Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers

Ann Oncol. 2016 Oct;27(10):1860-6. doi: 10.1093/annonc/mdw286.


Background: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy.

Materials and methods: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models.

Results: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1).

Conclusions: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Keywords: ER; ESR1; IDO1; PIK3CA; breast cancer; metastatic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • DNA Copy Number Variations / genetics
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics*
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Receptors, Estrogen / genetics*
  • Transcriptome / genetics


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Neoplasm Proteins
  • Receptors, Estrogen
  • indoleamine 2,3-dioxygenase 1, human