CHICAGO – Researchers have identified a new histologic subset of metastatic castration-resistant prostate cancer called intermediate atypical carcinoma.
“Despite being cytologically bland, this is an aggressive cancer with shortened survival similar to that seen with small-cell neuroendocrine cancer,” study author Dr. Eric J. Small said at the annual meeting of the American Society of Clinical Oncology.
Patrice Wendling/Frontline Medical News
Dr. Eric J. Small
Therapies targeting the androgen receptor (AR) like abiraterone and enzalutamide have revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC), but resistance to these agents is near-universal and leads to progressive disease and death. At the same time, clinicians are seeing an increasing number of patients with small cell neuroendocrine prostate cancer (SCNC), Dr. Small, professor of medicine at the University of California, San Francisco, said.
As part of a larger project designed to understand the mechanisms of resistance to abiraterone (Zytiga) and enzalutamide (Xtandi) undertaken by the West Coast Prostate Cancer Dream Team, biopsies were performed of a metastatic site in about 160 eligible men with mCRPC.Most (58%) had a Gleason score of 8 or more at diagnosis; 40% had been treated with abiraterone, 10% with enzalutamide, and 17% with both.
Formalin-fixed paraffin-embedded tissue was collected for histologic evaluation by three independent pathologists. Fresh frozen tissue, which underwent laser capture microdissection, was used for genomic analysis.
As of May 1, 173 of 300 planned biopsies have been conducted. In the 160 samples evaluated to date, there was adequate tissue for analysis in 124, for a 78% biopsy success rate, he said.
Among the 124 evaluable biopsies, 35% were classified as pure adenocarcinoma and 13% as pure SCNC.
A novel subtype was identified in another 26% that “consisted of a pure population of cells that was distinct from adenocarcinoma and distinct from small cell neuroendocrine cancer. We have termed this group intermediate atypical carcinoma (IAC),” Dr. Small said.
The remaining quarter of biopsies was composed of mixed populations.
In addition to the independent review, a consensus meeting with two additional pathologists confirmed that this was a new, highly reproducible pathologic subclass, he said.
The researchers next sought to determine whether IAC is phenotypically distinct. A survival analysis was performed based on biopsy pathology and revealed that men who develop IAC have poor survival.
Indeed, survival with IAC (median 11.9 months) tracks with that of SCNC (median 6.6 months) and is distinct from adenocarcinoma, with a log-rank P value of .041, Dr. Small said. Further, when IAC and SCNC were grouped together, there was a dramatically different survival curve (median 8.9 months) than that seen with adenocarcinoma (P = .006).
An analysis using microresected samples indicated that IAC is also genomically distinct, he said. Small cell nuclear clusters showed enrichment of neuronal and cell cycle elements and downregulation of androgen-receptor elements and the immune system.
Based on these findings, machine learning was used to develop a 50-gene signature, with 88.3% accuracy to distinguish small cell from non–small cell histology and 78.5% accuracy to distinguish small cell or IAC histology from adenocarcinoma. The test is not clinically available at this time, but is being used to identify new therapeutic targets.
“We are actively identifying the unique features of this subtype that can be targeted with therapy,” Dr. Small said in an interview. “There is a huge unmet need, since no one knows how to treat these patients, who comprise a significant portion of patients.”
Indeed, in the analysis, IAC represented a fourth of all metastatic castration-resistant biopsies and when combined with small cell neuroendocrine cancer accounted for 40% of all samples.
“This comprises the single largest group of abiraterone- and enzalutamide-refractory patients,” he concluded. “The increasing use of highly potent AR-targeted therapy may contribute to the increasing frequency of this entity, although that is conjecture at this point and certainly ascertainment bias may play a role.”
Discussant Dr. Scott Tomlins, a pathologist from the University of Michigan in Ann Arbor, said one of the study’s major findings is that collecting tissue for comprehensive molecular analysis is feasible in the context of a well-funded, team-based infrastructure, adding that this will likely have to be the way going forward. Despite limited sample numbers, there also appears to be a “strong signal” that gene expression signatures can discriminate various subtypes.
The study was funded by StandUpToCancer, the Prostate Cancer Foundation, and American Association for Cancer Research. Dr. Small reported having no disclosures.
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