TY - JOUR
T1 - PTEN, PIK3CA, p-AKT, and p-p70S6K status
T2 - Association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer
AU - Esteva, Francisco J.
AU - Guo, Hua
AU - Zhang, Siyuan
AU - Santa-Maria, Cesar
AU - Stone, Steven
AU - Lanchbury, Jerry S.
AU - Sahin, Aysegul A.
AU - Hortobagyi, Gabriel N.
AU - Yu, Dihua
N1 - Funding Information:
Supported in part by NIH grants P30-CA 16672 (MDACC), M.D. Anderson Cancer Center Breast SPORE P50 CA116199 (project 4), and the Breast Cancer Research Foundation (F.J.E) ; RO1-CA112567 , DOD Center of Excellence grant subproject W81XWH-06-2-0033 , DOD Synergistic Award W81XWH-08-1-0712 , and Susan G. Komen Breast Cancer Foundation Promise grant KG091020 (D.Y.). D.Y. is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at M.D. Anderson Cancer Center.
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.090885
DO - 10.2353/ajpath.2010.090885
M3 - Article
C2 - 20813970
AN - SCOPUS:77957352037
SN - 0002-9440
VL - 177
SP - 1647
EP - 1656
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -