Abstract P3-05-03: Characterization of PIK3CA mutations in lobular breast cancer
Authors: Desmedt C , Metzger O , Fumagalli D , Brown D , Singhal S , Vincent D , Adnet P-Y , Smeets D , Bertucci F , Galant C , Salgado R , Veys I , Saini K , Pruneri G , Krop I , Winer E , Michiels S , Piccart M , Lambrechts D , Larsimont D , Viale G , Sotiriou C 
Published: August 2014

Abstract
Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) histotype, after invasive ductal carcinoma (IDC), representing ∼10-15% of the global BC population. The vast majority of ILC are estrogen receptor (ER)-positive. PIK3CA has been reported to be the most frequently mutated gene in ER-positive BC. However, until now PIK3CA mutations have mainly been described in IDC. In this study, we sought to characterize the type, prevalence, intra-patient (pt) mutational heterogeneity, and the association with transcriptomic phenotype and clinical outcome of PIK3CA mutations in ILC.
Methods: Gene expression data (HG-U133 Plus2.0) was generated from frozen samples of 116 ILC (primary tumors). For the same series, PIK3CA mutation profiling (Sequenom) was performed on at least 2 formalin-fixed paraffin embedded (FFPE) tissue blocks of the primary tumor for 102 cases, and on the only available block for the remaining 14 cases. Matched local recurrence (LR) and multiple metastatic (M) samples were also characterized for 3 and 8 pts respectively. For the transcriptomic and survival analyses, we evaluated the association between PIK3CA mutation status and gene signatures recapitulating important biological processes, and invasive disease-free & overall survival, respectively.
Results: PIK3CA mutations were detected in the primary tumor of 40/116 (35%) ILC pts: 14 (35%) mutations in the helical domain and 25 (62.5%) in the kinase domain. PIK3CA analysis in different blocks from the same primary tumors revealed a mutational heterogeneity in 7/102 (7%) cases. There was a discordance between primary and LR samples in 1/3 patients with LR, with a mutation reported in the primary but in not the LR. In 3/8 pts for which M samples were available, we observed intra-pt heterogeneity. In the first pt, a mutation in the kinase domain was reported only in 1/2 investigated blocks from the primary tumor, and in only 1/2 liver Ms. In the second pt, a mutation in the helical domain was found in the primary tumor and in the LR but not in the pleura M. In the third pt, although no mutation was observed in the primary tumor, a mutation in the helical domain was found in the M of the epiploon, but not in the Ms from the diaphragm or the ovary. Transcriptomic analyses revealed that primary tumors with a PIK3CA mutation in the helical domain were associated with increased levels of 2 stroma signatures (Bonferroni p-val: PLAU sign -Desmedt 2008–0.042 and DCN sign- Farmer 2009 – 0.048) compared to tumors without mutation. The survival analyses did not reveal any significant difference in survival between pts with and without a PIK3CA mutation.
Conclusions: This study represents the largest series described so far which investigated PIK3CA mutations in ILC. The incidence of PIK3CA mutations reported here is similar to the one reported for IDC. The investigation of multiple tumor samples per pt revealed intra-tumor as well as primary/recurrence heterogeneity. To get a definitive answer on the prognostic role of PIK3CA mutation in ILC, we are currently performing a PIK3CA mutation profiling study (Sequenom) on a series of ∼1000 consecutive ILC with long-term follow up (Iorfida et al. 2012); results will be available by SABCS2012.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-03.