title: Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib.
abstract: OBJECTIVE
  Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab. Peripheral blood was analyzed for CTC enumeration, EGFR expression in CTCs, and detection of oncogenic mutations in CTCs and ctDNA. Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomographic (FDG-PET) and computed tomographic (CT) imaging and survival endpoints.
  
  
  RESULTS
  CTCs were detected (≥ 1 CTC) at baseline in 78% of patients. Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor. Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST, P = 0.009) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response (P = 0.014 and P = 0.019) and longer progression-free survival (P = 0.050).
  
  
  CONCLUSIONS
  These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC. These findings require prospective validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood.
authors.affiliation: Department of Oncology Biomarker Development and Oncology Clinical Development, Genentech, Inc, South San Francisco, California 94080, USA. punnoose.elizabeth@gene.com
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Punnoose
authors.forename: Siminder
authors.initials: S
authors.lastname: Atwal
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: Rajiv
authors.initials: R
authors.lastname: Raja
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Fine
authors.forename: Brett G M
authors.initials: BG
authors.lastname: Hughes
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirzkall
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood*; D018572:Disease-Free Survival; D023381:Endpoint Determination; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009154:Mutation; D009360:Neoplastic Cells, Circulating; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C485206:pertuzumab