PI3K/Akt/mTOR Pathway in HER2-positive Invasive Breast Carcinoma. An Immunohistochemical and Molecular Analysis
G Peiro, L Sanchez-Tejada, E Lerma, FI Aranda, J Sanchez-Paya, E Adrover. Hospital General Universitari, Alacant, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Background: Increased activity of PI3K/Akt signaling pathway due to the interaction between growth factor receptors and tumor suppressor genes has been shown in a number of human cancers. Recent mutational analyses of PIK3CA (3q26.3), which encodes the PI3K catalytic subunit p110, have suggested increasing also the PI3K activity inducing oncogenic transformation. PI3K/Akt pathway alterations in HER2-positive invasive breast carcinomas (IBC) according to the hormone receptor status have not been extensively evaluated.
Design: Tissue microarrays were constructed from pre-selected tumor areas of 185 IBC HER2-positive, determined by immunohistochemistry (IHC) and/or molecular (CISH and/or FISH in cases with <30% positive tumor cells) methods. Further IHC was performed to study the expression of p110, phospho-Akt (Ser473) and mTOR (Ser2448), IGF1R, ER and PTEN. The data were scored semiquantitatively based on staining intensity (0-3+) and distribution (0-100%) (score 0-300). We performed a mutational analysis of PIK3CA gene G1624A (E542K) and G1633A (E545K) in exon 9 (helical domain), and A3140G (H1047R) in exon 20 (kinase domain) from 80 tumors by allelic discrimination based on real-time chemistry TaqMan MGB probes in ABIPrism 7500 Sequence Detection System (Applied Biosystems). Direct DNA sequencing at exons 9 and 20 in ABIPrism 310 confirmed all positive samples. The results were correlated to standard clinical-pathological parameters.
Results: Mean follow-up was 73 months (SD +/-52 months); 16% of patients were younger than 40 years. Tumors were more frequently >2cm in size (53%), of ductal type (96%), grade 3 (67%), showing 55% necrosis and 56% vascular invasion. ER-positive was found in 43%, loss of PTEN in 20%, increased IGF1R in 63%, p110 in 36%, p-Akt in 65% and p-mTOR in 42% cases. PIK3CA mutations were detected in 17.5% (14/80) cases, predominantly at exon 20 (10/14; 71.4%). HER2/ER-positive tumors showed lower grade, increased IGF1R and p110, and PTEN was present (p<0.02). However, no association was observed with the levels of p-Akt, p-mTOR, PIK3CA mutations or the other clinical-pathological factors (all p>0.05).
Conclusions: IGF1R and PTEN are involved in the PI3K/Akt pathway aberrations playing a distinct role in the pathogenesis of HER2/ER-positive IBC. Apparently, PIK3CA mutations, more frequently present in exon 20, have different functional effects in this subset of tumors. Supported by grant FIS 06/1495.
Monday, March 9, 2009 1:00 PM
Poster Session II # 29, Monday Afternoon