I was recently blindsided by my "under control" prostate cancer, turning into High Grade Neuroendocrine Prostate cancer (NEPC). After 13 years of various therapies, the last few years included Lupron/Eligard, Zytiga, Xtandi. This kept the PSA low (around .2) and kept my MO happy. In 2021, I asked my MO if I should be getting a scan. He said with the PSA that low, nothing would show up. So I went along with the plan (Lupron & Xtandi). A lump developed under my jaw this past August, which created the need for the scan. Followed by a biopsy, confirming NEPC. Now I'm on carboplatin, etoposide and Atezolizumab- chemotherapy and immunotherapy.
The following article from Healthline is a great description of what took place, and possibly why. The reason I'm posting this is it may be that our trusted hormone therapy medications could be a reason for PCa transitioning to NEPC. I wish I had this information for discussion with my MO quite awhile ago.
Yikes! Coincidentally I was talking to my medical oncologist recently about transition to neuroendocrinecancer. As we with metastatic prostate cancer all know, some kind of transition to resistance is inevitable. But we want to see how long we can put it off!
The article you shared is interesting but a little shallow. There is quite a lot of good research that is available for reading now, although unfortunately there aren't a lot of answers yet.
Concerning the article here though, it's also off-putting because it confuses (1) people with prostate cancer that is not metastatic and (2) people with prostate cancer which is metastatic.
There's a big difference between the two circumstances when considering something like neuroendocrine cancer.
Thank you Allen. I remember a post from you a while ago warning against "treating the PSA, not the cancer." I'm thinking that is what occurred with my MO. It is a rarity that Castrate resistant metastatic PCa morphs into NEPC- so we weren't watching for that. Thank you for the trials info, I'm sure that' will be on the agenda down the road.
Kudos to you for requesting the scan! Fortunately for you, t-NEPC seems to be less virulent than originally-diagnosed NEPC. I suspect, that much of its lethality is attributable to not being diagnosed early enough, because patients and their doctors grow complacent with low PSAs.
You may wish to get a second opinion from Rahul Aggarwal at UCSF. He seems to be a world expert in t-NEPC.
As a reminder to others, let me take this opportunity to reprint that section of the article on "treating PSA":
"I. Selecting for low PSA subtypes
For most men with advanced prostate cancer, PSA is their best biomarker of progression - more detected PSA means more progression. This may change as the cancer evolves. A highly mutated tumor may put out less PSA. Highly undifferentiated kinds of prostate cancer, and other relatively rare sub-types (e.g., ductal, neuroendocrine, basal cell, "double negative," etc.) may evince little or no serum PSA.
So it is possible, when such phenotypes are present and they are mixed with "normal" prostate cancer, to provide treatments that kill off the "normal" prostate cancer cells, leaving the low-PSA subtypes behind. Such a situation has been identified in patients heavily treated with chemo and enzalutamide. It is called "treatment-emergent neuroendocrine prostate cancer" (see this link) and has been identified in 17% of heavily-treated patients.
Another example of a treatment that may select for low-PSA subtypes is Lu-177-PSMA. If the patient has two types of prostate cancer, one that expresses PSMA and PSA, while his other cancer expresses neither, PSMA-targeted therapy may eliminate the source of most of the PSA, leaving more virulent subtypes behind (see this link).
This type of situation is dangerous if one relies on PSA as the principal biomarker of progression. One may be lulled into complacency by deceptively low PSA.
It is worth noting that two FDA-approved therapies for prostate cancer, Provenge and Xofigo, have been proven to increase survival, but have little or no effect on PSA."
Here is a good paper discussing NEPC by Aggarwahl and his observations of t-NEPC in some study populations. He's written several papers and seems to be the foremost expert on it. I believe he will do a phone consult, it may be worth a call.
Wow. It took me back to 2nd grade where I was so focused on getting the complex words pronounced right, when I got to the end of the paragraph, I asked "What the hell did I just read"?
Yes, it's hard to grasp all of the pathways and mutations. It appears it's just now being understood what AR suppression does in the long run and that there is a complex response to it that mutates to NEPC some of the time. Wish you the best, you've had a long, successful fight against this monster!
Thank you for highlighting NEPC. Does anyone out there have a de novo neuroendocrine diagnosis?
More specifically, do you know how long it takes for prostate adenocarcinoma to morph into neuroendocrine before diagnosis/treatment, and is a CT sufficient to imagine NEPC?
CT isn't very useful to image anything other than really gross tumors. CT never showed even the DRE palpable tumors in my prostate. I don't know what it is useful for.
Probably good for those of us who are on long term ADT to get checked regularly for somatic mutations (mutations that occur within the cancer and are not hereditary). Dr. Sartor has ordered several of these for me over the past few years. Most recently he ordered a Tempus genetic test. They are a simple blood test. Depending on the mutation that is found there are treatments available. My insurance has covered all of these. Just a thought.
"...NEPC develops in neuroendocrine cells that can secrete many different substances in response to neural signals, such as: serotonin, histamine,..."
Interestingly, a high-throughput drug screen identified Ketotifen, an anti-histamine agent, as a potential therapeutic candidate for NEPC [pubmed.ncbi.nlm.nih.gov/371...]. Ketotifen is derived from cyproheptadine, which is an anti-serotonin, so ketotifen is expected to have the same effect!
Although NE subtypes based on the expression of those TFs have been previously described in SCLC7,10, the existence of these subtypes in treatment-emergent NEPC was unanticipated, as ASCL1 and NEUROD1 have been specifically associated with lung NE cells8,9,27, the putative cell of origin of the de novo SCLC.
Taken together, our results provide clear evidence of the existence of two molecular subtypes in NEPC model systems. These subtypes share NE phenotypic characteristics but differ in the expression of ASCL1 and NEUROD1, which is associated with distinct chromatin landscapes and gene expression profiles.
The similarity in the chromatin state across NECs is particularly pronounced between NEPC and SCLC, which is surprising given the distinct cells of origin in these neoplasms. We observed that treatment-emergent NEPC shows subtypes based on the expression of ASCL1 and NEUROD1 as seen in de novo SCLC. This was unexpected, as those TFs have been previously associated with lung development
The genetic and epigenetic characteristics of NEPC tumors and the newly revealed intra-tumoral heterogeneity of the subtypes can have direct clinical implications for the design of novel treatment strategies. Currently, the standard treatment based on platinum-containing combinations38,39 is applied to all patients and typically shows a short duration response. In this respect, our results showing the convergence to a NEC-specific chromatin state underlines the potential value of chromatin remodelers as promising therapeutic targets. Examples of chromatin remodelers already being targeted include enhancer of zeste-homolog 2 (EZH2)40 based on preclinical results reporting an effect of EZH2i to re-sensitize tumors to AR-signaling inhibitors in CRPC33,41. Notably, alterations in EZH2 have been implicated in de-repression of the TF SOX2 as a consequence of the functional loss of RB142,43, suggesting EZH2 inhibitors as potential agents for NEPC treatment. Another strategy is the targeting of the bromodomain and extraterminal (BET) family. The activity of BET inhibitors regulating the expression of MYC family genes suggests them as candidates for targeting the specific MYC members associated with NEPC44. In particular, BRD4 inhibitors have already entered clinical testing based on preclinical data, suggesting that BRD4 could be involved in the transcriptional reprogramming of CRPC45,46. The strong similarity in the chromatin state between NEPC and SCLC, and the existence of similar subtypes provides a rationale to extrapolate the previously identified ASCL1- and NEUROD1-specific vulnerabilities in SCLC.
We note the possibility that therapeutic strategies that target one but not the other subtype might rapidly succumb to the outgrowth of the resistant subpopulation. Altogether, this new understanding of subtype heterogeneity based on NEUROD1 and ASCL1 illustrates the epigenetic complexity that exists in clinical tumors and provides a rationale for targeting the inter- and intra-tumoral heterogeneity as a therapeutic strategy in NEPC
This meta‐analysis provides the most currently comprehensive prevalence of genomic alterations in NEPC. Our results confirm pervasive RB1 and TP53 alterations in NEPC. We also present the frequency of potentially actionable mutations, highlighting that genomic testing should be performed in NEPC patients to select candidates for precision medicine. Finally, our analyses reveal the genomic differences between de novo NEPC and t‐NEPC, provide insights for future studies and molecular characterizations of different NEPCs.
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Very quick update - NEPC
live with prostate cancer 
Update On My Metastatic Prostate Cancer 
Prostatitis , prostate cancer,
