The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers

Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016/j.ccell.2018.08.008.

Abstract

We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.

Keywords: breast cancer; cancer genomics; endocrine resistance; integrative genomics analysis; metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Breast Neoplasms, Male / drug therapy
  • Breast Neoplasms, Male / genetics*
  • Breast Neoplasms, Male / pathology
  • Drug Resistance, Neoplasm / genetics*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Humans
  • MAP Kinase Signaling System / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism
  • Prospective Studies
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Young Adult

Substances

  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • NF1 protein, human
  • Neurofibromin 1
  • Receptors, Progesterone
  • estrogen receptor alpha, human
  • ERBB2 protein, human
  • Receptor, ErbB-2