Retrospective comparison between breast cancer tissue- and blood-based next-generation sequencing results in detection of PIK3CA, AKT1, and PTEN alterations

Breast Cancer Res. 2025 Jul 1;27(1):122. doi: 10.1186/s13058-025-02055-0.

Abstract

Background: Based on the CAPItello-291 phase III trial results, capivasertib in combination with fulvestrant has been approved for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer harboring one or more PIK3CA, AKT1, and/or PTEN alterations. Given the growing interest in circulating tumor DNA (ctDNA) next-generation sequencing (NGS) to detect PIK3CA/AKT1/PTEN alterations, we retrospectively compared blood-based FoundationOne®Liquid CDx versus tumor tissue-based FoundationOne®CDx real-world data from patients with various breast cancer subtypes.

Methods: We utilized a database of patients profiled with FoundationOne®CDx and/or FoundationOne®Liquid CDx during routine clinical care. Analytical comparison of all pathogenic alterations in PIK3CA, AKT1, AKT2, AKT3, and PTEN, including alterations defined in the CAPItello-291 protocol (CAPItello-defined alterations), was performed in paired data from 289 patients with both tissue and liquid biopsies sampled within 90 days of each other.

Results: Overall positive percent agreement (PPA) for short variants across ctDNA tumor fraction (TF) subgroups in paired biopsy samples was: ctDNA TF ≥ 10%: PIK3CA, 93.9%; AKT1, 100%; PTEN, 100%; ctDNA TF 1%-10%: PIK3CA, 96.3%; AKT1, 100%; PTEN, 100%; ctDNA TF < 1%: PIK3CA, 34.7%; AKT1, 50.0%; PTEN, 37.5%. PPA for CAPItello-defined alterations was: ctDNA TF ≥ 10%: 92.5%; ctDNA TF 1%-10%: 97.1%; ctDNA TF < 1%: 33.9%. For PTEN homozygous deletions, PPA was 50.0% in cases with ctDNA TF ≥ 10%. Overall PPA for AKT2 and AKT3 copy number variations (CNVs) was 66.7% and 0%, respectively.

Conclusions: Blood-based NGS could offer a minimally invasive option to identify clinically relevant PIK3CA/AKT1/PTEN short variants in cases with ctDNA TF ≥ 1%. Confirmatory tissue-based NGS should be performed when blood-based NGS results are negative, especially when ctDNA TF is < 1% and for enhanced detection of CNVs in general.

Keywords: AKT inhibitor; Breast cancer; Capivasertib; Circulating tumor DNA; HR-positive/HER2-negative; Next-generation sequencing; Targeted therapy.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor* / blood
  • Biomarkers, Tumor* / genetics
  • Breast Neoplasms* / blood
  • Breast Neoplasms* / diagnosis
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics
  • Class I Phosphatidylinositol 3-Kinases* / genetics
  • Female
  • High-Throughput Nucleotide Sequencing* / methods
  • Humans
  • Middle Aged
  • Mutation
  • PTEN Phosphohydrolase* / genetics
  • Proto-Oncogene Proteins c-akt* / genetics
  • Retrospective Studies

Substances

  • PTEN Phosphohydrolase
  • PIK3CA protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • AKT1 protein, human
  • PTEN protein, human
  • Circulating Tumor DNA
  • Biomarkers, Tumor