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Clinical Trial
. 2017 Jan 17;116(2):175-185.
doi: 10.1038/bjc.2016.420. Epub 2016 Dec 22.

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6

Yi-Long Wu  1 , Lecia V Sequist  2 , Cheng-Ping Hu  3 , Jifeng Feng  4 , Shun Lu  5 , Yunchao Huang  6 , Wei Li  7 , Mei Hou  8 , Martin Schuler  9   10 , Tony Mok  11 , Nobuyuki Yamamoto  12 , Kenneth O'Byrne  13 , Vera Hirsh  14 , Neil Gibson  15 , Dan Massey  16 , Miyoung Kim  17 , James Chih-Hsin Yang  18
Affiliations
Clinical Trial

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6

Yi-Long Wu et al. Br J Cancer. .

Abstract

Background: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+).

Methods: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit.

Results: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients.

Conclusions: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

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Conflict of interest statement

LVS has participated in non-compensated consulting from Boehringer Ingelheim, Clovis Oncology, AstraZeneca, Novartis, Merrimack, Taiho, and Genentech. MSc has received grants from Novartis Pharma and personal fees from Novartis Pharma, AstraZeneca, Pfizer, GlaxoSmithKline, and Lilly. TM has received personal fees from AstraZeneca, Roche, Lilly, Merck Serono, Eisai, Bristol-Myers Squibb, AVEO, Pfizer, Boehringer Ingelheim, Novartis Pharmaceuticals, GlaxoSmithKline, Clovis Oncology, Amgen, Janssen, BioMarin Pharmaceuticals, and Threshold Pharmaceuticals. KO'B has received personal fees from Boehringer Ingelheim, MSD, Lilly, AstraZeneca, Bristol-Myers Squibb, Pfizer, and Roche. VH has participated on advisory boards for Boehringer Ingelheim. NG is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. DM is an employee of Boehringer Ingelheim Ltd UK. JC-HY has received advisory board and speaker honoraria from Boehringer Ingelheim, AstraZeneca, Roche/Genentech, Pfizer, Novartis, MSD, Merck Serono, Clovis Oncology, and Bayer. MK is an employee of Boehringer Ingelheim GmbH. All the other authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Patient disposition in LUX-Lung 3 and LUX-Lung 6. aPatients who were EGFR mutation positive based on tissue biopsy at screening. Abbreviations: cfDNA=cell-free DNA; EGFR=epidermal growth factor receptor.
Figure 2
Figure 2
Kaplan–Meier curves of PFS. Kaplan–Meier curves of PFS according to the presence of an EGFR mutation by cfDNA analysisa in patients with common EGFR mutations (Del19 or L858R; based on tumour biopsy) in (A) LUX-Lung 3 and (B) LUX-Lung 6. aPatients who were EGFR Del19 or L858R mutation positive based on tissue biopsy were grouped according to whether any EGFR mutation was detected by cfDNA analysis (cfDNA+ or cfDNA−). Abbreviations: cfDNA=cell-free DNA; cis=cisplatin; EGFR=epidermal growth factor receptor; gem=gemcitabine; pem=pemetrexed; PFS=progression-free survival.
Figure 3
Figure 3
Kaplan–Meier curves of OS. Kaplan–Meier curves of OS according to the presence of an EGFR mutation by cfDNA analysisa in patients with common EGFR mutations (Del19 or L858R; based on tumour biopsy) in (A) LUX-Lung 3 and (B) LUX-Lung 6. aPatients who were EGFR Del19 or L858R mutation positive based on tissue biopsy were grouped according to whether any EGFR mutation was detected by cfDNA analysis (cfDNA+ or cfDNA−). Abbreviations: cfDNA=cell-free DNA; cis=cisplatin; EGFR=epidermal growth factor receptor; gem=gemcitabine; OS=overall survival; pem=pemetrexed.
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References

    1. Aung KL, Donald E, Ellison G, Bujac S, Fletcher L, Cantarini M, Brady G, Orr M, Clack G, Ranson M, Dive C, Hughes A (2014) Analytical validation of BRAF mutation testing from circulating free DNA using the amplification refractory mutation testing system. J Mol Diagn 16(3): 343–349. - PubMed
    1. Bai H, Mao L, Wang HS, Zhao J, Yang L, An TT, Wang X, Duan CJ, Wu NM, Guo ZQ, Liu YX, Liu HN, Wang YY, Wang J (2009) Epidermal growth factor receptor mutations in plasma DNA samples predict tumor response in Chinese patients with stages IIIB to IV non-small-cell lung cancer. J Clin Oncol 27(16): 2653–2659. - PubMed
    1. Board RE, Williams VS, Knight L, Shaw J, Greystoke A, Ranson M, Dive C, Blackhall FH, Hughes A (2008) Isolation and extraction of circulating tumor DNA from patients with small cell lung cancer. Ann NY Acad Sci 1137: 98–107. - PubMed
    1. Brevet M, Johnson ML, Azzoli CG, Ladanyi M (2011) Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors. Lung Cancer 73(1): 96–102. - PMC - PubMed
    1. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, Walker J, Dearden S, Webster A, Milenkova T, McCormack R (2014. a) Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 9(9): 1345–1353. - PMC - PubMed

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