Concordant KRAS Mutations in Primary and Metastatic Colorectal Cancer Tissue Specimens: A Meta-Analysis and Systematic Review

Han, Cheng-Bo; Li, Fan; Ma, Jie-Tao; Zou, Huawei

doi:10.3109/07357907.2012.732159

Cited by 63 publications

(53 citation statements)

References 34 publications

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“…La frecuencia de mutaciones en los tumores primarios fue mayor que las observadas en las metástasis (42,3% versus 33,3%), sin embargo, esta diferencia no fue significativa tal y como ha sido reportado en series internacionales en las cuales esta diferencia es aún menor 45,46 .…”

Section: Resultsunclassified

Mutación del gen KRAS en el cáncer de colon y recto

Roa¹,

Sanchez

Majlis

et al. 2013

Rev. méd. Chile

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Section: Resultsunclassified

Mutación del gen KRAS en el cáncer de colon y recto

Roa¹,

Sanchez

Majlis

et al. 2013

Rev. méd. Chile

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“…Previous studies have primarily investigated mutational differences between CRCs and liver metastasis 5, 13, 14, 15. The mutational status of KRAS showed high concordance between CRCs and metastases 16, 17.…”

Section: Introductionmentioning

confidence: 99%

Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

Crobach

Ruano

Eijk

et al. 2016

The Journal of Pathology CR

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The mutational profiles of primary colorectal cancers (CRCs) and corresponding ovarian metastases were compared. Using a custom‐made next generation sequencing panel, 115 cancer‐driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases (four with bilateral metastases). To obtain a complete overview of the mutational profile, low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out. A subset of variants was validated using Sanger and/or hydrolysis probe assays. The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series. When comparing primary CRCs and their matching ovarian metastases, there was considerable overlap in the mutations of early affected genes. A subset of mutations demonstrated less overlap, presumably being passenger mutations. In particular, primary CRCs showed a substantially high number of passenger mutations. We also compared the primary CRCs and matching metastases for stratifying variants of six genes (KRAS, NRAS, BRAF, FBXW7, PTEN and PIK3CA) that select for established (EGFR directed) or future targeted therapies. In a total of 31 variants 12 were not found in either of the two locations. Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases. Half of these discordant variants were definitive class 4/5 pathogenic variants. However, in terms of temporal heterogeneity, no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases. This suggests that dormant metastases may be present from the early days of the primary tumours.

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“…Concordance between primary tumor and liver metastases RAS status appears high in colorectal cancer, ranging from 90% to 100%; however, discordance of up to 32% has been reported between lung or lymph node metastases and primary tumors. 7,8 In the reported case, a partial response was noted in the pulmonary metastases, although whether the liver or primary tumor responded to therapy is unclear. Given that the primary tumor is where the KRAS mutant clone was sampled, this information is particularly important.…”

Section: Is Kras A59t Truly Sensitive To Anti-egfr Therapy?mentioning

confidence: 96%

Why a One Size Fits All Approach toRASMight Not Fit Colorectal Cancer

Loree¹,

Kopetz²

2017

J Natl Compr Canc Netw

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Since the discovery that KRAS exon 2 mutations predict a lack of benefit from antiepidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer, our understanding of RAS mutations has expanded considerably. Guidelines now suggest extended RAS characterization, which includes assessment of KRAS and NRAS for mutations at exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146).1 Extended RAS mutations appear to confer resistance to anti-EGFR therapy. With their inclusion, approximately 56% of patients will be defined as having a RAS mutation and will not be eligible for anti-EGFR therapy.2,3 In addition, atypical RAS mutations exist that are of unclear significance and difficult to study in any prospective manner given their rarity. Even within guideline-described codons there are mutations, such as KRAS A59T, that are of unclear significance. Studying these mutations individually would be nearly impossible, and they highlight a pressing issue of how we deal with variants of unknown significance (VUS). The number of uncommon VUS is likely to expand exponentially as clinical sequencing moves to more comprehensive sequencing platforms, and we will need solutions to deal with these variants.In this issue of JNCCN, Lou et al ("Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab") present the case of a 50-year-old woman with a KRAS A59T-mutated metastatic colon cancer who received 4 cycles of FOLFIRI plus panitumumab and showed a radiographic partial response accompanied by a decline in carcinoembryonic antigen. The patient subsequently experienced disease control lasting 8 months while receiving FOLFIRI plus panitumumab. She was noted to have a KRAS A59T mutation after the treating institution changed from a Sanger sequencing platform specific to KRAS exon 2 to a more comprehensive amplicon-based next-generation sequencing (NGS) panel that included extended RAS coverage. The NGS panel was performed on DNA extracted from the same biopsy of the primary tumor as the Sanger sequencing. The authors propose that patients with KRAS A59T mutations may represent a population with continued sensitivity to anti-EGFR therapy. Challenges and Opportunities in Studying Rare BiomarkersGiven the infrequency of many extended RAS mutations, they have not been well described individually and were considered as a group of mutations in the studies that support extended RAS mutation testing. Codon 59 mutations are particularly lacking in evidence to support their role in predicting resistance to anti-EGFR therapy. Only 7 patients with codon 59 mutations were described in the landmark PRIME trial analysis of extended RAS mutations, and these mutations were not part of the extended RAS mutation analysis. The evidence to support these mutations as a predictive marker was only the fact that removing these patients from the population with wild-type RAS resulted in a hazard ratio that made anti-EGF...

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Concordant KRAS Mutations in Primary and Metastatic Colorectal Cancer Tissue Specimens: A Meta-Analysis and Systematic Review

Cited by 63 publications

References 34 publications

Mutación del gen KRAS en el cáncer de colon y recto

Mutación del gen KRAS en el cáncer de colon y recto

Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

Why a One Size Fits All Approach toRASMight Not Fit Colorectal Cancer

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