Association of concurrent AURKA and MYCN amplification in primary prostate adenocarcinoma with the development of lethal neuroendocrine prostate cancer (NEPC).

TitleAssociation of concurrent AURKA and MYCN amplification in primary prostate adenocarcinoma with the development of lethal neuroendocrine prostate cancer (NEPC).
Publication TypeJournal Article
Year of Publication2012
AuthorsBeltran H, Park K, Tagawa ST, Macdonald T, Nanus DM, Mosquera JMiguel, Rubin MA
JournalJ Clin Oncol
Volume30
Issue5_suppl
Pagination120
Date Published2012 Feb 10
ISSN1527-7755
Abstract

120 Background: NEPC is an aggressive variant of prostate cancer that most commonly arises from prostate adenocarcinoma (PCA), with likely clonal origin. There is currently no effective therapy with most patients surviving < 1 yr. Recent work identified overexpression and amplification of Aurora kinase A (AURKA) and N-myc (MYCN) in metastatic NEPC, evidence that they cooperate to directly induce a NE phenotype in PCA, and are targetable with Aurora kinase inhibitor therapy (AKI) (Beltran et al). NEPC xenografts demonstrate dramatic and preferential sensitivity to AKI therapy with complete reversal of NE marker expression. We evaluated primary prostate tumors of patients that later developed lethal NEPC for presence of AURKA and MYCN alterations.

METHODS: 226 primary PCA tumors were evaluated, of which 57 tumors were from patients with NEPC. 22 benign prostate and 57 metastatic NE carcinomas from prostate (38) or other primary site were also evaluated. Histology, immunohistochemistry (IHC), Fluorescence In Situ Hybridization (FISH) were performed and correlated with clinical variables (ie, Gleason, PSA, OS).

RESULTS: AURKA and concurrent MYCN amplification were identified by FISH in 75% of primary PCA of patients with NEPC (> 95% cells). In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in 5% of 169 cases. These results are independent of NE marker expression by IHC. In only one case did MYCN gain occur in absence of AURKA amplification. When metastatic NEPC was compared to primary PCA in same patient, there was 100% concordance of AURKA and MYCN amplification. In prostate tumors with mixed features, there was 94% concordance between NEPC and PCA. 0% benign prostate and 40% metastatic NEPC harbored AURKA and MYCN amplifications.

CONCLUSIONS: AURKA and MYCN amplification occurs early and are nearly always concurrent despite separate chromosomes. Their presence in primary PCA identifies patients predisposed to the development of an aggressive lethal NEPC variant. These patients may benefit from early intervention with AKI therapy. Therefore, AURKA and MYCN amplification may be new prognostic and predictive biomarkers.

DOI10.1200/jco.2012.30.5_suppl.120
Alternate JournalJ. Clin. Oncol.
PubMed ID28143260