Key Molecular Alteration in The PI3K/Akt mTOR Pathway among Egyptian Women With Early Breast Cancer : A Clinico-Molecular Study

Abstract

The PI3K/AKT/mTOR pathway alterations have significant roles in the development, progression and metastatic potential of breast cancer in addition to enhancing resistance to many of the drugs used to control breast cancer, specially anti hormonal therapies. In this study we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules of this pathway in the samples of Egyptian patients with luminal breast cancer. Methods Next generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 10 and 21). Immunohistochemistry (IHC) was performed on TMA blocks prepared from samples of 35 operable luminal (ER positive and HER2 negative) breast cancer patients who presented for postoperative treatment at Cairo University hospitals between 2007 and 2011. The intensity and the percentage of stained tumor cells were taken into consideration in defining high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Correlation was done between PI3K mutations and the IHC expression of pAKT, LKB1, p4EBP1 and pS6 ribosomal protein (pS6RP) expression with the clinico-pathologic parameters using Pearson’s chi-square test. Kaplan-Meier (KM) method was used to estimate disease free survival (DFS) and the difference between the subgroups was evaluated with log-rank test. Results Thirty two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP and 24 were assessed for PI3K mutations. Median age at diagnosis was 51.3 years (range: 25 to 82 years). Tumors were larger than 20 mm in 79.2% and 57.9% had axillary lymph node (LN) metastasis. Only 3.5% of the patients had SBR grade I tumors, 71.9% grade II tumors and 24.6% grade III tumors. Estrogen receptors (ER) were found to be