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

Renaud Sabatier, Cécile Vicier, Séverine Garnier, Arnaud Guille, Nadine Carbuccia, Nicolas Isambert, Florence Dalenc, Marie Robert, Christelle Levy, Jihane Pakradouni, José Adelaïde, Max Chaffanet, Patrick Sfumato, Emilie Mamessier, François Bertucci, Anthony Goncalves, Renaud Sabatier, Cécile Vicier, Séverine Garnier, Arnaud Guille, Nadine Carbuccia, Nicolas Isambert, Florence Dalenc, Marie Robert, Christelle Levy, Jihane Pakradouni, José Adelaïde, Max Chaffanet, Patrick Sfumato, Emilie Mamessier, François Bertucci, Anthony Goncalves

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 [CI] [1.34-8.90], 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 at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma-based copy number analysis may help to identify alterations involved in resistance to treatment.

Keywords: AKT; breast cancer; circulating tumor DNA; copy number alterations; low-coverage whole genome sequencing; survival.

Conflict of interest statement

A.G. declares nonfinancial support from Novartis. R.S. declares research grants from EISAI and AstraZeneca; advisory board for Roche, GSK, and Novartis; nonfinancial support (travel, accommodation and meeting registration fees) was from Pfizer, Roche, GSK, BMS, and AstraZeneca. The other authors declare no conflicts of interest.

© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Figures

Fig. 1
Fig. 1
Study flow diagram detailing the patients included in this ancillary analysis and the number of samples evaluated at each timepoint.
Fig. 2
Fig. 2
Kaplan–Meier curves for progression‐free survival (PFS) according to baseline circulating tumor fraction (TF). Patients with TF > 0 (red line) display a worse PFS than patients with TF = 0 (blue line). Wald test P‐value.
Fig. 3
Fig. 3
Tumor fraction dynamics under treatment. Data for patients with at least baseline and End of Treatment (EoT) ctDNA samples available are represented (N = 19). Blue: responders to paclitaxel‐LY2780301 according to RECIST 1.1 criteria; red: nonresponders to paclitaxel‐LY2780301. Triangles represent cases with tumor progression at time of EoT visit; circles represent cases without tumor progression at time of EoT visit.
Fig. 4
Fig. 4
Correlation of baseline tumor and plasma CNA profiles in patients with tumor fraction >0. Analysis was performed using discrete values. Each row/line represents a baseline tumor sample (analyzed with aCGH) or a baseline plasma sample (analyzed with LC‐WGS). Positive correlations are displayed in blue and negative correlations in red, with 1 (dark blue) as the highest correlation. Circles size and color intensity are proportional to the correlation coefficient.

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