Prospective Characterization of Circulating Tumor Cell Kinetics in Patients with Localized Lung Cancer Treated with Radiotherapy or Chemoradiotherapy with Definitive Intent

Abstract

To characterize circulating tumor cell (CTC) kinetics in response to definitive therapy in patients with local or locoregional lung cancer and identify CTC kinetic profiles associated with favorable disease response versus progression. In this single-institution prospective correlative biomarker study, we enrolled patients receiving definitive intent radiotherapy (RT) or chemoradiotherapy for non-metastatic lung cancer. Blood specimens were collected prior to RT (baseline), during RT and at follow up visits up to 24 months post RT. Subsequent lines of therapy were administered per standard of care. CTCs were captured and enumerated using a previously reported nanotechnology-based assay functionalized with aEpCAM, aHER-2, and aEGFR to facilitate biomimetic cell rolling and dendrimer-mediated multivalent binding. Disease status was assessed per RECIST 1.1 criteria. CTC kinetics and absolute values were analyzed to identify patterns associated with disease control versus progression. We enrolled 24 patients with median follow up of 8 months corresponding to 114 CTC measurements. Seven patients (30%) had biopsy proven disease, while 17 (70%) were diagnosed based on clinical and radiographic features alone. Nineteen patients (79%) received stereotactic body radiation therapy. Median baseline CTC count was 12.6 CTCs/ml (range 0-290) and post RT decreased to median 4 CTCs/ml (0-42.7). For 95% of patients, a favorable kinetic profile (defined as stable CTC count, decreased CTC count or <24 CTCs/ml corresponding to the 80th percentile) during radiotherapy or at the time of first follow up corresponded to local control of the irradiated lesion. Five patients (20%) experienced disease progression within the follow up period. In the two patients with local progression of the irradiated lesion, the CTC count rose >10 fold prior to or at the time of radiographic detection of progression. In the three patients with systemic progression, CTC count rose 1.46-5.8-fold at the time of progression. Notably, four of the five patients with disease progression did not have initial biopsy confirmation of disease but did experience a CTC elevation at the time of progression. Our data suggests CTCs may serve as a biomarker for response to therapy in patients being treated with RT with definitive intent for early stage or locally advanced lung cancer. This finding is of importance given important limitations in obtaining pathologic confirmation of disease in select patients and challenges distinguishing disease progression versus benign post radiotherapy radiographic changes. Further studies are needed to characterize the predictive and prognostic value of circulating biomarker levels and kinetics in lung cancer.