2013
DOI: 10.1093/annonc/mds620
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Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

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Cited by 96 publications
(63 citation statements)
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“…16 A recent report has indeed suggested that the presence of low levels of KRAS mutant alleles are associated with a reduced response rate and progression-free survival in mCRC patients treated with EGFR-based therapies. 20 However, a major bias of this latter study is that patients that showed resistance to anti-EGFR agents were also in more advanced lines of therapy as compared with sensitive patients, and this unbalance might have clearly affected the results of this study. Actually, the presence of resistance mutations in a small fraction of tumor cells is unlikely to cause primary resistance, although it may lead to a reduced progression free survival as demonstrated for treatment with EGFR tyrosine kinase inhibitors and the T790M resistance mutations in non-small-cell lung carcinoma (NSCLC).…”
Section: Discussionmentioning
confidence: 90%
“…16 A recent report has indeed suggested that the presence of low levels of KRAS mutant alleles are associated with a reduced response rate and progression-free survival in mCRC patients treated with EGFR-based therapies. 20 However, a major bias of this latter study is that patients that showed resistance to anti-EGFR agents were also in more advanced lines of therapy as compared with sensitive patients, and this unbalance might have clearly affected the results of this study. Actually, the presence of resistance mutations in a small fraction of tumor cells is unlikely to cause primary resistance, although it may lead to a reduced progression free survival as demonstrated for treatment with EGFR tyrosine kinase inhibitors and the T790M resistance mutations in non-small-cell lung carcinoma (NSCLC).…”
Section: Discussionmentioning
confidence: 90%
“…Previous studies suggested that patients with mCRC tumors containing no more than 1%-2% of KRAS-mutated subclones may benefit from anti-EGFR therapies. 111,112 However, no cut-off level for KRASmutated ctDNA that predicts resistance to anti-EGFR therapies has yet been established, thus, it is not known, for example, whether detection of 1% of cfDNA harboring a RAS mutation in a clinically responding wild-type RAS tumor should prompt a change in treatment.…”
Section: Discussionmentioning
confidence: 99%
“…There is no uniform standard for KRAS testing and the majority of commonly used, commercially available assays assess only point mutations at codons 12 and 13, and lack sufficient coverage to detect less frequent KRAS alterations, which have been shown to predict resistance to anti-EGFR therapy [57,58]. Molecular test results returned to treating physicians can be misleading because published validation for the majority of assays indicating performance limitations is not readily available.…”
Section: Discussionmentioning
confidence: 99%