment of colorectal cancer [12,23]. Panitumumab, a fully human IgG2κ monoclonal antibody, was recently approved in the US and Europe as third-line treatment of metastatic colorectal cancer [12,24]. Both antibodies have been shown to reduce the risk of tumor progression and to improve overall survival (OS), progression-free survival (PFS) and quality of life in patients with refractory colorectal cancer [11,23,[25][26][27][28].…”

Section: Egfr and Colorectal Cancermentioning

confidence: 99%

“…Considering the molecular basis of EGFR-targeting agents, blocking EGFR at the receptor level will not ablate downstream signaling activities in tumors with KRAS mutations and hence constitutively active RAS proteins. Indeed, several studies have reported that KRAS mutations confer resistance to anti-EGFR monoclonal antibodies [24,48,[61][62][63][64][65]. KRAS mutations are associated with poor responses to therapy, reduced PFS and shorter OS in colorectal cancer patients treated with cetuximab alone or in combination with chemotherapy [48,[62][63][64][65].…”

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

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KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

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Section: Egfr and Colorectal Cancermentioning

confidence: 99%

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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“…[1][2][3][4][5][6][7] Indeed, KRAS mutations result in constitutively active KRAS proteins that lead to continuous activation of the RAS signaling pathway independently of the upstream stimulation by EGFR ligands. As only patients with wild-type KRAS tumors benefit from therapies with anti-EGFR antibodies, accurate determination of the KRAS mutation status is crucial for ethical and economic reasons.…”

mentioning

confidence: 99%

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Boissière‐Michot¹,

Lopez-Crapez²,

Frugier³

et al. 2012

Modern Pathology

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KRAS status assessment is mandatory in patients with metastatic colorectal cancer before therapy with antiepidermal growth factor receptor monoclonal antibodies, as KRAS mutations are associated with resistance to this treatment. However, KRAS genotyping may be very challenging in case of poor tumor cellularity, particularly when major tumor regression is achieved in locally advanced rectal adenocarcinomas after radiochemotherapy. We aimed at identifying the most reliable strategy to detect KRAS mutations in such samples. DNA was extracted from 31 surgical specimens with major tumor regression, following manual dissection, and from paired pre-treatment biopsies and analyzed by high-resolution melting. DNA samples displaying altered melting curve shapes were then sequenced. Samples with unmodified melting curves or wild-type sequence were further investigated by using an allele-specific PCR assay (TheraScreen) and laser microdissection (followed by high-resolution melting and sequencing analyses). In the 31 post-radiochemotherapy surgical specimens, seven KRAS mutations were identified by high-resolution melting analysis/sequencing. One additional mutation was detected by the TheraScreen assay and two mutations, including the one identified by the TheraScreen assay, were detected following laser microdissection. Altogether, 9/31 surgical specimens (29%) presented KRAS mutations. In the manually dissected pre-treatment biopsies, 12 mutations (39%) were identified by high-resolution melting analysis and sequencing. No additional mutations were found by using the TheraScreen assay or laser microdissection. These results indicate that, in the case of post-radiochemotherapy surgical specimens of colorectal cancer with low tumor cellularity, pre-treatment biopsies might represent the most cost-effective option for reliable KRAS genotyping. The use of more sensitive assays, such as allelespecific PCR or laser microdissection, can be envisaged but with higher costs and longer delays.

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“…17 Another group reported that panitumumab monotherapy is effective only in patients in whom tumors are wild-type for KRAS, and that consideration of KRAS genotype should be applied in selection of patients with mCRC for this treatment. 5 KRAS mutations are increasingly acknowledged as predictive for resistance to anti-EGFR antibody therapy, and several studies involving first-and subsequent-line treatments suggest that patients with tumors that have KRAS mutations are clinical utility: For KRAS mutation analysis, the EWG found adequate evidence that improved health outcomes are achieved by avoiding ineffective chemotherapy and potential side effects and expediting access to the next most effective treatment. Inadequate evidence was found regarding association of BRAF V600E mutation testing or loss of PTEN expression with improved health outcomes among patients with mCRC undergoing anti-EGFR therapy as compared with patients with tumors bearing wild-type BRAF sequence and PTEN expression levels, respectively.…”

Section: Background and Clinical Context For The Recommendationmentioning

confidence: 99%

Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?

2013

Genetics in Medicine

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EGAPP REcommEndAtion stAtEmEnt summary of recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.The EWG found insufficient evidence to recommend for or against testing for mutations in NRAS, or PIK3CA, and/or loss of expression of PTEN or AKT proteins. The level of certainty for this evidence was low. In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes.Rationale: It has been suggested that patients with mCRC whose tumors harbor certain mutations affecting EGFR pathway signaling are typically unresponsive to therapy with anti-EGFR antibodies (cetuximab and panitumumab). The EWG identified recent evidence reviews that have addressed this topic, and this recommendation statement is based on results of these reviews. In developing these recommendations the EWG considered evidence in the areas described below. Analytic validity:Although no research syntheses that have formally evaluated analytic validity of these tests were found, the EWG was able to draw the following conclusions from assessments included in the evidence reviews under consideration. There is adequate evidence that KRAS mutation analysis reliably and accurately detects common mutations (codons 12 and 13), whereas evidence was inadequate for less frequent KRAS mutations (e.g., codon 61). There is also adequate evidence that testing for BRAF V600E accurately and reliably detects the mutation. For common mutations in NRAS, PIK3CA, and expression of PTEN AKT, there is adequate evidence of accurate and reliable detection. However, much less data exist in support. Furthermore, in the specific context of mCRC, no evidence was found on the analytic validity of immunohistochemistry (IHC) assays for PTEN or AKT expression.clinical val...

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Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Cited by 2,956 publications

References 36 publications

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?

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