Aggressive Variant Prostate Cancer (AVPC)

[Javelin18]

During my visit with Dr Aparcio at MD Anderson, I asked her what trials might be appropriate for me if Lu-PSMA doesn’t lead to a durable response. She started by talking about Aggressive Variant Prostate Cancer (AVPC). Nueroendocrine Prostate Cancer is one form of AVPC , but adenocarcinoma can exhibit AVPC characteristics.

She talked about three trials for AVPC that I’ll talk about later. She said that not separating AVPC patients from patients from those without it clouds stage the trial results, and the new trials only include AVPC patients.

It took a while to sink in that the reason she was talking about AVPC, is that I’ve had AVPC since my diagnosis. In hindsight, de novo mCRPC with a PSA doubling time of three weeks is obviously an aggressive variant. I’d just never had it named that until now.

Coming to the realization was depressing for a few days, but at least now I have a framework to guide my studies. While researching tonight I came across an article linking TP53 mutation to prostate cancer.

genengnews.com/topics/cance...

My biopsy showed 10% of the cancer with the mutation. I had discounted joining a trial for this, because I wanted a treatment for 100% of the cancer. I realize that doesn’t exist. It may be that the most aggressive subtype of my cancer contains the TP53 mutation. Treating that would slow the cancer down and give me time to find treatments for the less aggressive remaining cancer.

Once again, much to learn.

[Tall_Allen]

Have you had IHC done?

[Javelin18 in reply to Tall_Allen]

No I haven’t. I will discuss it with my MO on Thursday. Can you point me to a resource to learn more about it?

I understand that NEPC can develop from heavily treated cancer, I think that it would be good to test for it. Both UCLA and MD Anderson reference labs did not find it on my original biopsy sample, so I think at least at first my AVPC was the adenocarcinoma variety.

I’m reading this article now to learn about AVPC.

ncbi.nlm.nih.gov/pmc/articl...

[Javelin18 in reply to Tall_Allen]

At first glance it appears that IHC Is a staining technique to classify cancer types in biopsy samples. Wouldn’t that be a normal part of biopsy analysis at a reference lab?

[Tall_Allen in reply to Javelin18]

It's done on biopsy tissue. Not every pathology lab has every stain, but the Wang Lab at Duke is known to be one of the best. The nice thing about IHC is it allows you to quantify as well as qualify. It also depends on how much tissue they can get. I think more recent metastases would show the most but there's probably a trade-off between size and recentness. Here's my list of stains I'd want to look at. Dr. Aparicio may have other ideas.

AR (androgen receptor), PSA, PSMA, MSH2, MSH6, PD-L1,chromogranin A (CGA), neuron-specific enolase (NSE), synaptophysin (SYP), DLL-3, CD56, Somatostatin (SST)

[tango65]

What are the clinical trials for AVPC?

[Javelin18 in reply to tango65]

She drew some diagrams to explain the protocols, but didn’t give me the trial numbers. I’ll ask for the trial numbers.

[tango65 in reply to Javelin18]

Thanks, please let us know. I wish you the best of luck on your journey.!!

[Javelin18 in reply to tango65]

I sent a message to Dr Aparicio last night, decided to look them up, so I could reply sooner. Here is a link to one the studies. The search came up with 14 hits, including other institutions

clinicaltrials.gov/ct2/show...

In this study they do biopsies at the beginning and as each drug is added, to understand changes to the tumor micro environment

[kklott01 in reply to Javelin18]

I am currently participating in the NCT04592237 clinical trial aka as CCC Nira. I underwent 6 cycles of carboplatin along with cabazitaxel and the immunotherapy cetrelimab. I entered into the maintenance phase two months ago and now receive the oral pill niraparib along with a monthly IV of the cetrelimab.

Since June, my PSA has continued to rise at every blood draw from 8.8 to the most recent result on 12/3/21 of 12.6. Additionally, my CEA has always been stable since starting the trial however with the most recent blood work, it rose from 3.5 to 8.1!

My MO is Dr. Sumit Subudhi and his guidance is that we ignore the rising numbers for the time being and look at the next set of CT & Bone scans scheduled for late January 2022 to review tumor sizes and status. Of course, I have mixed emotions about this guidance and wonder if I will wash out of the trial?

I have undergone both Molecular Tumor Testing: AR, TP53 (10/15/2018 tissue); AR, TP53 (08/06/2019 tissue) as well as had an evaluation of PTEN IHC Loss: Positive (08/06/2019 tissue). My LDH has been hovering around 200 for the duration of this trial and was 197 at the last recent measurement. In three plus years of bone scans, no metastases identified to this point, thank the dear Lord!

Participation in this trial is the third one for me since engaging MD Anderson for options in my ongoing cancer fight in October 2018.

[Javelin18 in reply to kklott01]

Glad to hear from someone with experience in the trial. With my current Lu-PSMA treatment, they keep telling me to ignore the PSA, but that is hard to do. I have a regular meeting with my MO today, and second Lu-PSMA treatment tomorrow.

I feel much less pain,, and have much more energy after the first treatment. I’m glad to hear that no metastases are visible on your scans. How is your pain, mobility energy after the treatment?

[kklott01 in reply to Javelin18]

I currently have no pain and very little fatigue to speak of. All in all, I feel about as close to a normal human being my age, 57, as one could wish!

That was not the case while undergoing the chemotherapy phase where I was extremely fatigued and experienced significant muscle cramping. I will say however that with the platinum chemotherapy regimen from the trial, I did not lose my hair, nor did I experience mouth sores, both of which were present when I went through a Docetaxel standard of care protocol.

[Javelin18 in reply to kklott01]

Wow, that is great. I hope that continues.

I’ll let you know if I continue to improve on the Lu-PSMA. I don’t know if it works well for AVPC, but I’m hopeful.

[LearnAll]

Long term continuous, combined ADT can lead to treatment emergent Neuro-Endocrine aggressive variant in 15 to 20% men.(by various estimates)The easiest way to start investigating this Neuro-Endocrine change is to check Bio-Markers like Chromogranin A, LDH, Neuron Specific Enolase (NSE) and Synaptophysin.

If they show a rising trend, the possibility of NE change is very very high. Also, getting X Ray or CT to look for any OSTEOLYTIC type lesion on bones. Biopsy gives final answer. Wish you all the best.

[Javelin18 in reply to LearnAll]

Thanks, I’ll ask about those tests. My current hypothesis is that it started as nueroedocrine AVPC. it has become less aggressive after treatment. That implies it was aggressive Variant from the start, which is also confirmed by the rapid doubling time early on.

I attribute the changes to the way chemotherapy works. Since it only kills actively dividing cells during the few days it is in one’s system, the most active cancer will be selected.

[LearnAll in reply to Javelin18]

De Novo...the type of NEPC which is present from beginning occurs in less than 1% of total. But, many men have a small number of NE cells scattered in their prostate. When the regular, non aggressive, adenocarcinoma cells are killed with powerful, combined ADTthese scattered NE cells starts growing uncontrollably due to what is called "competitive deselection" Means the tumor now changes from sensitive to resistant type.

This is the hypothesis of researchers who are engaged in mathematical modeling about Adaptive therapy. Researchers like JingSong Zhang and many of his co-researchers at Moffit Cancer Center in Tampa Florida have been pioneers in this area and have published many studies in last few years.

[Hidden in reply to LearnAll]

I'd like to see some literature on these studies if you have a citation to the URL.

[GeorgeGlass in reply to LearnAll]

I’ve met with Zhang, Aparicio, and Armstrong at Duke. My psa doubling rate is 3 weeks as well but two of them recommend ADT mono therapy. Aparicio wanted zytiga added. I have coronary artery disease too. I don’t have any biopsies post radiation treatment/failure.

[LearnAll in reply to GeorgeGlass]

By ADT monotherapy..do they mean Lupron like Med only ? Continuous or intermittent ?

[GeorgeGlass in reply to LearnAll]

Yes. Mono therapy of orgovyx. Intermittent or continuous. I’ve done intermittent for a little over five years so far.

[GeorgeGlass in reply to LearnAll]

Based on your research, do you think intermittent ADT is a good idea, in order to avoid the neuro- endocrine aggressive variant?

[LearnAll in reply to GeorgeGlass]

In carefully selected men analysing the behavior of their PCa, Androgen sensitivity ,age, comorbid medical conditions and biomarker patterns etc. If it is found that they are suitable candidates for Intermittent ADT..then undoubtedly Intermittent ADT is a good idea. Men who have aggressive variants or NEPC should better avoid Intermittent ADT.

Looking at your limited data, I think you will do good with Intermittent ADT. (its my opinion not recommendation or prescription)

There are 4 major advantages of intermittent ADT..

(1) Time and again ,in many reliable studies, Intermittent ADT has been found to be Non-Inferior to Continuous ADT.

(2) During Off periods, when Teststerone recovers..body restores its natural state and strengthens itself ...besides freedom from side effects at least during off periods.

(3) Intermittent ADT reduces the damaging effect of ADT on heart and lowers blood pressure and blood sugar during off periods. High blood pressure, Diabetes, heart disease and dementia are notorious side effects of continuous ADT.

(4) Based on many studies mostly from Japan, Korea ,canada and other nations, it is indicated that intermittent ADT does prolong time to castration resistance. Prolonged use of heavy and conituous ADT does cause change to Neuro endocrine Variant in 20 to 30% men.

I am on intermittent therapy for last 2 and 1/2 years (30 months) and am doing well.

One last word of caution, If you are on Intermittent ADT, its important to check PSA and total T every 2 to 3 weeks and remain vigilant to any symptoms or unexpected findings.

I check biomarkers esp PSA, and Total T every 2 weeks and chart them to see pattern.

[Javelin18]

There seems to be an assumption that since my cancer is aggressive it must be NEPC, and all tests that were negative must be incorrect tests. The new perspective I was trying to provide is that adenocarcinoma can be aggressive in the absence of NEPC.

[Hidden in reply to Javelin18]

Plus there are other variants. Signet Ring cell, Sarcomatoid, Adenosquamous, Ductal, and Mucinous. Though Muscinous would be the most desireable of all. though they are all rare.

[Javelin18 in reply to Hidden]

Even more complexity. This should be a snap. 😉

[NickJoy in reply to Javelin18]

My feelings exactly!

[LearnAll in reply to Javelin18]

Certainly. NEPC is just one type of Aggressive variant.. there are others..Like anamolous just named. Yes..they are very very uncommon. First thing is Rule Out NEPC by checking biomarkers and then think of any other variant.

[Javelin18 in reply to LearnAll]

Good advice

[Javelin18]

I’ve been reading about AVPC in preparation for my meeting with the MO tomorrow, snd want to add a bit more information. AVPC is characterized by TP53, and RB1 gene defects with or without a PTEN defect, rather than the subtype of the cancer. I need to look at my germline and somatic genetic results to see if there was more than TP53 mutation

Also, in regards to the low probability of de novo AVPC, the assistant head of urology at UCLA told me that I was only the third case they had seen in twenty years. At the time, I thought he was referring to de novo mCRPC, but he may have also been referring to the aggressive nature.

[GeorgeGlass in reply to Javelin18]

I’ve met with Zhang, Aparicio, and Armstrong at Duke. My psa doubling rate is 3 weeks as well but two of them recommend ADT mono therapy. Aparicio wanted zytiga added. I have coronary artery disease too. I don’t have any biopsies post radiation treatment/failure.

[Javelin18 in reply to GeorgeGlass]

What treatment did you decide on? I think trying ADT first is a smart step. Hopefully it is still hormone sensitive.

[GeorgeGlass in reply to Javelin18]

I’ve been doing lupron intermittent for four years and then orgovyx in 2021. Ice dive Three intermittent breaks for about 8-9 months each time. I wish i had done the chemo indefinitely after the failed radiation treatments, but the moni therapy of adt has worked well for me. I’d like to add nubeqa but the fda hasn’t approved it for castration sensitive men.

[Hidden in reply to Javelin18]

There is a positive association between having a tp53 mutation and BAT (Bipolar Androgen Therapy) which you may want to discuss with your doctor. The link below says, "Next-generation somatic DNA sequencing was obtained on 15 patients with mCRPC who achieved over a 70% PSA response to BAT. 93% were found to have a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. This data supports the hypothesis that BAT is most effective for DNA repair-deficient mCRPC patients and warrants prospective investigation."It may be a small study, but my husband also has a TP53 mutation and was a BAT responder. Here is one link: vjoncology.com/video/sohnul...

[Javelin18 in reply to Hidden]

Thanks. Was there any other therapy simultaneous to the BAT?

[Hidden in reply to Javelin18]

No, just Lupron/ orchiectomy.

[MateoBeach]

Thanks for elucidating these considerations about AVPCs

[Javelin18 in reply to MateoBeach]

Your welcome. I’m also glad for the feedback and experience of other members.

[Javelin18]

Just came from MO. She had copy of Tempus genetic test I had misplaced. No RB2 or PTEN defects. 1.8% of biopsy showed TP53 mutation. No germline mutations. Doctor said she would check which stains were used in the biopsy. She previously checked chromagranin which didn’t show a rise.

All this contraindicates AVPC, so I’m not concerned for now. Going to schedule another PSMA PET, to look at progress.

Thanks to everyone for their suggestions and inputs. I think humility is important to finding correct answers, so I always try to welcome challenges to my analysis.