PTEN, PIK3CA, p-AKT, and p-p70S6K status: Association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer

Francisco J. Esteva, Hua Guo, Siyuan Zhang, Cesar Santa-Maria, Steven Stone, Jerry S. Lanchbury, Aysegul A. Sahin, Gabriel N. Hortobagyi, Dihua Yu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1647-1656
Number of pages10
JournalAmerican Journal of Pathology
Volume177
Issue number4
DOIs
Publication statusPublished - Jan 1 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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