<i>EGFR</i> Mutation Heterogeneity and the Mixed Response to EGFR Tyrosine Kinase Inhibitors of Lung Adenocarcinomas

Chen, Zhi Yong; Zhong, Wen Zhao; Zhang, Xu-Chao; Su, Jian; Yang, Xue; Chen, Zhi Hong; Yang, Jin; Zhou, Qing; Yan, Hong; An, She Juan; Chen, Hua Jun; Jiang, Ben‐Yuan; Mok, Tony; Wu, Yi‐Long

doi:10.1634/theoncologist.2011-0385

Cited by 148 publications

(132 citation statements)

References 30 publications

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“…Candidate recipients include patients with lesions difficult for biopsy sampling, those with obscure biopsy results, and those who prefer not to have biopsy. The presence of intertumor heterogeneity of EGFR mutations (19 ) indicates that the mutation status of primary lesions may not represent that of metastatic lesions. Because ctDNA includes DNA from both lesions, mutation screening with plasma DNA may be beneficial to detect mutations in lesions other than biopsy sites.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA

Uchida¹,

Kato²,

Kukita³

et al. 2015

Clinical Chemistry

104

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BACKGROUND Genotyping of EGFR (epidermal growth factor receptor) mutations is indispensable for making therapeutic decisions regarding whether to use EGFR tyrosine kinase inhibitors (TKIs) for lung cancer. Because some cases might pose challenges for biopsy, noninvasive genotyping of EGFR in circulating tumor DNA (ctDNA) would be beneficial for lung cancer treatment. METHODS We developed a detection system for EGFR mutations in ctDNA by use of deep sequencing of plasma DNA. Mutations were searched in >100 000 reads obtained from each exon region. Parameters corresponding to the limit of detection and limit of quantification were used as the thresholds for mutation detection. We conducted a multi-institute prospective study to evaluate the detection system, enrolling 288 non–small cell lung cancer (NSCLC) patients. RESULTS In evaluating the performance of the detection system, we used the genotyping results from biopsy samples as a comparator: diagnostic sensitivity for exon 19 deletions, 50.9% (95% CI 37.9%–63.9%); diagnostic specificity for exon 19 deletions, 98.0% (88.5%–100%); sensitivity for the L858R mutation, 51.9% (38.7%–64.9%); and specificity for L858R, 94.1% (83.5%–98.6%). The overall sensitivities were as follows: all cases, 54.4% (44.8%–63.7%); stages IA–IIIA, 22.2% (11.5%–38.3%); and stages IIIB–IV, 72.7% (60.9%–82.1%). CONCLUSIONS Deep sequencing of plasma DNA can be used for genotyping of EGFR in lung cancer patients. In particular, the high specificity of the system may enable a direct recommendation for EGFR-TKI on the basis of positive results with plasma DNA. Because sensitivity was low in early-stage NSCLC, the detection system is preferred for stage IIIB–IV NSCLC.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA

Uchida¹,

Kato²,

Kukita³

et al. 2015

Clinical Chemistry

104

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“…The authors attempted to explain this apparent inconsistency in terms of the heterogeneity of genetic tumour abnormalities, where tumour cells may or may not carry the mutation. A recent study has demonstrated a high discordance rate among multiple pulmonary nodules in terms of EGFR mutation, emphasizing the problem of tumour heterogeneity (90) and suggesting that CTC or circulating DNA analyses are crucial in the identification of the presence of mutations and tumour heterogeneity.…”

Section: Biological Samples Suitable For Molecular Characterisationmentioning

confidence: 99%

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Ulivi

Zoli

Capelli

et al. 2013

Molecular and Clinical Oncology

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Abstract. In recent years, a number of new agents that target specific molecular pathways in non-small cell lung cancer (NSCLC) have been investigated. Much effort has been focused on identifying specific markers that are predictive of treatment response, given that a tailored approach would maximise the therapeutic index and cost-effectiveness. Gefitinib and erlotinib are selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) and have produced good results in selected cases in terms of objective response rate and overall survival. At present, EGFR gene mutations are considered the most important predictors of clinical response to TKI therapy and tumour characterisation for these alterations is mandatory prior to any decision making. Echinoderm microtubule-like protein 4-anaplastic lymphoma kinase (EML4-ALK) translocation is another alteration capable of predicting the efficacy of anti-ALK agents, such as crizotinib. Moreover, emerging target agents, such as MET inhibitors, are likely to increase the amount of molecular characterisation required before a decision is made on treatment. The main limiting factor for adequate characterisation of metastatic NSCLC patients is the small quantity of tumour cells available for molecular analysis. In this study, we provided an overview of the most important and clinically relevant target agents in NSCLC patients as well as the most important mechanisms of resistance. The issue of the scant amount of biological samples available for analysis as well as alternative sampling approaches such as plasma-or serum-derived DNA were also examined.

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“…Consequently this can be of use in guiding further treatment and predicting survival in cancer patients (6,7,9).…”

Section: Discussionmentioning

confidence: 99%

“…With advances in high-throughput technologies, such as next-generation sequencing, intra-or inter-tumoral genomic heterogeneity has been highlighted in the area of molecular oncology and can improve our understanding of this response (8). For example, inter-tumoral heterogeneity of an EGFR mutation has been well described in adenocarcinoma (9). Therefore, the HRR leads clinicians to switch to another anticancer regimen due to the clinically high suspicion of resistance, as histological confirmation is not feasible in the majority of cases.…”

Section: Introductionmentioning

confidence: 99%

Interpretation of a heterogeneous radiological response as tumor heterogeneity or a non-tumor diagnosis: A case report

Ryu

Kim

et al. 2015

Oncology Letters

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Abstract. Heterogeneous radiological responses (HRRs) among tumor lesions are usually observed following chemotherapy or radiation treatment in cancer patients. When HRR is observed after chemotherapy or radiation treatment, a change in anticancer treatment is recommended due to the clinically high suspicion of resistance in the majority of cases. The present study reports the case report of a patient with limited-stage small cell lung cancer, diagnosed by bronchoscopy, who received concurrent chemoradiation therapy. Upon response evaluation, the majority of lesions irradiated had nearly completely disappeared following treatment, but one lesion had apparently increased in size. For histological confirmation, a percutaneous needle biopsy for the lesion was performed, however, non-specific necrosis was found and the results were inconclusive for the differentiation of other causes from tumor necrosis. Several acid-fast bacilli were identified on Ziehl-Neelsen staining for the differential diagnosis. This case suggests that a non-tumor diagnosis should be considered when HRR presents after treatment that is expected to result in a higher response rate, particularly in tuberculosis endemic areas.

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EGFR Mutation Heterogeneity and the Mixed Response to EGFR Tyrosine Kinase Inhibitors of Lung Adenocarcinomas

Cited by 148 publications

References 30 publications

Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA

Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Interpretation of a heterogeneous radiological response as tumor heterogeneity or a non-tumor diagnosis: A case report

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