Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls

Lamy, Aude; Blanchard, F.; Pessot, Florence Le; Sesboüé, Richard; Fiore, Frédéric Di; Bossut, Jessie; Fiant, Elodie; Frébourg, Thierry; Sabourin, Jean‐Christophe

doi:10.1038/modpathol.2011.60

Cited by 90 publications

(89 citation statements)

References 29 publications

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“…Of the 572 patients in the randomized population, 394 were tested for KRAS status with bidirectional sequencing and 453 were tested with the therascreen KRAS kit. Intratumoral heterogeneity with respect to KRAS mutation status has been previously reported 24,25 and may have contributed to the discordance between the analyses. In addition, several other factors may have contributed to the observed differences between the results from the therascreen KRAS kit and bidirectional sequencing, including differences in available tumor tissue samples between the analyses and the relative sensitivities of the assays.…”

Section: Commentmentioning

confidence: 85%

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Harbison

Horak

Ledeine

et al. 2013

Archives of Pathology & Laboratory Medicine

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Context.-The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.Objective.-To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy.Design.-Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes.Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P ¼ .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P ¼ .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing.Conclusions.-These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.

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Section: Commentmentioning

confidence: 85%

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Harbison

Horak

Ledeine

et al. 2013

Archives of Pathology & Laboratory Medicine

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“…Determination of K-Ras and BRAF mutation status has been suggested to be included in the clinical algorithm in CRCs (Lamy et al, 2011;Heideman et al, 2012;Tan and Du, 2012). Mutation status of K-Ras helps predict the response to EGFR targeted therapy, which is becoming an integral part of progress control for advanced disease (Yen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations of K-Ras and BRAF in Thai Colorectal Cancer and their Prognostic Value

Chaiyapan¹,

Duangpakdee²,

Boonpipattanapong³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…[39][40][41] To reduce such artifacts, it is recommended to use a minimum of 1 mg of formalin-fixed paraffin-embedded-recovered DNA and to confirm each identified mutation by an independent analysis. 38,42 In our practice, manual dissection of pre-treatment biopsies allowed the recovery of an amount of DNA that was enough for our study protocol. Unlike Lamy et al, 42 we did not observe artifactual mutations, even when using small amounts of template DNA.…”

Section: Discussionmentioning

confidence: 99%

“…38,42 In our practice, manual dissection of pre-treatment biopsies allowed the recovery of an amount of DNA that was enough for our study protocol. Unlike Lamy et al, 42 we did not observe artifactual mutations, even when using small amounts of template DNA. Indeed, when identified, the KRAS mutation was the same in the paired biopsy and surgical specimen, whatever the molecular assay used.…”

Section: Discussionmentioning

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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Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls

Cited by 90 publications

References 29 publications

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Validation of Companion Diagnostic for Detection of Mutations in Codons 12 and 13 of theKRASGene in Patients with Metastatic Colorectal Cancer: Analysis of the NCIC CTG CO.17 Trial

Somatic Mutations of K-Ras and BRAF in Thai Colorectal Cancer and their Prognostic Value

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

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