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

Abstract

The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial (NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2-negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell-free DNA was sequenced using low-coverage whole-genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression-free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m-PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval ], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post-progression samples. In conclusion, ctDNA detection

The Clinical Utility of Droplet Digital PCR for Profiling Circulating Tumor DNA in Breast Cancer Patients

“… Mutation detection before neoadjuvant anti-HER2 therapies is associated with decreased pathological complete response. Sabatier et al, 2022 [ 121 ] R88Q, E542K, E545K, H1047L, H1047R, and TP53 and AKT1 mutations HER2 negative metastatic breast cancer ctDNA as surrogate marker of treatment efficacy within the phase IB/II TAKTIC trial in which patients received dual AKT and p70 ribosomal protein S6 kinase inhibitor in combination with paclitaxel. Progression-free survival at 6 months 92% for mutation negative patients and 68% for mutation positive cases at baseline.…”

“…ctDNA status at week 7 was informative on prognosis. The authors concluded that plasma-based ctDNA analysis may be useful in identifying alterations contributing to resistance development to therapy [ 121 ]. The impact of PIK3CA hotspot mutations (H1047R, E545K, and E542K) was also assessed on the everolimus efficacy, an mTOR inhibitor, in the BOLERO-2 trial by ddPCR.…”

“…As described above, few studies investigated TP53 mutations in plasma of BCa patients using ddPCR, doing so mainly in combination with PIK3CA [ 118 , 120 , 121 ]. In the work of Darrigues et al R175H and H179R mutations of TP53 along with PIK3CA and AKT1 hotspot mutations were used for serial monitoring of mBCa patients receiving palbociclib and fulvestrant.…”

“…ctDNA detection (e.g., PIK3CA and TP53 mutations) before NAC was found to be associated with decreased pCR rates [ 120 ]. In the phase IB/II TAKTIC trial in which AKT and p70 ribosomal protein S6 kinase inhibitor was combined with paclitaxel in patients with HER2-negative BCa, ctDNA detection—also including TP53 mutations by ddPCR at baseline—was predictive of shorter PFS [ 121 ].…”