title: Oncogenic PIK3CA mutations in lobular breast cancer progression.
abstract: Infiltrating lobular breast cancer (ILBC) is a tumor-biologically distinct breast cancer subtype. A high frequency of oncogenic PIK3CA mutations has been reported in ILBC, which may allow for targeted therapy with newly developed PI3K inhibitors. This is of particular clinical relevance for ILBC patients, who have failed to respond to current treatment regimes and suffer from tumor recurrence or dissemination. In anticipation of this therapeutic strategy, we investigated PIK3CA mutations in ILBC with special reference to late stage tumor progression. A total of 88 ILBCs from 73 patients, including primary tumors (PTs, n = 43), ipsilateral locally recurrent tumors (LRTs, n = 15), and distant organ metastases (DOMs, n = 30), were compiled on tissue microarrays. Established ILBC marker proteins were evaluated by immunohistochemistry and PIK3CA hot spot mutations in exons 9 and 20 by direct sequencing. Matched PT/LRT, PT/DOM, and DOM/DOM cases were characterized on a patient-by-patient basis. Following correction for redundant patient representations, mutation frequencies were compared in PTs versus LRTs or DOMs. Nearly all specimens were E-cadherin-negative (99%), estrogen receptor (ER)-positive (91%), and lacked basal epithelial markers (100%), demonstrating correct ILBC classification. PIK3CA mutations were detected in 32/88 (36%) specimens. The mutation rate was similar in PTs (33%) and DOMs (26%, P = 0.769), but approximately two-fold increased in LRTs (69%, P = 0.022). Consistently, matched PT/LRT and LRT/DOM cases showed additional PIK3CA mutations in LRTs. Intriguingly, these findings imply that PIK3CA mutations are positively selected for during ILBC progression to local recurrence but not distant metastasis, which may have clinical implications for PI3K inhibitor-based therapy.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany. Christgen.Matthias@MH-Hannover.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Christgen
authors.forename: Monika
authors.initials: M
authors.lastname: Noskowicz
authors.forename: Elisa
authors.initials: E
authors.lastname: Schipper
authors.forename: Henriette
authors.initials: H
authors.lastname: Christgen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Heil
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
mesh_terms: D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D018450:Disease Progression; D005260:Female; D005557:Formaldehyde; D006651:Histocytochemistry; D006801:Humans; D009154:Mutation; D016612:Paraffin Embedding; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics*; D015203:Reproducibility of Results; D046888:Tissue Array Analysis; D016707:Tissue Fixation
chemical_list: D014408:Biomarkers, Tumor; D005557:Formaldehyde; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human