Abstract S1-5: PIK3CA mutations are linked to PgR expression: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) pathology study.
Authors: Sabine VS , Crozier C , Drake C , Piper T , van de Velde CJH , Hasenburg A , Kieback DG , Markopoulos C , Dirix L , Seynaeve C , Rea D , Bartlett JMS 
Published: August 2014

Background: PIK3CA is mutated in about 26% of breast cancers (BC) and is the most frequently mutated gene in (BC). Almost 95% of mutations occur in exons 9 (E9) or 20 (E20). PIK3CA mutations may be associated with increased survival in endocrine-treated patients; however the impact of mutations in E9 vs E20 is not clear. We assessed 10 common PIK3CA mutations (95% of all mutations), in ER-positive (+ve) samples from the TEAM pathology study (n = ∼4500), and determined the impact of PIK3CA mutations on survival. We report an interim analysis of 1969 TEAM cases.

Methods: DNA was extracted from formalin-fixed paraffin embedded sections. Mutational analyses were performed on 25 mutations in 6 genes (PIK3CAx10, Akt1x1, KRASx5, HRASx3, NRASx2 & BRAFx4), using Sequenom MassArray.

Results: Mutations were found in PIK3CA: 37.5%; Akt1: 3.3%; KRAS: 0.3%; and BRAF: 0.1% of cases. No mutations were found in HRAS or NRAS (n = 1969). 90% of PIK3CA mutations were located in E9 and E20. Outcome data was available for 1958/1969 patients. Patients whose tumours contained any PIK3CA mutations (n = 739) were at lower risk of distant metastasis, Hazard ratio=0.86 (0.67–1.11), when compared to those without PIK3CA mutations (n = 1219); although this difference was not statistically significant (Cox Regression; p = 0.24). PIK3CA mutations were significantly more frequent in HER2-negative (−ve) (39%) than in HER2+ve samples (25%) (p = 0.001), without evidence that PIK3CA mutations differentially impacted outcome in HER2+ve vs HER2-ve patients. A positive correlation was demonstrated between PIK3CA mutations and PgR Allred score (p = 0.002) but not ER Allred score (p = 0.37). With increasing PgR Allred score increase there is an increased frequency of mutations in E20 but not E9 (Table 1).

Discussion: This study indicates a higher percentage of PIK3CA mutations in ER+ve BC samples than previously demonstrated, either for BC as a whole or for ER+ve cases, suggesting that in ER+ve early BC, PIK3CA mutations are more common than previously reported.

Furthermore, increased PIK3CA mutation frequency is significantly associated with increasing PgR Allred score and this appears solely due to increased numbers of patients with E20 mutations further complicating the analysis of the impact of PIK3CA mutations in BC. This may explain current uncertainty regarding the impact of PIK3CA mutations in E9 vs E20 with respect to clinical outcome. Whilst we were unable to show a significant impact on outcome in patients whose tumours contained PIK3CA mutations, we believe the complex relationship between PgR expression (good prognosis indicator) and PI3K mutations requires further exploration in the full dataset using interaction techniques adjusting for the impact of PgR on outcome.

Mutational analysis and correlation with clinical outcome data for the remaining ∼2500 DNA samples, along with the existing data for 1969 patients, will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-5.