July 09, 2018
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Deadly subtype makes up 17% of metastatic prostate cancers

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Treatment-emergent small cell neuroendocrine prostate cancer, a particularly deadly subtype of the disease, occurs in nearly one-fifth of all cases of metastatic, castration-resistant prostate cancer, study data showed.

Researchers suggested that the subtype should be treated with novel targeted therapies that are currently in the development or testing phase.

“Think of advanced, hormone treatment-resistant prostate cancers as a pie,” Rahul Aggarwal, MD, assistant professor of medicine at University of California, San Francisco, said in a press release. “Instead of treating these advanced cases homogenously as we do with today’s standard treatments, we want to split the pie according to tumor characteristics, and develop treatment protocols tailored to individual slices, based on the cancer’s distinctive growth-driving genetic mutations and gene expression patterns.”

Androgen receptor-targeting therapies have provided significant clinical benefit for metastatic castration-resistant prostate cancer. However, a subset of patients who experience therapeutic resistance to this therapy develop a new histologic subtype — treatment-emergent small cell neuroendocrine prostate cancer — that resembles the highly aggressive de novo small cell subtype.

Aggarwal and colleagues evaluated the prevalence and characteristics of this treatment-emergent subtype to inform tumor classification, clinical recommendations and future therapies.

The researchers performed metastatic tumor biopsies on 202 patients with castration-resistant prostate cancer. All biopsy specimens were independently reviewed and underwent DNA/RNA sequencing.

Seventy-three percent of patients (n = 148) experienced progression after being treated with abiraterone (Zytiga, Janssen) and/or enzalutamide (Xtandi, Astellas).

Seventy-nine percent of biopsies were evaluable.

The overall incidence of detected treatment-emergent small cell neuroendocrine prostate cancer was 17%.

Androgen receptor amplification occurred in 67% of treatment-emergent small cell neuroendocrine prostate cancer biopsies, and androgen receptor protein expression was present in 75%.

Similar proportions of the disease subtype occurred in bone, node and visceral organ biopsies.

Alterations in DNA repair pathway genes — such as BRCA1, BRCA2, ATM, CDK12, RAD51, PALB2, FANCA, CHEK2, MLH1, MSH2, MLH3 and MSH6 — were “almost entirely mutually exclusive” with treatment-emergent small cell neuroendocrine prostate cancer tumors (8% vs. 40%; P = .035).

Treatment-emergent small cell neuroendocrine prostate cancer was associated with a shorter OS among men who had received previous androgen receptor-targeting therapy (HR = 2.02; 95% CI, 1.07-3.82).

Researchers used unsupervised hierarchical clustering of the transcriptome to identify “a small cell-like cluster” that appeared associated with worsened survival (HR = 3; 95% CI, 1.25-7.19).

Aggarwal and colleagues developed a transcriptional signature for treatment-emergent small cell neuroendocrine prostate cancer and validated the signature with greater than 90% accuracy.

The researchers identified several transcriptional regulators of the disease subtype, identifying the pancreatic neuroendocrine marker PDX1 as the most active.

“With novel therapies in clinical development, there is the potential to improve disease outcomes for this high-risk and increasingly prevalent subset of metastatic castration-resistant prostate cancer,” the researchers wrote. – by Andy Polhamus

Disclosures: The authors report no relevant financial disclosures.