Molecular Signature for Neuroendocrine Prostate Cancer Represents Progress

September 2015, Vol 6, No 8

Boston, MA—Researchers have defined an 81-feature molecular signature to identify neuroendocrine prostate cancer (NEPC), an aggressive and rapidly progressing entity that is increasingly being recognized in patients with advanced disease and signals poor overall survival. The signature, derived from genomic, transcription, and methylation analysis, relies heavily on epigenetic alterations.

NEPC is characterized by the presence of visceral metastasis, low prostate-specific antigen (PSA) levels, low or absent androgen receptor (AR) expression, and is generally insensitive to hormone therapy. Thus far, reliable biomarkers are lacking for NEPC, and diagnosis remains challenging.

“This is the largest study to date focused on the molecular landscape of NEPC, and it provides novel insights about the biology of this entity. We need to develop a molecular signature that can distinguish NEPC from adenocarcinoma,” stated Terence W. Friedlander, MD, Assistant Clinical Professor of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, who discussed this abstract at the 2015 Best of ASCO meeting.

The authors of this abstract, originally presented at the 2015 ASCO annual meeting, performed whole-exome sequencing of 124 biopsies obtained from metastatic tumors from 81 patients (35 had morphologic features of NEPC). The biopsies underwent integrative genomic profiling, DNA and RNA analysis, and analysis of epigenetics and methylation. NEPC biopsies were compared with castration-resistant prostate cancer (CRPC) biopsies.

Few significant differences were found in mutational landscape between NEPC and CRPC. RB1 loss was observed in 70% of NEPC versus 32% of CRPC (P = .003); TP53 mutations or deletions were observed in 66.6% versus 31.4%, respectively (P = .04). No AR gene alterations or point mutations were seen in NEPC versus 13% of CRPC (P = .0075).

A significant overlap was observed in the genomic landscape of NEPC and CRPC. Serial biopsies taken during disease progression showed that the 2 entities share common genetic alterations, which suggests a branched evolutional pattern and divergent clonal evolution with a common CRPC ancestor, rather than a linear pattern, Dr Friedlander noted.

“Genomic changes do not sufficiently explain transformation from CRPC to NEPC. Methylation and epigenetics may be better at classifying and distinguishing between them,” said lead investigator Himisha Beltran, MD, Assistant Professor of Medicine in Urology, Weill Cornell Medical College, NY, speaking at the annual meeting.

The research team found epigenetically dysregulated pathways in NEPC related to epithelial mesenchymal transition and neuron differentiation.

The molecular signature for NEPC, based on DNA, methylation, and mRNA, was then validated in more than 500 cases of local and advanced prostate cancer. Precision and recall was 99% in identifying cases of NEPC in this discovery data set. The signature was also validated in 2 other smaller data sets.

The next step is to use the signature in noninvasive liquid biopsies of patients with CRPC to look for emergence of NEPC features. This signature may help identify patients with AR-independent CRPC at risk for progression and NEPC. The signature can also be used for research purposes as part of studies.

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