A new UC San Francisco study of prostate cancer in 202 men found that a surprisingly large number of these cancers — about 17% — belong to a deadlier subtype of metastatic prostate cancer.
All of the men’s cancers had spread and were resistant to standard treatment,
Previously, it was thought that these cancers constituted less than 1% of all prostate cancers.
The study shows that this prostate cancer subtype, called treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC), might in the future be routinely and more successfully treated with targeted drugs that already are being developed or tested in clinical trials.
The research team identified specific genetic mutations and patterns of gene expression that are found in t-SCNC, but are distinct from the more common type of prostate cancer known as adenocarcinoma.
Among the patterns identified in t-SCNC was higher activity of specific “transcription factor” proteins — proteins that switch on production of other proteins that drive cancer growth.
Two of the transcription factors over-activated in t-SCNC are targets of drugs already in clinical trials, with several more in pre-clinical testing.
In contrast, mutations that previously have been discovered to play a role in many adenocarcinomas were almost never present in t-SCNC, the researchers found.
Treatments targeting specific mutations in prostate cancer are not yet available in standard practice, which relies on hormonal treatment and chemotherapy as the mainstays of treatment.
However, as the number of targeted treatments available for cancer grows, genetic analysis of tumors is expected to become increasingly valuable in helping to guide treatment.
The American Cancer Society estimates that 29,430 men will die from prostate cancer in 2018, making it second only to lung cancer as a cause of cancer death among U.S. men.
About one in 10 prostate cancers has spread beyond the prostate at the time of initial diagnosis and is more difficult to treat successfully.
In these advanced cancers, additional mutations and alterations in gene expression patterns give rise to treatment-resistant tumor cells.
These treatment-resistant cells and the clones they generate through cell division live on and enable the tumor to grow again, according to the team.
The pattern of gene mutations observed in the study suggests that t-SCNC in these advanced cases of treatment-resistant prostate cancer arises from a pre-existing adenocarcinoma.
The study, which was undertaken by a consortium of five different academic medical centers, enrolled patients at the time their cancers were discovered to have become resistant to conventional hormonal treatment, known as androgen deprivation therapy.
Among patients who had previously stopped responding to second-line hormonal treatment with abiraterone or enzalutamide — drugs usually administered when initial hormone therapy fails — men with the t-SCNC subtype survived on average just 36.6 months, compared to 44.5 months for men without t-SCNC.
Three-quarters of men in the study had received one or both these drugs.
In 160 of the men, there was enough tumor in biopsy specimens to classify the cancer, which was done independently by three different pathologists blinded to clinical and genetic characteristics of the cancers.
They found t-SCNC in specimens from 27 of these men.
The researchers surveyed genetic mutations and gene activation within tumor cells and identified patterns of genetic mutations that were associated with t-SCNC and with worse survival.
The team suggests that it is important to provide hormonal therapy in metastatic prostate cancer, because these hormonal treatments prolong survival.
But they are not curative. In nearly every patient the cancer will become resistant to these treatments. It’s just a matter of when.
They believe the emergence of t-SCNC is one important mechanism through which they evolve and evade treatment.
The study was funded by the Prostate Cancer Foundation, Movember, and Stand Up To Cancer through a Stand Up To Cancer Dream Team Award, which Small led.
The study is published in the Journal of Clinical Oncology.
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News source: UCSF.
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