Radiotherapy increases plasma levels of tumoral cell-free DNA in non-small cell lung cancer patients.

Shun-Ichiro Kageyama,Fumiaki Koizumi,Takeshi Sawada,Hidehiro Hojo,Keiji Nihei,Atsuhi Motegi,Shigeo Yamaguchi,Tetsuo Akimoto,Shunsuke Kato,Katsuya Tsuchihara,Katsuyuki Karasawa

doi:10.18632/oncotarget.25053

Shun-Ichiro Kageyama, Fumiaki Koizumi + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.25053

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Journal: Oncotarget	Publication Date: Apr 10, 2018
Citations: 20	License type: cc-by

Affiliation: National Cancer Center Hospital East

Abstract

We investigated the plasma levels of tumor-specific cell-free DNA (cfDNA) in 17 stage I–II (early) and IV (advanced) non-small cell lung cancer (NSCLC) patients who underwent radiotherapy. Digital polymerase chain reaction (PCR) and targeted sequencing showed that total and tumor-specific cfDNA levels increased in response to radiotherapy in both early- and advanced-stage NSCLC patients. We detected high copy numbers of epidermal growth factor receptor mutations (L858R and T790M) in the cfDNA samples from stage IV NSCLC patients who underwent stereotactic body radiation therapy to treat brain metastasis related to tyrosine kinase inhibitor (TKI) treatment failure. In conclusion, our study demonstrates that radiotherapy increases tumoral cfDNA levels in the plasma and shows potential to serve as an indicator for diagnosing drug-resistant tumor-related gene mutations in early-stage NSCLC patients or those undergoing molecular targeted therapy.

Highlights

Analysis of tumoral cell-free DNA represents a cost-effective, non-invasive method to detect tumor-related gene mutations and drug resistance in human cancers; higher degree tumor cell necrosis is associated with higher plasma levels of cfDNA [1,2,3,4,5,6]
Eleven stage I non-small cell lung cancer (NSCLC) patients rejected surgery and chose radiotherapy, whereas, the remaining 6 stage IV NSCLC patients were positive for epidermal growth factor receptor (EGFR) mutations and showed new brain metastasis, suggesting failure of tyrosine kinase inhibitor (TKI) treatment
The 11 stage I primary NSCLC patients were treated with curative stereotactic body radiotherapy (SBRT) or 3D-CRT, whereas, the six stage IV NSCLC patients received palliative SBRT against brain metastasis

Summary

Introduction

Analysis of tumoral cell-free DNA (cfDNA) represents a cost-effective, non-invasive method to detect tumor-related gene mutations and drug resistance in human cancers; higher degree tumor cell necrosis is associated with higher plasma levels of cfDNA [1,2,3,4,5,6]. Diehl et al showed that the majority of the tumoral cfDNA fragments represent nucleosomal units (160 to 200 base pairs long) [7, 8, 12], with half-lives ranging from a few minutes to several hours [10, 13]. These fragments are cleared in the spleen, liver, and kidneys [9,10,11], thought the specific cfDNA clearance mechanisms are not well understood. Most studies have used PCR to make diagnoses based on known genetic variations in cfDNA samples, which have a sensitivity of 70–90% and a specificity of 90% [2, 8, 14, 15]

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