The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.
<h4>Background</h4>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 trea...
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oai:doaj.org-article:96570f731e5b47eda63fe7f906eaa8722021-11-25T05:55:52ZThe Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.1932-620310.1371/journal.pone.0109611https://doaj.org/article/96570f731e5b47eda63fe7f906eaa8722014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0109611https://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Angelo Gámez-PozoRamón M Pérez CarriónLuis MansoCarmen CrespoCesar MendiolaRocío López-VacasJulia Berges-SoriaIsabel Álvarez LópezMireia MargeliJuan L Bayo CaleroXavier González FarreAna SantaballaEva M CiruelosRuth AfonsoJuan LaoGustavo CatalánJosé V Álvarez GallegoJosé Miramón LópezFrancisco J Salvador BofillManuel Ruiz BorregoEnrique EspinosaJuan A Fresno VaraPilar ZamoraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e109611 (2014) |
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Medicine R Science Q 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 Borrego Enrique Espinosa Juan A Fresno Vara Pilar Zamora The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| description |
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| format |
article |
| author |
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 Borrego Enrique Espinosa Juan A Fresno Vara Pilar Zamora |
| author_facet |
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 Borrego Enrique Espinosa Juan A Fresno Vara Pilar Zamora |
| author_sort |
Angelo Gámez-Pozo |
| title |
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| title_short |
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| title_full |
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| title_fullStr |
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| title_full_unstemmed |
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| title_sort |
long-her study: clinical and molecular analysis of patients with her2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/96570f731e5b47eda63fe7f906eaa872 |
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