Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients

J Transl Med. 2022 May 13;20(1):211. doi: 10.1186/s12967-022-03421-8.

Abstract

Background: The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized.

Methods: Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance.

Results: Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications.

Conclusions: This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression.

Trial registration: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529 .

Keywords: Advanced breast cancer; Next generation sequencing; Survival outcomes; Tumor mutation burden; ctDNA fraction.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Breast Neoplasms* / genetics
  • Circulating Tumor DNA* / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA Copy Number Variations
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mutation / genetics
  • Prognosis
  • Triple Negative Breast Neoplasms*

Substances

  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Class I Phosphatidylinositol 3-Kinases

Associated data

  • ClinicalTrials.gov/NCT03792529