A Prospective Evaluation of Circulating Tumor Cells and Cell-Free DNA in EGFR-Mutant Non-Small Cell Lung Cancer Patients Treated with Erlotinib on a Phase II Trial.
OBJECTIVE
Genotype-directed therapy is the standard of care for advanced non-small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression.


METHODS
EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression.


RESULTS
Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival.


CONCLUSIONS
cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. Clin Cancer Res; 22(24); 6010-20. ©2016 AACR.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Masahiko
M
Yanagita
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Amanda J
AJ
Redig
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cloud P
CP
Paweletz
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Suzanne E
SE
Dahlberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Allison
A
O'Connell
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Nora
N
Feeney
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Myriam
M
Taibi
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
David
D
Boucher
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Geoffrey R
GR
Oxnard
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Bruce E
BE
Johnson
Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Daniel B
DB
Costa
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
David M
DM
Jackman
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Pasi_Janne@dfci.harvard.edu.|Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Belfer Center for Applied Cancer Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
Pasi A
PA
Jänne
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000073888:Cell-Free Nucleic Acids / Q000187:drug effects* / Q000235:genetics; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000172:deficiency*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000473:pathology; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000073888:Cell-Free Nucleic Acids; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors