Genetics - Some answers but not all

[spw1]

Received my husband's somatic mutation report from the liver and lymph biopsy. Not clear yet if the MSI test report is back. In the meantime, the lack of good response to hormonal drugs and chemo might be explained by the following. Out of the hundreds of genes tested, they flagged only TP53 and TMPRSS2-ERG. What could this information give us as actionable something in the UK?

The following research may indicate why nothing seems to work at all or for very long -

TP53mutations were the only marker independently associated with an unfavorable response to abiraterone and enzalutamide and, remarkably, outperformed genomic AR alterations and expression of AR splice variants - De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam PJ, Van Oyen P, et al.

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25(6):1766–73.  doi​.org/10.1158/1078-0432​.... [PMC free article] [PubMed] [Reference list]

The response of prostate cancer cells to docetaxel has been found to be compromised by mutant p53 - Liu C, Zhu Y, Lou W, Nadiminty N, Chen X, Zhou Q, et al. Functional p53 determines docetaxel sensitivity in prostate cancer cells. Prostate. 2013;73(4):418–27.  doi​.org/10.1002/pros.22583. [PMC free article] [PubMed] [Reference list]newsroom.uw.edu/news/inheri... 

Additionally, in agreement with in vitro and in vivo preclinical studies showing that ERG interacts with tubulin and alters microtubule dynamics leading to impaired docetaxel or cabazitaxel engagement, detection of TMPRSS2-ERG fusion in the blood of CRPC patients is predictive of resistance to taxanes [157,158]. 157. Reig Ò., Marín-Aguilera M., Carrera G., Jiménez N., Paré L., García-Recio S., Gaba L., Pereira M.V., Fernández P., Prat A., et al. TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer. Eur. Urol. 2016;70:709–713. doi: 10.1016/j.eururo.2016.02.034. [PubMed] [CrossRef] [Google Scholar] 158. Galletti G., Matov A., Beltran H., Fontugne J., Miguel Mosquera J., Cheung C., Macdonald T.Y., Sung M., O’Toole S., Kench J.G., et al. ERG induces taxane resistance in castration-resistant prostate cancer. Nat. Commun. 2014;5:5548. doi: 10.1038/ncomms6548. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

[Seasid]

You should try this ore something similar. You are eligible:

4 years OS for CRPC using Zytiga and Olaparib:

healthunlocked.com/fight-pr...

[Seasid in reply to Seasid]

Your husband only had enza.

He could have Abi plus Olaparib (PARP inhibitors) this is the best treatment now.

[Seasid in reply to Seasid]

You may find a similar current clinical trial.

[Seasid in reply to Seasid]

clinicaltrials.gov/ct2/show...

[spw1 in reply to Seasid]

Will look into this as the trial is also at Manchester which is achievable; London is a bit far at the moment. ECOG status 0 or 1 is unlikely. More like a 2. May be excluded for that reason.

[spw1 in reply to Seasid]

Hi he has been on Abiraterone since 23 Dec and it appears not to be working really.

[Seasid in reply to spw1]

Than he is not passing the criteria for that. Enza would be still ok, but they don't want someone who was already on Abi. Sorry I didn't see Abi in his profile, only Enza.

[Seasid]

I don't know if he would qualify for this? What is his SUV max?

Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer:

Locations

Australia

St. Vincent's Hospital Research Office-Translational Research Center

Recruiting

Darlinghurst, Australia

Principal Investigator: Louise Emmett, Prof

clinicaltrials.gov/ct2/show...

Than you would be my neighbours.

[spw1 in reply to Seasid]

Thank you but the PSMA avidity is not great so that is not an option. More cancer is FDG avid.

[Seasid in reply to spw1]

Therefore he has psma negative cancer? You could still contact professor Emmett with your situation and see what she will say.

[spw1 in reply to Seasid]

I will try. My husband is not in a state to travel and we are reliant on what the NHS can do.

[Tall_Allen]

Sadly, those are two of the most common mutations in advanced prostate cancer, and there are no clinical trials I know of tailored to them.

He may have more luck with a combination of abiraterone and a PARP inhibitor or by adding carboplatin to Jevtana. I think the abi/PARPi combination will be approved in the US and probably the NHS next month. He should be able to get Jevtana+carboplatin already.

prostatecancer.news/2022/06...

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

If there is anything new, Johan De Bono at the Royal Marsden would know.

[spw1 in reply to Tall_Allen]

I will send the report to Prof De Bono. The NHS does not allow Abiraterone as he had Enza before. They refused Carboplatin when I had asked to add to Cabazitaxel. Their view is that Carboplatin is only useful where there is evidence of NEPC. Prof De Bono also was not enthusiastic about it. Now we know from the liver biopsy that it is not NEPC. Sadly, I feel that we are pushed into a 'no more treatments left' zone. The hospice nurses have been home giving things to make life comfortable. It just seems difficult to believe that this is happening so fast.

[Tall_Allen in reply to spw1]

Their response makes sense for mono therapies, but not for the combinations I am talking about. I suggest you email those links.

[spw1 in reply to Tall_Allen]

I will try. Thank you so much.

[Seasid]

I am really not a doctor but just wandering would any doctor recommend BAT at this stage? Could you find some doctor who could tell you more if maybe BAT is a possibility?

I believe you really need someone to help you. Contact a doctor for second opinion even if they are in US, Canada, Australia etc.

[exeinoo in reply to Seasid]

BAT has particularly good response in men with TP53 mutations.onlinelibrary.wiley.com/doi...

[Seasid in reply to exeinoo]

I agree, but BAT is usually only performed on asymptomatic cases. I believe that is a rule.

[Seasid in reply to Seasid]

They mentioned asymptomatic 13 times in your link. Nobody recommended BAT in symptomatic cases. But I am not a doctor and it would be great to consult a knowledgeable doctor about it. Unfortunately they don't do BAT on symptomatic men as far as I know.

[spw1 in reply to exeinoo]

Thank you but we have not yet met an oncologist willing to offer it and given that my husband is now in a frail state, it is unlikely to be offered.

[Hidden in reply to spw1]

It is very difficult to accept that we have run out of options. When the patient is very weak and unable to withstand any more drastic treatments, we have to face the reality that we are probably not thinking of their best interest, but rather our own unwillingness to accept the inevitable. It is difficult to accept I know. Your doctor would surly try another treatment of it was an option.

[spw1 in reply to Hidden]

Actually, medics not trying options when there was time and more fitness is at the heart of some of our problems. I am not selfish enough not to let him go if he was beyond saving and suffering. The soul is immortal and love survives - the rest is just a body which is always here for a finite time. It is my duty to do my best for him until there is definite proof that nobody has anything to offer. He would do it for me.