Methylation patterns of circulating cell-free DNA to detect treatment related organ specific adverse effects in esophageal cancer patients

Background/ Objective: Thoracic high dose radiation therapy (RT) for cancer has been associated with the development of late cardiac toxicity. The purpose of this study was to characterize the onset of cardiac, lung and brain adverse events of thoracic radiation therapy in combination with chemotherapy by using clinical observations of outcomes and changes in circulating, cell-free DNA methylation patterns in patient serum before, during and after treatment.

Materials/ Methods: We enrolled 11 patients with distal esophageal cancer who were treated with neoadjuvant chemoradiation to 50.4 Gy with concurrent carboplatin and taxol followed by esophagectomy. Subjects underwent fasting blood draw and cardiac MRI prior to the initiation of RT and 4-6 months following RT. Quantitative parameters of cardiac function including brain natriuretic peptide (BNP), and C-reactive protein (CRP). Deep sequencing of tissue-specific DNA amplicons generated from bisulfite treated, circulating cell-free DNA (cfDNA) was used to detect signs of organ damage as a result of the treatments. cfDNA amplicons with the specific methylation patterns were quantified relative to non-specific cfDNA amplicons from the respective genomic loci to derive a measure of tissue damage.

Results and Conclusions: Organ specific change in cfDNA methylation patterns indicative of tissue damage were detectable after radiation and chemotherapy. We will discuss the potential value and further development needed to use methylated cfDNA biomarkers as a basis to access organ specific adverse events during and after cancer treatment.