Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 177, Issue 4, Pages 1647-1656Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.090885
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Funding
- NIH [P30-CA 16672]
- M.D. Anderson Cancer Center [P50 CA116199]
- Breast Cancer Research Foundation [RO1-CA112567]
- DOD Center of Excellence [W81XWH-06-2-0033]
- DOD [W81XWH-08-1-0712]
- Susan G. Komen Breast Cancer Foundation [KG091020]
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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 path-way activation plays a pivotal role in trastuzumab resistance. Our findings may facilitate the evaluation of tumor response to trastuzumab-based and targeted therapies. (Am J Pathol 2010, 177:1647-1654. DOI: 10.2353/ajpath.2010.090885)
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