New study "released Monday by researchers at the University of California at San Francisco." [1]
"The study looked at 202 men with prostate cancer that had spread beyond the prostate and was resistant to standard treatment. It found that about 17 percent of these cases of metastatic prostate cancer were a deadlier subtype with specific genetic mutations. Researchers previously believed that less than 1 percent of all prostate cancers were in that category."
One in six men in that sample.
"The findings ... suggest that this kind of cancer -- called treatment-emergent small cell neuroendocrine prostate cancer ... -- could be more successfully treated with targeted drugs."
Unfortunately, as treatment options become more & more sophisticated, resistant cells can become more & more difficult to manage.
It's a potential downside to early adoption of palliative therapies.
SAN FRANCISCO -- A deadly form of prostate cancer is far more common than previously thought, leading researchers to believe that more specific diagnoses could lead to better treatment and survival rates, according to a study released Monday by researchers at the University of California at San Francisco.
The study looked at 202 men with prostate cancer that had spread beyond the prostate and was resistant to standard treatment. It found that about 17 percent of these cases of metastatic prostate cancer were a deadlier subtype with specific genetic mutations. Researchers previously believed that less than 1 percent of all prostate cancers were in that category.
The findings, published in Journal of Clinical Oncology, suggest that this kind of cancer -- called treatment-emergent small cell neuroendocrine prostate cancer, or t-SCNC -- could be more successfully treated with targeted drugs.
``Think of advanced, hormone-treatment-resistant prostate cancers as a pie,'' said Dr. Rahul Aggarwal, assistant professor of medicine in the UCSF Division of Hematology and Oncology and one of the study's authors. ``Instead of treating these advanced cases homogeneously as we do with today's standard treatments, we want to split the pie according to tumor characteristics.''
That way, it may be possible to develop treatments tailored to individual tumors, based on their unique genetic mutations and other characteristics, he said.
In breast cancer, he said, there is already a clear understanding of subtypes, and different treatments are available for them.
``We're trying to get to that same place in prostate cancer,'' Aggarwal said.
He added that knowing the prevalence of this aggressive form of prostate cancer will help inspire trials to treat it.
Only men have a prostate, which is a gland related to semen production located just below the bladder.
Typically, prostate cancer is treated with hormones and chemotherapy, according to the study. In cancers resistant to conventional treatment, patients with t-SCNC died, on average, nearly eight months sooner after their treatment failed than those without that type of cancer.
Nearly 30,000 men die from prostate cancer each year, with about 1 in 10 cases spreading beyond the prostate at the time of diagnosis.
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"It's a potential downside to early adoption of palliative therapies." That is why I delayed palliative therapy for 17 years. For over 10 years the doctors wanted to put me on ADT. I am now on Lupron, Zytiga, and Prednisone for 6 months. It was time.
Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study.
Aggarwal R1, Huang J1, Alumkal JJ1, Zhang L1, Feng FY1, Thomas GV1, Weinstein AS1, Friedl V1, Zhang C1, Witte ON1, Lloyd P1, Gleave M1, Evans CP1, Youngren J1, Beer TM1, Rettig M1, Wong CK1, True L1, Foye A1, Playdle D1, Ryan CJ1, Lara P1, Chi KN1, Uzunangelov V1, Sokolov A1, Newton Y1, Beltran H1, Demichelis F1, Rubin MA1, Stuart JM1, Small EJ1.
Author information
Abstract
Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.
This paper describes me perfectly. It also makes me appreciate my oncologist and the time he is putting into my treatment planning. Hopefully the genetics done on my tumor will pay off. I continue, however, to be reminded that at this point my oncology care is considered palliative and not curative.
My pleural tumors did not change on the last PET scan so we will complete two more courses of current chemo and then if the scan is stable, take a chemo holiday and let my bone marrow recover. Pleural effusion is down to about 65 cc per day and tolerable.
It appears that with each cycle of any type of treatment, PCa becomes more aggressive. Although very frustrating, this makes sense from an evolutionary perspective. Each treatment puts a selective pressure on populations of PCa cells. PCa cells have a high mutation rate, hence the repeated recurrences. It would appear that efforts should be invested in keeping PCa cells in a dormant or suppressed state. Using AIDS treatments as an example, the therapies only became effective when a cocktail of three different drugs were used that affected the various stages of the viruses lifecycle. In the case of PCa, the cells have to be suppressed on as many fronts as possible. In my view, the goal is not to cure but to live with PCa. I hope this view does not unset too many people - it has taken me more than a year to reach this point after much reading. Phil
Also out this month is a German paper which claims that:
"Approximately 30-40% of patients with metastatic castration-resistant prostate cancer (mCRPC) also have neuroendocrine involvement."
"A t‑NEPC should be clinically suspected in patients who have particularly aggressive mCRPC but a disproportionately low prostate-specific antigen (PSA) level and elevated neuroendocrine tumor markers, such as chromogranin A and neuron-specific enolase."
"In patients with negative PSA levels, chemotherapy with cisplatin and etoposide is the first line treatment, for which response rates in the range of 30-60% with a median survival time of usually less than 1 year can be achieved."
Neuroendocrine prostate cancer (NEPC) mostly occurs as a treatment-emergent adaptive response under the pressure of intensive androgen deprivation treatment (t-NEPC). Approximately 30-40% of patients with metastatic castration-resistant prostate cancer (mCRPC) also have neuroendocrine involvement. In contrast primary small cell prostate cancer is very rare (<1%). A t‑NEPC should be clinically suspected in patients who have particularly aggressive mCRPC but a disproportionately low prostate-specific antigen (PSA) level and elevated neuroendocrine tumor markers, such as chromogranin A and neuron-specific enolase. The initial Gleason score was shown to be an independent factor correlated to the risk of development of t‑NEPC. Treatment is oriented to that of small cell lung cancer. In patients with negative PSA levels, chemotherapy with cisplatin and etoposide is the first line treatment, for which response rates in the range of 30-60% with a median survival time of usually less than 1 year can be achieved. In patients with much higher serum PSA levels, chemotherapy with carboplatin plus docetaxel should be considered.
"...with a median survival time of usually less than 1 year can be achieved..." That's not encouraging. Neither is my PSA of 2.7 / gleason 8 when diagnosed. I'm doing OK so far.
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