Detection of Circulating Giant Cancer Associated Macrophage like Cells During and after Radiation Therapy Is Associated with Disease Progression in Thoracic Cancers

Abstract

Personalizing therapy in cancer patients requires individualized determination of the likelihood of cancer progression after start of therapy. We assessed the predictive value of circulating giant cancer associated stromal cell type called Cancer Associated Macrophage-Like cells (CAMLs) in predicting disease progression or death during and after definitive radiotherapy in non-small cell lung cancer (NSCLC) and esophageal cancer (EC). This is a 2-year prospective, single blinded study to assess the role of CAMLs in determining progression free survival (PFS) in patients after completing definitive radiotherapy or chemoradiotherapy. We have previously described that CAMLs ≥50 μm found in pretreatment samples, which we call giant CAMLs, were strongly prognostic. This has led us to hypothesize that giant CAMLs that are detected throughout therapy will also be predictive of disease progression. For this, we analyzed 52 NSCLC (stage I, n=7, stage II, n=7, stage III, n=29, and stage IV, n=9) and 21 esophageal cancer (stage III n=20 and Stage IV (n=1) patients. Baseline (BL) blood sample was obtained prior to start of radiation, a 2nd blood sample (T1) was taken midway during therapy and a 3rd sample (T2) was taken at the end of radiotherapy. Peripheral blood was processed using CellSieve® microfiltration and CAML size was determined. CAMLs <49 or ≥50 μm sizes were quantified but the observer was blinded to the disease type or clinical information. This measure was used to evaluate PFS hazard ratios (HRs) by censored univariate & multivariate analysis at each time point. CAMLs were found in 97% of all BL samples. On average 2.9 CAMLs/7.5 mL of blood were found. Giant CAMLs at BL had significantly reduced PFS for NSCLC (HR=2.9, 95%CI 1.3-6.2, p=0.015) and marginally for EC (HR=3.0, 95%CI 0.9-9.9, p=0.14). At T1, patients with detectable giant CAMLs further reduced PFS after treatment (NSCLC, HR=5.0, 95%CI 2.3-10.9, p<0.001; EC, HR=4.0, 95%CI 1.2-13.2, p=0.05), and even more significantly at T2 (NSCLC, HR=7.1, 95%CI 3.4-14.8, p<0.001; EC, HR=5.6, 95%CI 1.6-18.8, p=0.01). Combining the two disease data sets, giant CAMLs at BL was 70% accurate at predicting eventual progression within 24 months while giant CAMLs at T2 was 84% accurate at predicting progression. On multivariable analysis, giant CAMLs was the most significant independent prognostic factor, regardless the site of disease. Our data suggests monitoring the presence of giant CAMLs throughout the course of radiotherapy could be predictive of cancer progression or death. Prospective validation of giant CAMLs as a blood-based biomarker to stratify patient risk is needed to individualize cancer therapies in disease subtypes.