Abstract
Phosphatase and tensin homolog (PTEN) is a key modulator of trastuzumab sensitivity in HER2-overexpressing breast cancer. Because PTEN opposes the downstream signaling of phosphoinositide 3-kinase (PI3K), we investigated the role of PTEN and other components of the PI3K pathway in trastuzumab resistance. We analyzed the status of PTEN, p-AKT-Ser473, and p-p70S6K-Thr389 using immunohistochemistry. PIK3CA mutation status was analyzed by direct sequencing. Primary tumor tissue was available from 137 patients with HER2-overexpressing metastatic breast cancer who had received trastuzumab-based chemotherapy. We observed that each of the four biomarkers alone did not significantly correlate with trastuzumab response, whereas PTEN loss alone significantly correlated with shorter survival times (P = 0.023). PI3K pathway activation, defined as PTEN loss and/or PIK3CA mutation, was associated with a poor response to trastuzumab (P = 0.047) and a shorter survival time (P = 0.015). PTEN loss was significantly associated with a poor response to trastuzumab (P = 0.028) and shorter survival time (P = 0.008) in patients who had received first-line trastuzumab and in patients with estrogen receptor- (P = 0.029) and progesterone receptor-negative tumors (P = 0.033). p-AKT-Ser473 and p-p70S6K-Thr389 each had a limited correlation with trastuzumab response. When these markers were combined with PTEN loss, an increased correlation with patient outcome was observed. In conclusion, PI3K pathway activation plays a pivotal role in trastuzumab resistance. Our findings may facilitate the evaluation of tumor response to trastuzumab-based and targeted therapies.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adult
-
Aged
-
Antibodies, Monoclonal / therapeutic use*
-
Antibodies, Monoclonal, Humanized
-
Bone Neoplasms / drug therapy
-
Bone Neoplasms / mortality
-
Bone Neoplasms / secondary
-
Brain Neoplasms / drug therapy
-
Brain Neoplasms / mortality
-
Brain Neoplasms / secondary
-
Breast Neoplasms / drug therapy
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / mortality*
-
Carcinoma, Ductal, Breast / drug therapy
-
Carcinoma, Ductal, Breast / metabolism
-
Carcinoma, Ductal, Breast / mortality
-
Carcinoma, Lobular / drug therapy
-
Carcinoma, Lobular / metabolism
-
Carcinoma, Lobular / mortality
-
Class I Phosphatidylinositol 3-Kinases
-
Female
-
Humans
-
Immunoenzyme Techniques
-
In Situ Hybridization
-
Liver Neoplasms / drug therapy
-
Liver Neoplasms / mortality
-
Liver Neoplasms / secondary
-
Lung Neoplasms / drug therapy
-
Lung Neoplasms / mortality
-
Lung Neoplasms / secondary
-
Lymphatic Metastasis
-
Middle Aged
-
Mutation / genetics
-
Neoplasm Invasiveness
-
PTEN Phosphohydrolase / genetics*
-
PTEN Phosphohydrolase / metabolism
-
Phosphatidylinositol 3-Kinases / genetics*
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphorylation
-
Prognosis
-
Proto-Oncogene Proteins c-akt / metabolism*
-
Receptor, ErbB-2 / genetics
-
Receptor, ErbB-2 / metabolism
-
Receptors, Estrogen / metabolism
-
Receptors, Progesterone / metabolism
-
Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
-
Survival Rate
-
Trastuzumab
-
Young Adult
Substances
-
Antibodies, Monoclonal
-
Antibodies, Monoclonal, Humanized
-
Receptors, Estrogen
-
Receptors, Progesterone
-
Phosphatidylinositol 3-Kinases
-
Class I Phosphatidylinositol 3-Kinases
-
PIK3CA protein, human
-
Receptor, ErbB-2
-
Proto-Oncogene Proteins c-akt
-
Ribosomal Protein S6 Kinases, 70-kDa
-
PTEN Phosphohydrolase
-
PTEN protein, human
-
Trastuzumab