Highly Sensitive Detection of EGFR T790M Mutation Using Colony Hybridization Predicts Favorable Prognosis of Patients with Lung Cancer Harboring Activating EGFR Mutation

Fujita, Yoshihiko; Suda, Kenichi; Kimura, Hideharu; Matsumoto, Kazuko; Arao, Tokuzo; Nagai, Tatsuo; Saijo, Nagahiro; Yatabe, Yasushi; Mitsudomi, Tetsuya; Nishio, Kazuto

doi:10.1097/jto.0b013e3182653d7f

Cited by 105 publications

(125 citation statements)

References 16 publications

(24 reference statements)

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“…Choosing higher sensitivity methods may reveal more primary lung tumors carrying the resistance mutation in addition to the classic sensitizing EGFR mutation. Recent studies have shown that alternate methods reveal T790M mutations in up to 79% of EGFR-mutant primary NSCLC tumors [54,55,57,58]. Although, applying more sensitive detection methods such as NGS, dPCR or Beaming technology will provide more insight into the molecular mechanisms of tumor development and tumor progression, heterogeneity is one reason treatment relevant mutations such as T790M are missed at initial diagnosis.…”

Section: Tumor Type Genementioning

confidence: 99%

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Hinrichsen

Dworniczak

Wachter

et al. 2016

LaboratoriumsMedizin

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Abstract:The term liquid biopsy comprises methods of blood-based analysis of nucleic acids, which are increasingly under discussion in oncology and personalized medicine, and are already applied in individual cases. The analysis of tumor markers, which in certain tumor diseases can be found as protein markers in vast amounts in the blood, constitutes a primary form of liquid biopsy. Cell-free circulating DNA fragments in the blood (ctDNA), which reflect the genetic profile of a tumor cell and are released in different ways by the tumor, represent a new class of more specific and sensitive biomarkers that can be correlated with the dynamics of the tumor disease. New technologies based on PCR and sequencing techniques pave the way for diagnostic approaches to define molecular tumor characteristics, not only in tumor tissue but also in the blood, by analyzing cell-free circulating DNA.The combination of molecular profiling of the tumor with ctDNA analytics by liquid biopsy is a promising step in the advancement of precision medicine.

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Section: Tumor Type Genementioning

confidence: 99%

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Hinrichsen

Dworniczak

Wachter

et al. 2016

LaboratoriumsMedizin

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“…The T790M mutation has been detected in some patients who have not been treated with EGFR-TKIs (11)(12)(13)(14)(15)(16). Since the incidence of a T790M mutation has been reported to range from 0.02 to 0.05% in all surgically resected NSCLC patients based on studies using direct sequencing (2,17), it is difficult to clarify the association due to the T790M mutation and clinicopathological factors because of the limitation in the number of cases.…”

Section: Introductionmentioning

confidence: 99%

“…Since the incidence of a T790M mutation has been reported to range from 0.02 to 0.05% in all surgically resected NSCLC patients based on studies using direct sequencing (2,17), it is difficult to clarify the association due to the T790M mutation and clinicopathological factors because of the limitation in the number of cases. Using highly sensitive assays, the clinical impact of the minor T790M mutation in NSCLC patients with EGFR-TKI treatment has been previously investigated (11,14,15). However, the impact on EGFR-TKI-naive NSCLC patients has not been adequately investigated (12,13,16).…”

Section: Introductionmentioning

confidence: 99%

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

et al. 2014

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Abstract. The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFRtyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was <0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

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“…De novo T790M EGFR mutations have been observed in TKI-naïve patients and could predict a shorter response duration following EGFR-TKI treatment (2,3). Furthermore, the incidence of de novo T790M mutation may be more prevalent than expected due to the limited sensitivity of detection methods, such as direct sequencing (2)(3)(4)(5). Next generation EGFR-TKIs, including AZD9291, CO-1686 and HM61713, could inhibit EGFR T790M and activating mutations, and have been proven beneficial to NSCLC patients with EGFR-TKI (gefitinib or erlotinib) resistance caused by secondary T790M mutation (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

A sensitive and practical method to detect the T790M mutation in the epidermal growth factor receptor

et al. 2016

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Abstract. The current study aimed to develop a method to rapidly, sensitively and practically screen for the epidermal growth factor receptor (EGFR) T790M mutation. This method combines an allele-specific competitive blocker (ACB) with a TaqMan quantitative polymerase chain reaction (PCR) amplification refractory mutation system (ARMS) in a one-step reaction. Using a mimic of a human genomic DNA panel containing serially diluted mutant alleles, the performance efficacy of this method was assessed. Using this method, the EGFR T790M mutation was detected in tyrosine kinase inhibitor (TKI)-naïve samples obtained from 27 non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. The association between de novo T790M mutations and the clinical benefit of EGFR-TKI treatment was also analysed. The sensitivity of this method was as low as 0.01%. In the samples from the 27 NSCLC patients, this method identified 6 mutant patients (22.2%), which was higher than the detection rate with scorpion ARMS (0.0%). No clinical variables were associated with the occurrence of a de novo T790M mutation. The median progression-free survival time in the TKI-naïve patients with a T790M mutation was shorter that that of patients without the mutation, but the difference was not significant (3.2 vs. 19.5 months, respectively; P=0.256). The median overall survival time in the groups with or without T790M mutation also did not significantly differ (10 vs. 20 months, respectively; P=0.689). Overall, the ACB-ARMS PCR method could be useful for detecting the EGFR T790M mutation in clinical samples that contain only a small number of mutant alleles. The clinical significance of a de novo T790M mutation should be further investigated.

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Highly Sensitive Detection of EGFR T790M Mutation Using Colony Hybridization Predicts Favorable Prognosis of Patients with Lung Cancer Harboring Activating EGFR Mutation

Abstract: Our highly sensitive CH method showed that a subgroup of non-small-cell lung cancer patients with the EGFR mutation harbored the rare T790M allele before EGFR-TKI treatment. A high proportion of T790M allele may define a clinical subset with a relatively favorable prognosis.

Cited by 105 publications

References 16 publications

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Detection and characterization of circulating cell free tumor DNA in cancer patients with malignant solid tumors. Liquid biopsy: a new tool in molecular pathology?

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

A sensitive and practical method to detect the T790M mutation in the epidermal growth factor receptor

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