Abstract

The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.

Highlights

  • The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear

  • We demonstrated the clinical significance of the burden of on-treatment hotspot mutations: PIK3CA Ex9:p.Glu542Lys/Val, Glu545Val/Gly/Ala/Gln/ Lys and Gln546Leu/Arg/Pro/Glu/Lys and PIK3CA Ex20:p.His1047Leu/Arg/Tyr and Gly1049Arg/Ser and AKT1:p.Glu17Lys, and ESR1:p.Tyr537Ser/Asn and Asp538Gly in cell-free DNA (cfDNA) in comparison with estrogen receptor (ER)+ primary BC (PBC) patients in each TL of ER+ metastatic BC (MBC) patients using multiplex droplet digital PCR assays

  • Plasma PIK3CA mutations were found in 15.1% (11/73) of the PBC patients, the plasma AKT1 mutation was detected in 1.4% (1/73), and the plasma ESR1 mutations were observed in 2.7% (2/73) (Additional file 1: Table S2)

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Summary

Introduction

The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. * Correspondence: hiwase@kumamoto-u.ac.jp 1Department of Breast and Endocrine surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan Full list of author information is available at the end of the article magnitude of PI3K/AKT activation [1]. Recent digital PCR assays on plasma cell-free DNA (cfDNA) of several cohorts demonstrated the difference in the clinical features between the representative hotspot mutations in MBC, PIK3CA and ESR1 mutations [6–10].

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