PI3K Pathway Activity and Response to First-Line Chemotherapy in Combination with Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer.

Abstract

Abstract Background. Not all patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) respond to trastuzumab and most that initially respond, ultimately develop resistance to treatment. Activated PI3K signalling has been proposed to predict trastuzumab resistance.Patients and Methods. PI3K pathway activity was evaluated in tumor samples from pts with HER2-overexpressing MBC treated with first-line chemotherapy in combination with trastuzumab by: a) assessing PIK3CA mutation status by our recently developed High Resolution Melting Analysis (HRMA) for the detection of mutations in exons 9 and 20, performed in the HR-1 High Resolution Melter (Idaho Technology, USA) and b) PTEN expression levels using immunohistochemical analysis. All samples with mutant melting transitions were verified by DNA sequencing. PI3K pathway activation defined by the presence of PIK3CA hotspot mutations and/or low or absent PTEN was correlated to the response to trastuzumab-based therapy.Results. Fifty-six pts received trastuzumab in combination with vinorelbine (n=15) or taxane-based chemotherapy (n=41). Median age was 62 years, 55 pts (98.2%) had PS 0-1, 10 (17.9%) were premenopausal, 27 (48.2%) had hormone receptor negative tumors and 37 (66.1%) had visceral metastases. HRMA identified the presence of PIK3CA mutations in 22 (39.3%) pts [exon 9 mutations in 5 (8.9%) and exon 20 mutations in 17 (30.4%) pts]. Subsequent PIK3CA sequence analysis demonstrated exon 9 mutations (E542K and E545K) in 4 (7.1%) pts and exon 20 mutations in 17 (30.4%; H104R in 16, and H1047L in 1) corresponding to a PIK3CA hotspot mutation frequency of 35.7%. Only in one sample that showed a mutant melting transition by HRMA, DNA sequencing did not confirm the presence of a PIK3CA mutation in exon 9, possibly due to lower sensitivity. Absent or reduced PTEN expression was detected in 22 (39.3%) of 47 pts. In 9 (16.1%) pts, PTEN score could not be retrieved. A trend for lower response rates was observed for patients with PI3K hotspot mutations compared to pts with wild-type tumors (35% vs 60%, p= 0.074). No difference in response rates was identified for pts with low or absent compared to normal PTEN expression (p=0.920). However, activated PI3K pathway (presence of PI3K mutations and/or low or absent PTEN expression) was associated with significantly lower response rates compared to non-activated one (40.6% vs 72.2%; p=0.032).Conclusions. The activation of PI3K pathway is predictive of response to first-line chemotherapy plus trastuzumab in pts with HER2-overexpressing MBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2022.