Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2-negative breast cancer and has been implicated in taxane resistance. Results from the phase IB/II TAKTIC trial (NCT01980277) indicate that combining an orally administered dual inhibitor of AKT and p70 ribosomal protein S6 kinase (p70S6K) (LY2780301) with weekly paclitaxel is feasible in advanced HER2-negative breast cancer, showing initial signs of efficacy. Here, we investigated whether circulating tumor DNA (ctDNA) could serve as a surrogate marker for treatment response in this context. Serial plasma samples were collected, and cell-free DNA was sequenced using low-coverage whole-genome sequencing, complemented by droplet digital polymerase chain reaction (PCR) analysis for patients with driver mutations. We compared baseline tumor fraction (TF) and TF after 7 weeks of treatment with progression-free survival (PFS) and overall response rate. Additionally, we explored circulating copy number alterations associated with treatment resistance.

Among the 51 patients enrolled, plasma samples were available for 44 cases (96 timepoints). All patients with tumor mutations in TP53, PI3KCA, or AKT1 exhibited at least one corresponding alteration in plasma. Baseline TF correlated with PFS (6-month PFS: 92% for ctDNA-negative vs. 68% for ctDNA-positive patients; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34-8.90], P = 0.007). However, ctDNA status at week 7 did not show prognostic significance. Although most circulating copy number alterations persisted at disease progression, specific genomic regions were altered in post-progression samples.

In summary, detection of ctDNA at baseline was associated with shorter PFS in patients from the TAKTIC trial. Analysis of plasma-based copy number alterations may aid in identifying mechanisms of treatment resistance.