Rebiopsy of non-small cell lung cancer patients with acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and -negative populations.

Hata, Akito; Katakami, Nobuyuki; Yoshioka, Hiroshige; Takeshita, Jumpei; Tanaka, Kosuke; Nanjo, Shigeki; Kaji, Ryuji; Fujita, Shiro; Imai, Yukihiro; Monden, Kazuya; Matsumoto, Takeshi; Nagata, Kazuma; Otsuka, Kyoko; Tachikawa, Ryo; Tomii, Keisuke; Kunimasa, Kei; Iwasaku, Masahiro; Nishiyama, Akihiro; Ishida, Tadashi

doi:10.1200/jco.2012.30.15_suppl.7528

Cited by 30 publications

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“…In the present study, the T790M mutation frequency at rebiopsy (33%) was also low compared with previous studies (30-83%). (13,(15)(16)(17)(18) The incidence of T790M mutation in Japanese patients with EGFR- CT, computed tomography. Fig.…”

Section: Discussionmentioning

confidence: 99%

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Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

et al. 2016

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Although third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) can overcome T790M‐mediated resistance in non‐small‐cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR‐TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)‐guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR‐TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.

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Section: Discussionmentioning

confidence: 99%

“…mutant NSCLC following EGFR-TKI therapies might be lower than that in Caucasians. (15,16) T790M mutations are possibly induced by EGFR-TKI exposure, and EGFR-TKI treatment beyond PD or duration of EGFR-TKI before rebiopsy might be related to the incidence of T790M mutation. However, little data is available that supports these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

et al. 2016

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“…Indeed, reports from other laboratories show that most rebiopsy is performed from intra-thoracic lesions, including the enlarging primary lesion, intra-pulmonary lesion and pleural effusion. (15,(20)(21)(22) Recently, inter-tumor and intra-tumor heterogeneity has been reported. (23,24) In addition to different genomic alterations between primary and metastatic lesions, spatial variation in the primary lesion has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study

et al. 2016

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Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re-biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment.C ompanion diagnostics has seen growing importance, especially for molecular targeted therapy such as EGFR tyrosine kinase inhibitors (EGFR-TKI) in lung cancer. Recently, a second generation EGFR-TKI, afatinib, evidenced a potent anti-cancer effect against lung cancer cells harboring T790M,(1) but the anti-cancer effect in a phase 2b ⁄ 3 randomized trial was unsatisfactory considering the results of preclinical studies.(2) Because examination of biomarkers related to acquired resistance to EGFR-TKI was not performed in that trial, it is speculated that the patients included those with cancers possessing various mechanisms of acquired resistance to EGFR-TKI. Recently, third generation EGFR-TKI, such as AZD9291 and CO-1686, have shown potent anti-cancer effects in T790M positive non-small cell lung cancer patients. (3,4) Considering this evidence, examination of biomarkers is indispensable for accurate assessment of anti-cancer effects, and timely monitoring of genetic alterations is necessary for determining appropriate treatment.The use of circulating free DNA to detec...

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“…NSCLC harboring activating EGFR mutation and T790M mutation exhibit indolent progression compared with NSCLC harboring only activating EGFR mutations, (31) and the prognosis of patients with T790M after EGFR-TKI failure was better than that of patients lacking this mutation. (32) In addition, T790Mmutant EGFR-selective EGFR-TKIs were recently developed. (33,34) In the current and our previous studies, (12) the strict selection of cancer cells with a sufficient concentration of EGFR-TKIs may prevent the acquisition of conventional resistance mechanisms, such as T790M or MET amplification, and may cause cancer cells to acquire stem cell-like properties.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of cancer stem cell‐like properties in non‐small cell lung cancer with acquired resistance to afatinib

et al. 2015

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Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

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Rebiopsy of non-small cell lung cancer patients with acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and -negative populations.

Cited by 30 publications

References 0 publications

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study

Acquisition of cancer stem cell‐like properties in non‐small cell lung cancer with acquired resistance to afatinib

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