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Circulating tumor DNA (ctDNA) 'tumor fraction' (TF) may correlate with therapy response, but little is known regarding TF dynamics immediately after therapy initiation. Plasma samples from a single-arm clinical trial enrolling patients with triple-negative breast cancer were collected at a variety of time points following infusion of onalespib (day -7), paclitaxel (day 1), and onalespib + paclitaxel (day 8). 313 samples from 14 patients underwent shallow whole genome sequencing and TF determination. The primary objective was to evaluate TF change from pre-infusion to 6 h and 24 h post-infusion. There was significant TF decline from pre-infusion to 6 h for paclitaxel (p = 0.03) but no change for onalespib or onalespib+paclitaxel at 6hl. There was no ctDNA TF surge within minutes to 24 h of onalespib, paclitaxel, or combination, despite an overall decline in TF during the first therapy cycle. However, there was significant decline in TF from pre-infusion to D9 (16% to 6.5%, p = 0.004). These findings support further research on ctDNA dynamics immediately after therapy initiation.