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.
Angiogenesis Inhibitors
/ therapeutic use
Biomarkers, Tumor
/ genetics
Breast Neoplasms
/ drug therapy
Circulating Tumor DNA
/ genetics
Female
Humans
Mutation
/ genetics
Paclitaxel
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ genetics
Ribosomal Protein S6 Kinases, 70-kDa
/ genetics
Toluidines
AKT
breast cancer
circulating tumor DNA
copy number alterations
low-coverage whole genome sequencing
survival
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
07
01
2022
received:
30
11
2021
accepted:
03
02
2022
pubmed:
6
2
2022
medline:
24
5
2022
entrez:
5
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35122700
doi: 10.1002/1878-0261.13188
pmc: PMC9120890
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Biomarkers, Tumor
0
Circulating Tumor DNA
0
Protein Kinase Inhibitors
0
Toluidines
0
amitraz
33IAH5017S
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Ribosomal Protein S6 Kinases, 70-kDa
EC 2.7.11.1
Paclitaxel
P88XT4IS4D
Banques de données
ClinicalTrials.gov
['NCT01980277']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2057-2070Informations de copyright
© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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