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

TLDR

Elevated circulating tumor cells predict poor prognosis in epithelial cancers, yet their utility as surrogate endpoints or predictive biomarkers is not well established. This study assessed whether CTC enumeration and ctDNA mutation detection could serve as biomarkers in advanced NSCLC patients receiving erlotinib and pertuzumab. Peripheral blood from 41 patients was analyzed with CellSearch for CTC count, EGFR expression, and oncogenic mutations, while ctDNA was screened for mutations, with changes correlated to FDG‑PET, CT imaging, and survival outcomes. Higher baseline CTC counts predicted RECIST response (P = 0.009), reductions in CTCs correlated with PET/RECIST response and longer progression‑free survival (P = 0.014–0.050), and ctDNA demonstrated higher mutation detection sensitivity and concordance with tumor tissue.

Abstract

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).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.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).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.