PI3K pathway activation in high-grade ductal carcinoma in situ-implications for progression to invasive breast carcinoma

Rita A. Sakr, Britta Weigelt, Sarat Chandarlapaty, Victor P. Andrade, Elena Guerini-Rocco, Dilip Giri, Charlotte K Y Ng, Catherine F. Cowell, Neal Rosen, Jorge S. Reis-Filho, Tari A. King

Research output: Contribution to journalArticle

Abstract

Purpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure highgrade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations. Experimental Design: 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 PIK3CA and AKT1 hotspot mutations. Results: 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 PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P 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 P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components. Conclusion: 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).

Original languageEnglish
Pages (from-to)2326-2337
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number9
DOIs
Publication statusPublished - May 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Sakr, R. A., Weigelt, B., Chandarlapaty, S., Andrade, V. P., Guerini-Rocco, E., Giri, D., Ng, C. K. Y., Cowell, C. F., Rosen, N., Reis-Filho, J. S., & King, T. A. (2014). PI3K pathway activation in high-grade ductal carcinoma in situ-implications for progression to invasive breast carcinoma. Clinical Cancer Research, 20(9), 2326-2337. https://doi.org/10.1158/1078-0432.CCR-13-2267