Plasma cell-free tumor DNA, PIK3CA and TP53 mutations predicted inferior endocrine-based treatment outcome in endocrine receptor-positive metastatic breast cancer

Breast Cancer Res Treat. 2023 Oct;201(3):377-385. doi: 10.1007/s10549-023-06967-3. Epub 2023 Jun 21.

Abstract

Purpose: How to factor both tumor burden and oncogenic genomic mutations as variables to predict the outcome of endocrine-based therapy (ET) in ER-positive/HER2-negative metastatic breast cancer patients (MBC) remains to be explored.

Method: Blood samples prospectively collected from 163 ER-positive/HER2-negative female MBC patients, before ET, were used for cell-free tumor DNA (cfDNA) analysis. cfDNA was subjected to next-generation sequencing (NGS) to interrogate oncogenic PIK3CA hotspot and TP53 DNA-binding domain (DBD) mutations, including single nucleotide variants (SNVs) or small insertions and deletions (InDels). The variant calling threshold was set at 0.5%. Progression-free survival (PFS) was measured from the start of the ET treatment to the time of disease progression of the same treatment regimen.

Results: Overall, the median PFS was 8.3 months (95% CI 5.7-11.1 months). The median cfDNA was 38.5 ng (range 4.4-1935 ng). The proportion of patients with PIK3CA and TP53 alterations were 25.1 and 15.3%, respectively. Patients with high total cfDNA (HR 1.74, p = 0.003), PIK3CA mutation (HR 1.74, p = 0.007), and TP53 mutation (HR 1.64, p = 0.047) in liquid biopsy conferred worse outcome after ET. Even for patients with low tumor burden, the detrimental effect of PIK3CA or TP53 mutation remained significant (p < 0.001). For patients with either PIK3CA (p < 0.001) or TP53 mutation (p = 0.004), there was significant positive correlation between allele frequency (AF) and total cfDNA.

Conclusion: After adjustment of cfDNA level, PIK3CA and TP53 mutations observed in liquid biopsy exerted detrimental effects on the outcome of ET-based regimens. The AF of PIK3CA or TP53 may be a surrogate marker for PFS.

Keywords: Breast cancer; Cell-free tumor DNA; Endocrine receptor; Liquid biopsy.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Cell-Free Nucleic Acids*
  • Circulating Tumor DNA* / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Female
  • Humans
  • Mutation
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Circulating Tumor DNA
  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids
  • Class I Phosphatidylinositol 3-Kinases
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • PIK3CA protein, human