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Molecular Signature for Neuroendocrine Prostate Cancer Represents Progress

Researchers have defined an 81-feature molecular signature to identify neuroendocrine prostate cancer—an aggressive and rapidly progressing type of prostate cancer that is increasingly being recognized in patients with advanced disease and signals poor overall survival. This molecular signature relies heavily on epigenetic alterations in the prostate.

Neuroendocrine prostate cancer is characterized by the presence of visceral metastasis, low prostate-specific antigen levels, and low or absent androgen receptor expression, and is generally insensitive to hormone therapy. Thus far, reliable biomarkers that can help identify neuroendocrine prostate cancer are lacking, and the diagnosis remains challenging.

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

The researchers performed whole-­exome sequencing of 124 biopsies that were obtained from the metastatic tumors of 81 patients (35 had morphologic features of neuroendocrine prostate cancer). The biopsies underwent integrative genomic profiling, DNA and RNA analyses, and analyses of epigenetics and methylation. Biopsies from patients with neuroendocrine prostate cancer were compared with those from patients with castration-resistant prostate cancer (CRPC).

Few significant differences were found in the mutational landscapes of neuroendocrine prostate cancer, and CRPC. The loss in RB1 was observed in 70% of patients with neuroendocrine prostate cancer versus in 32% of patients with CRPC; TP53 mutations or deletions were observed in 66.6% versus 31.4% of patients, respectively.

No androgen receptor gene alterations or point mutations were seen in patients with neuroendocrine prostate cancer versus 13% of patients with CRPC.

A significant overlap was observed in the genomic landscapes of neuroendocrine prostate cancer and CRPC. Serial biopsies taken during disease progression showed that the 2 entities share common genetic alterations.

“Genomic changes do not sufficiently explain transformation from CRPC to neuroendocrine prostate cancer. Methylation and epigenetics may be better at classifying and distinguishing between them,” said lead investigator Himisha Beltran, MD, Assistant Professor, Urology, Weill Cornell Medical College, NY.

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

The next step is to use the signature in noninvasive liquid biopsies of patients with CRPC to look for the emergence of features of neuroendocrine prostate cancer. This molecular signature may help identify patients with androgen receptor–independent CRPC who are at risk for progression and neuroendocrine prostate cancer. The molecular signature can also be used for research purposes in studies.

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