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

Angelo Gámez-Pozo, Ramón M Pérez Carrión, Luis Manso, Carmen Crespo, Cesar Mendiola, Rocío López-Vacas, Julia Berges-Soria, Isabel Álvarez López, Mireia Margeli, Juan L Bayo Calero, Xavier González Farre, Ana Santaballa, Eva M Ciruelos, Ruth Afonso, Juan Lao, Gustavo Catalán, José V Álvarez Gallego, José Miramón López, Francisco J Salvador Bofill, Manuel Ruiz BorregoEnrique Espinosa, Juan A Fresno Vara, Pilar Zamora

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)e109611
JournalPloS one
Issue number10
Publication statusPublished - 2014


  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized/therapeutic use
  • Breast Neoplasms/drug therapy
  • 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


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