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.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 1.2 million deaths annually [1]
Greater sensitivity for mutation detection was observed in circulating tumor DNA (ctDNA) than in circulating tumor cells (CTC) 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 1⁄4 0.009) and decreased CTC counts upon treatment were associated with fluoro-2-deoxy-D-glucose–positron emission tomographic (FDG-PET) and RECIST response (P 1⁄4 0.014 and P 1⁄4 0.019) and longer progression-free survival (P 1⁄4 0.050)
Summary
Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 1.2 million deaths annually [1]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The majority of patients with NSCLC are diagnosed with inoperable, metastatic disease. In these patients, 5-year survival rates are around 2% [1]. The signaling pathway regulated by the EGF receptor (EGFR) is an important axis in the pathogenesis of lung cancer, and EGFR mutations are found in 10% to 20% of lung adenocarcinomas [2, 3]. Erlotinib (TARCEVA) is designed to inhibit the tyrosine kinase activity of EGFR, and erlotinib treatment has been shown to prolong survival of patients with advanced NSCLC who have failed at least one round of prior chemotherapy [4]. Previous phase II studies in NSCLC have shown signs of www.aacrjournals.org
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