Abstract P2-08-03: Phosphatidylinositol-3-kinase mutations are common in lobular neoplasia
Authors: Troxell ML , Ang D , Warrick A , Beadling C , Corless CL 
Published: August 2014

Abstract
The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated in invasive breast carcinoma, with PIK3CA mutations present in ∼25% of invasive carcinomas, and several studies demonstrating an even higher prevalence of PIK3CA mutations in invasive lobular carcinomas. Lobular neoplasia (LN), including lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH), are controversial lesions that may represent non-obligate precursor of invasive lobular carcinoma. However, lobular neoplasia has not yet been systematically studied for activating point mutations.
Twenty-six breast resection specimens containing LN and/or invasive lobular carcinoma (ILC) were identified from the files of Oregon Health & Science University. Adjacent lesions including columnar cell change (CCC), usual ductal hyperplasia (UDH), invasive or in-situ ductal carcinoma, and lymph node metastases were separately isolated where available. DNA was prepared from punches of formalin-fixed paraffin-embedded tissue blocks using standard methods. DNA extracts were screened for a panel of point mutations using a multiplex PCR panel with a mass-spectroscopy readout (Sequenom MassArray). The panel covers 643 point mutations in 53 genes including AKT1/2/3, ALK, BRAF, CDK4, CSF1R, CTNNB1, EGFR, ERBB2, ERCC6, FBX4, FBXW7, FES, FGFR1/2/3/4, FOXL2, GNA11, GNAQ, GNAS, HRAS, IDH1/2, IGF1R, KDR, KIT, KRAS, MAPK2K1/2/7, MET, MYC, NEK9, NRAS, NTRK1/2/3, PDGFRA, PIK3CA, PIK3R1/4/5, PKHD1, PRKCB1, RAF1, RET, SMO, SOS1, STAT1, TEC, and TP53; covering 41 substitutions in 23 codons of the PIK3CA gene.
PIK3CA mutations were identified in 8/22 LN (36%; PIK3CA exon 4 N345K-1; exon 9 E542K-1; E545K-3; exon 20 H1047R-3), and in 11/16 ILC (68%; PIK3CA exon 4 N345K-2; exon 9 E542K-1, E545K-2, Q546R-1; exon 20 H1047L-1, H1047R-4, one with concomitant HRAS G12D mutation). LN and coincident ILC were tested in 11 patients; 4 patients had the same point mutations in LN and ILC (concordant mutant); 4 patients were wildtype for all codons tested in LN and ILC (concordant wildtype); 3 patients had discordant mutation status (LCIS-E545K/ILC-H1047R; LCIS-E542K/ILC-H1047R; ALH-WT/ILC-H1047R & HRAS G12V). Four patients had LN and invasive ductal carcinoma (IDC); of these, 2 were discordant (LCIS-H1047R/IDC-wildtype; ALH-wildtype/IDC-E545K) and 2 concordant wildtype. Two additional patients had discrete IDC and ILC tumors; in both the IDC was wildtype, but the ILC harbored a PIK3CA mutation. Concurrent CCC and UDH were also screened, yielding 10/22 (45%) lesions with PIK3CA point mutations; in 3 instances the UDH mutation was concordant with LN/ILC, whereas CCC from the same specimen has discordant mutational status.
Our study confirms the high prevalence of PIK3CA hotspot point mutations in ILC (68%). Importantly, we screened LCIS and ALH for a large panel of point mutations, and found only PIK3CA mutations (36% of lesions). Although a small cohort, the mutation status of concurrent LN and ILC was frequently concordant (8/11=72%), and in fact, quite similar to the degree of mutational concordance between paired DCIS and IDC in the literature and in our own experience (66–77%). This provides some support to the notion of LN as a precursor to ILC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-08-03.