Landscape of circulating tumour DNA in metastatic breast cancer

Andrew A. Davis, Saya Jacob, Lorenzo Gerratana, Ami N. Shah, Firas Wehbe, Neelima Katam, Qiang Zhang, Lisa Flaum, Kalliopi P. Siziopikou, Leonidas C. Platanias, William J. Gradishar, Amir Behdad, Massimo Cristofanilli*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background: We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer. Methods: 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed. Findings: 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1, and TP53. For HER2+, these were TP53, PIK3CA, and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA, and the most frequent CNVs were MYC, CCNE1, and PIK3CA. TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients (P<0.05). Overall, alterations in PIK3CA, ESR1, and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79–91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging (P<0.0001). Interpretation: These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging. Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422.

Original languageEnglish (US)
Article number102914
JournalEBioMedicine
Volume58
DOIs
StatePublished - Aug 2020

Keywords

  • Circulating tumour DNA
  • Genomics
  • Metastatic breast cancer
  • Next-generation sequencing
  • cell-free DNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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