TY - JOUR
T1 - The Long-HER study
T2 - clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy
AU - Gámez-Pozo, Angelo
AU - Pérez Carrión, Ramón M
AU - Manso, Luis
AU - Crespo, Carmen
AU - Mendiola, Cesar
AU - López-Vacas, Rocío
AU - Berges-Soria, Julia
AU - López, Isabel Álvarez
AU - Margeli, Mireia
AU - Calero, Juan L Bayo
AU - Farre, Xavier González
AU - Santaballa, Ana
AU - Ciruelos, Eva M
AU - Afonso, Ruth
AU - Lao, Juan
AU - Catalán, Gustavo
AU - Gallego, José V Álvarez
AU - López, José Miramón
AU - Bofill, Francisco J Salvador
AU - Borrego, Manuel Ruiz
AU - Espinosa, Enrique
AU - Vara, Juan A Fresno
AU - Zamora, Pilar
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antibodies, Monoclonal, Humanized/therapeutic use
KW - Breast Neoplasms/drug therapy
KW - Gene Expression Profiling
KW - Genomics
KW - Humans
KW - Middle Aged
KW - Mutation
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Receptor, ErbB-2/metabolism
KW - Retrospective Studies
KW - Survivors
KW - TOR Serine-Threonine Kinases/metabolism
KW - Time Factors
KW - Trastuzumab
KW - Treatment Failure
U2 - 10.1371/journal.pone.0109611
DO - 10.1371/journal.pone.0109611
M3 - Article
C2 - 25330188
SN - 1932-6203
VL - 9
SP - e109611
JO - PloS one
JF - PloS one
IS - 10
ER -
