Mutations in K-ras Codon 12 Detected in Plasma DNA Are Not an Indicator of Disease in Patients with Non-Small Cell Lung Cancer

Trombino, Sonya; Neri, Monica; Puntoni, Riccardo; Angelini, Cristiano; Loprevite, Maura; Cesario, Alfredo; Granone, Pierluigi; Imperatori, Andrea; Dominioni, Lorenzo; Ardizzoni, Andrea; Filiberti, Rosangela; Russo, Patrizia

doi:10.1373/clinchem.2004.043976

Cited by 17 publications

(14 citation statements)

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“…Although high consistency of KRAS mutation in tissues and matched plasma DNA was observed in our study, which is consistent with studies by Kimura et al and Gautschi et al (14,17), it is notable that 4.4% KRAS mutation was identified in plasma DNA samples only and 2.6% in the tumor DNA samples only. This phenomenon has also been observed in previous studies with smaller sample sizes (15,16). Possible explanations might include, first, the intratumor heterogeneity of genetic abnormalities.…”

Section: Discussionsupporting

confidence: 83%

“…A study by Gautschi and his colleagues (17) found matching codon 12 sequences in blood and tumor in 78% evaluable cases, which support that circulating KRAS mutations originate from tumors and are prognostically relevant in lung cancer. However, contrasting results were also reported (16,18,19). For example, Trombino et al (16) failed to find a correlation between KRAS mutations in serum and the matched tumor tissues.…”

Section: Discussionmentioning

confidence: 91%

“…However, contrasting results were also reported (16,18,19). For example, Trombino et al (16) failed to find a correlation between KRAS mutations in serum and the matched tumor tissues. These data together suggest that consistency of KRAS mutation in circulating DNA and tissue remains to be of great controversy.…”

Section: Discussionmentioning

confidence: 91%

“…Recently, several studies have focused on investigating the association of KRAS mutation between plasma or serum-free DNA and tumor tissues, and their clinical significance in the patients with advanced NSCLC and other cancers, regardless of the type of cancer therapy (14)(15)(16). Kimura et al (14) analyzed KRAS gene mutation in 25 plasma specimens from NSCLC patients with paclitaxel/carboplatin chemotherapy, among whom, there were 12 cases of matched tumor tissues after treatment.…”

Section: Discussionmentioning

confidence: 99%

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Potential Clinical Significance of a Plasma-Based KRAS Mutation Analysis in Patients with Advanced Non–Small Cell Lung Cancer

Wang

et al. 2010

Clinical Cancer Research

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Purpose: Non-small cell lung cancer (NSCLC) with KRAS mutation may be resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). This study aims to evaluate a plasma-based KRAS mutation analysis and the clinical significance of plasma KRAS mutation as a predictive marker for tumor resistance to EGFR-TKIs in patients with NSCLC.Experimental Design: DNA extracted from plasma and matched tumor tissues were obtained from 273 patients with advanced stage NSCLC. Patients were followed up prospectively for treatment outcomes. KRAS mutations in codon 12 and 13 were detected using PCR-restriction fragment length polymorphism. Mutations in plasma and matched tumors were compared. Associations between KRAS mutation status and patients' clinical outcomes were analyzed.Results: KRAS mutation was found in 35 (12.8%) plasma samples and 30 (11.0%) matched tumor tissues. The consistency of KRAS mutations between plasma and tumors is 76.7% (23 of 30; κ = 0.668; P < 0.001). Among 120 patients who received EGFR-TKI treatment, the response rate was only 5.3% (1 of 19) for patients with plasma KRAS mutation compared with 29.7% for patients with no KRAS mutation in plasma DNA (P = 0.024). The median progression-free survival time of patients with plasma KRAS mutation was 2.5 months compared with 8.8 months for patients with wild-type KRAS (P < 0.001).Conclusions: KRAS mutation in plasma DNA correlates with the mutation status in the matched tumor tissues of patients with NSCLC. Plasma KRAS mutation status is associated with a poor tumor response to EGFR-TKIs in NSCLC patients and may be used as a predictive marker in selecting patients for such treatment. Clin Cancer Res; 16(4); 1324-30. ©2010 AACR.Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib are selective TKIs that can block the intracellular receptor binding sites of ATP, thus inhibiting the downstream signaling transmission. Several EGFR-TKIs have been approved as second-or third-line agents for advanced non-small cell lung cancer (NSCLC) patients who failed in platinumbased chemotherapy (1, 2).The discovery that EGFR tyrosine kinase domain mutations were strongly associated with greater sensitivity of NSCLC to EGFR-TKIs in vitro and higher response rates in clinical studies provided rationale for using molecular markers to identify patients who are most likely to benefit from EGFR-TKI therapy. Subsequent prospective studies focusing on exploring the possibility of EGFR-TKIs as first-line therapy, such as IPASS (IRESSA Pan-Asia Study, a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced NSCLC in Asia) and the Spanish Lung Cancer Group trial (a multicenter prospective phase II trial of customized erlotinib for advanced NSCLC patients with EGFR mutations), have shown an outstanding survival benefit for patients with EGFR mutant tumors who received first-line EGFR-TKI therapy, which is superior to the outc...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Potential Clinical Significance of a Plasma-Based KRAS Mutation Analysis in Patients with Advanced Non–Small Cell Lung Cancer

Wang

et al. 2010

Clinical Cancer Research

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“…Glioma) showed a very low level of ctDNA. Moreover, Trombino et al (2005) found no concordance between KRAS mutations found in circulating DNA and tumour tissue from patients with NSCLC. Ramirez et al (2003), on the other hand, found more mutations in KRAS gene in the serum of patient compared to the primary NSCLC.…”

Section: Applicability Of Ctdna As a Diagnostic Biomarkermentioning

confidence: 87%