Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients

Marchetti, Antonio; Palma, John F.; Felicioni, Lara; Pas, Tommaso Martino De; Chiari, Rita; Grammastro, Maela Del; Filice, Giampaolo; Ludovini, Vienna; Brandes, Alba Ariela; Chella, Antonio; Malorgio, Francesco; Guglielmi, Flavio; Tursi, Michele De; Santoro, Armando; Crinò, Lucio; Buttitta, Fiamma

doi:10.1097/jto.0000000000000643

Cited by 163 publications

(138 citation statements)

References 16 publications

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“…Patients with M1a disease had lower EGFR T790M detection compared to patients with M1b disease suggesting extra-thoracic metastasis is more predictive of ctDNA detection. Our study is the first significant attempt to our knowledge to describe the kinetic rise in the number of copies of ctDNA immediately after therapy, and our findings are consistent with previously reported studies in plasma demonstrating an overall decrease in ctDNA levels for patients responding to targeted therapy with samples collected weeks to months after initiation of therapy (13, 29-30). Studies are ongoing to further understand the impact of biological factors including urine volume and residency time, timing of collection, locus dependent pattern of ctDNA degradation, and patients’ hydration status on the dynamics and detection of ctDNA in urine.…”

Section: Discussionsupporting

confidence: 90%

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Husain

Melnikova²,

Kosco³

et al. 2017

Clinical Cancer Research

107

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Purpose Non-invasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. Experimental Design We tested the hypothesis that dynamic changes in epidermal growth factor receptor (EGFR) activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second line third generation anti-EGFR tyrosine kinase inhibitor. Results Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pre-treatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1 suggesting apoptosis with an overall decrease in fragment numbers between baselines to day 7 preceding radiographic response assessed at 6-12 weeks. Conclusions These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development.

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Section: Discussionsupporting

confidence: 90%

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Husain

Melnikova²,

Kosco³

et al. 2017

Clinical Cancer Research

107

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“…Most recently, Marchetti et al performed PCR and ultra-deep NGS on serial plasma samples of advanced-stage patients (n 5 20) with known tissue and plasma EGFR mutations before TKI treatment. Patients who had a 50% decrease in plasma EGFR copy number at 14 days (rapid responders; n 5 14) had a greater mean percentage of tumor shrinkage than that of slow responders (n 5 6) who had not achieved this change (70% vs. 30%; p , .0001) [27]. Finally, using a deep sequencing method (cancer personalized profiling by deep sequencing) that quantifies cancer-specific genomic alterations, Newman et al was able to demonstrate that plasma ctDNA levels isolated from longitudinal samples in advanced-stage patients (n 5 3) receiving either chemotherapy or targeted therapy highly correlated with the tumor volumes during therapy [28].…”

Section: Predictive and Prognostic Utility Of Egfr Mutations Identifimentioning

confidence: 97%

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Levy

Cordova

et al. 2016

The Oncologist

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A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non-small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced-stage patients has been tissue acquisition via computed tomography-guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood-based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell-free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high-risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.

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“…This methodology is also relevant when patients show no tolerance to a new biopsy, if there are several metastases in different localizations, when the tissue is insufficient or has artefacts related for instance to decalcification, when there are problems related to heterogeneity or when biopsy imposes risks [124]. ctDNA can be used to identify resistance to TKIs [126][127][128][129][130][131][132][133][134][135]. Weber et al [136] demonstrated a concordance rate of 90% (179/199) for EGFR mutations between biopsy tissue and ctDNA (plasma) before EGFR TKIs.…”

Section: Doi: 101159/000487440mentioning

confidence: 99%

Heterogeneity in Lung Cancer

2018

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Lung cancer diagnosis is a challenge since it is also one of the most frequently diagnosed cancers. Diagnostic challenges are deeply related to the development of personalized therapy and molecular and precise histological characterizations of lung cancer. When addressing these features, it is very important to acknowledge the issue of tumour heterogeneity, as it imposes several questions. First of all, lung cancer is a very heterogeneous disease, at a cellular and histological level. Cellular and histological heterogeneity are addressed with emphasis on the diagnosis, pre-neoplastic lesions, and cell origin, trying to contribute to a better knowledge of carcinogenesis. Molecular intra-tumour and inter-tumour heterogeneity are also addressed as temporal heterogeneity. Lung cancer heterogeneity has implications in pathogenesis understanding, diagnosis, selection of tissue for molecular diagnosis, as well as therapeutic decision. The understanding of tumour heterogeneity is crucial and we must be aware of the implications and future developments regarding this field.

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Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients

Abstract: Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management.

Cited by 163 publications

References 16 publications

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Heterogeneity in Lung Cancer

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