The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy

PLoS One. 2014 Oct 20;9(10):e109611. doi: 10.1371/journal.pone.0109611. eCollection 2014.

Abstract

Background: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.

Methods: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.

Results: 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.

Conclusions: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Gene Expression Profiling
  • Genomics
  • Humans
  • Middle Aged
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptor, ErbB-2 / metabolism*
  • Retrospective Studies
  • Survivors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Trastuzumab
  • Treatment Failure

Substances

  • Antibodies, Monoclonal, Humanized
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Receptor, ErbB-2
  • Trastuzumab

Grant support

The Long-HER study was supported by an unrestricted grant from Roche. AGP (CA12/00258) and RLV (CA12/00264) are supported by Instituto de Salud Carlos III, Spain. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript.