Acute circulating tumor DNA dynamics during and after infusional therapy initiation.

Abstract

1099 Background: For patients with advanced breast cancer, the proportion of tumor-derived DNA in circulation (‘tumor fraction’/TF) has been shown to be prognostic. There is evidence that early change in TF may correlate with response to therapy, potentially providing a rapid, minimally-invasive predictive biomarker. However, there is little known regarding TF dynamics during and in the hours immediately after infusion of targeted or cytotoxic therapies, including whether there is a ‘surge’ in ctDNA corresponding to acute cell death. We hypothesized that tracking TF change peri-infusion would provide insight regarding acute ctDNA dynamics. Methods: Banked plasma samples were derived from a phase 1b trial of HSP90 inhibitor onalespib with paclitaxel in patients with advanced triple negative breast cancer. Plasma was collected during the first cycle of therapy on study pre-infusion, end-of-infusion (EOI), then 0.5/1/2/4/6/8/24 hours post-infusion for 1) onalespib alone (day -7); 2) paclitaxel alone 7 days later (day 1); 3) onalespib+paclitaxel 7 days later (day 8) for a total of maximum 26 time points per patient. 317 samples from 14 patients underwent shallow whole genome sequencing (sWGS) and TF determination. The objective was to evaluate change in TF from pre-infusion to 6-hours and 24-hours post-infusion. Exploratory objectives included association of TF dynamics with progression-free survival (PFS) and overall survival (OS). Results: 313/317 (98.7%) of available plasma samples completed sWGS. Of these, 104/313 (33.2%) were collected on onalespib alone, 114/313 on paclitaxel alone (36.4%), and 95/313 (30.4%) on onalespib+paclitaxel. For the co-primary objectives, there was a significant decline in TF from pre-infusion to 6 hours for paclitaxel alone (Wilcoxon signed rank p = 0.03) but no significant change for onalespib alone/onalespib+paclitaxel or from pre-infusion to 24 hours for any treatment group (all Wilcoxon signed rank p > 0.05). There was a significant decline in TF from pre-infusion day -7 (median TF 16%) to 24 hours after C1D8 (median TF 6.5%, Wilcoxon signed rank p = 0.004). Baseline TF≥20% was associated with significantly worse PFS (log-rank p = 0.002) with a trend toward worse OS (log-rank p = 0.067) but categorization of TF change using ctDNA-RECIST was not associated with significant differences in PFS or OS. Conclusions: In this study of > 300 plasma timepoints during the first cycle of treatment on a phase Ib clinical trial, there was no significant ‘surge’ in ctDNA TF within minutes to 24 hours of infusion of onalespib, paclitaxel or both in combination. However, there was a significant decline in TF over the first full cycle of therapy. This suggests that despite ctDNA half-life of minutes-to-hours, consistent change in TF may not be detectable for days or weeks, providing important insight in the design of studies evaluating ctDNA change as a minimally-invasive biomarker.