Data from PI3K Pathway Activation in High-Grade Ductal Carcinoma <i>In Situ</i>—Implications for Progression to Invasive Breast Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma <i>in situ</i> (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.</p><p><b>Experimental Design:</b> Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of <i>PIK3CA</i> and <i>AKT1</i> hotspot mutations.</p><p><b>Results:</b> Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that <i>PIK3CA</i> hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (<i>P</i> values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a <i>P</i> value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the <i>in situ</i> and invasive components of cases of DCIS and adjacent IBC. Analysis of the <i>PIK3CA</i>-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which <i>PIK3CA</i> mutations were either restricted to the DCIS or to the invasive components.</p><p><b>Conclusion:</b> Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). <i>Clin Cancer Res; 20(9); 2326–37. ©2014 AACR</i>.</p></div>