Determination of chemotherapy response in pancreatic cancer (PDAC) relies on imaging such as CT or MRI scan, where reliable results can be obtained not earlier than 12 weeks after treatment start. Herein we report, that determination of cell-free DNA (cfDNA) can improve treatment monitoring and may allow prediction of treatment response after administration of the first cycle of chemotherapy.
26 patients with advanced PDAC were treated with the FOLFIRINOX regime. Cell-free DNA (cfDNA) was determined from blood samples before treatment start and before each cycle (d1 and d15) for 3 months. In a subset, cfDNA was also determined during first FOLFIRINOX administration after infusion of oxaliplatin and irinotecan (8hrs). Tumor status was evaluated before treatment start and after 3 month by CT scan. cfDNA was extracted from at least 2 mL of plasma and ≥10ng total cfDNA was used for sequencing library preparation. Sequencing reads, obtained with a NextSeq500 (Illumina) were mapped to the reference genome (HG19) and read counted in 701 bins of autosomes, with an average size of 5.5Mb. After normalization and transformation into log2 ratios, Z-values were calculated versus a healthy reference group (133 cfDNA samples). Z-Scores of bins significantly different from the reference were summed to generate the CNI-score.
The risk of patients (n = 11) with an elevated pre-therapeutic CNI-Score of > 200 for not responding to chemo was 82%. Patients with CNI-Score above the 95thpercentile of the reference population (CNI >24) after cycle 3, had a significantly higher risk to progress (80%), with a 73% accuracy of prediction (p = 0.03). The prediction of therapy failure was even better after 4 cycles with a 90% predictive value and an overall 83% accuracy (p = 0.02). In 13 patients CNI-score was determined after 8hrs of initiation therapy to assess a possible cytolytic tumor burst. Only patients showing a significant increase of CNI-scores, compared to pre-therapeutic values were responders (n = 2), one of three stable patients had a borderline burst, whereas all progressive patients (n = 8) did not show any sign of tumor burst.
Determination of cell free DNA represents a powerful tool to predict outcome very early during medical treatment of advanced PDAC.
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