Association of PIK3CA Mutations in Exon 9 with Luminal Immunophenotype Breast Carcinoma
L Sanchez-Tejada, FJ Gutierrez-Avino, FI Aranda, J Segui, E Lerma, D Giner, G Peiro. Hospital General Universitari, Alacant, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Background: The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in human cancers. The most frequent reported mutations are G1624A (E542K) and G1633A (E545K) in exon 9 (helical domain), and A3140G (H1047R) in exon 20 (kinase domain). The aim of our study was to investigate the relationship between the presence of PIK3CA mutations and tumor characteristics in a series of Luminal A and B, and HER2+ immunophenotypes of breast carcinoma (BC).
Design: In this control-case study, we analyzed PIK3CA mutations in 373 human BC samples: 146 Luminal A (ER and PR >50% positive nuclei; and p53 <20% or Ki67 <20%), 47 Luminal B (ER and/or PR <50%, and p53 >20% or Ki67 >20%), and 180 HER2+ (>30% 3+ or amplified by FISH). We used allelic discrimination based on real-time chemistry TaqMan MGB probes in ABI Prism 7500 Sequence Detection System (Applied Biosystems). Direct DNA sequencing of exons 9 and 20 in ABI Prism 310 confirmed all positive samples. Immunohistochemical (IHC) staining was performed in whole sections for HER2, ER and PgR (cut-off 10%), Ki-67, p53 (cut-off 20%) and Bcl2 (cut-off 50%). Chi-square and Fisher's exact tests were used for statistical analysis of qualitative variables and T-Student test or U. Mann-Whitney test for quantitative variables.
Results: We identified PIK3CA mutations in 25.2% (94/373) tumors: 30.6% in Luminal subtypes and 19.4% in HER2+ (p=0.013; OR:1.824 (1.129-2.947)). Stratification of Luminal tumors into A and B versus HER2+ showed mutations in 31.5%, 27.7% and 19.4%, respectively (p=0.041). Mutations in exon 9 (G1624A and G1633A) were more frequently detected in Luminal than in HER2+ tumors (p=0.057 and p=0.006, respectively) but no differences were found for those in exon 20 (A3140G) (p=ns). Mutated phenotype correlated negatively with the proliferation marker Ki-67 (p= 0.007) (with a median of 10% (range 5-20%) for mutated, and 17% (range 8-27%) for wild-type cases); and positively with Bcl2 expression (p=0.014, OR:1.860 (1.131-3.059)). Interestingly, the presence of mutations was associated with bilateral tumors (p=0.021, OR=0.208 (0.048-0.901)).
Conclusions: Our findings show that PIK3CA mutations in exon 9 (G1624A and G1633A), are associated with good prognostic factors, such as Luminal A and B immunophenotypes BC, low proliferation index and Bcl2 overexpression. Supported by Grant FIS 06/1495, and FCVI-HGUA (2009 PI-C/03).
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 5, Wednesday Afternoon