Genetic Codes - PTEN loss (exons 6–9) - Any Clear Studies?

All of this is definitely aggressive
Cancer Association: While normal PTEN maintains genomic stability, loss of this segment is strongly associated with high-grade, aggressive cancers (such as prostate and endometrial) and poor survival outcomes.
PubMed Central (PMC) (.gov)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4310752/.
The one treatment limitation is that Pluvicto Does not work well with someone that has PTEN. That doesn’t affect chemo or other treatments.

HRAS Q61K
The HRAS Q61K mutation in prostate cancer acts as an oncogenic driver that locks the HRAS protein in a "constitutively active" GTP-bound state. This prevents GTP hydrolysis, leading to uncontrolled signaling through the RAS/RAF/MAPK pathway, which promotes cancer cell proliferation, survival, and aggressive behavior. Although rare in conventional prostate cancer, it is seen in rare subtypes like PIN-like ductal carcinoma.

Similar RAS mutations, especially at codon 61, are generally associated with poor response to standard treatments and higher rates of recurrence.
PubMed Central (PMC) (.gov)

MED12 L1224V
The MED12 L1224V mutation in prostate cancer is a somatic, hotspot mutation occurring in exon 26 that often promotes the progression to aggressive, castration-resistant prostate cancer (CRPC). This mutation disrupts the MED12 protein's ability to properly regulate cell growth, often driving tumor growth even when androgens are depleted.

This particular, genetic problem may cause issues with drugs that are given for prostate cancer. You should discuss this with your doctor. You need a Genito Urinary Oncologist To be treating you. Someone that is aware of what’s going on genetically. He definitely should be working with the center of excellence on treating this. I know that UC SF has a specific group that handles genetic issues.

@jeffmarc Wow, this adds another layer of worry. Thank you for offering these details. We meet with the medical oncologist at Duke who ordered these tests at the end of this month and will have many questions. I did see that AKT inhibitors often work best with these mutations. We also have three sons, and I wonder which of these are genetic, and what caused all these mutations? I guess these genetic issues will make for an ongoing fight.

My husband is doing well so far on Orgovyx and Nubeqa, and we've been playing tennis at an active level (although he's exhausted afterward).

Duke is a good place to get treatment. This doctor is supposed to be one of the best. You might ask if you can get a second opinion from him, Unless he’s already treating you.

Dr Daniel James George GU Oncologist

You definitely should try to get your son’s tested. These three things do cause prostate cancer to come on and be aggressive. It would be good for your sons to know their risks because their children could have these risks. The fact that your husband has it more than doubled a chance that one of your sons could have it. I got BRCA2 from my grandfather through my mother. Her mother had no problems. My mother had no problems, but both of her sisters got breast cancer, and one of them died from it as did her daughter. Fortunately, I am the only remaining relative from that family Line that has BRCA2. My son and daughter do not have it. My brother got prostate cancer at 77 but does not have BRCA2. I got it at 62 because I do.

I’ve had prostate cancer for 16 years. I’ve Had surgery and radiation but did not find out I had BRCA2 until about five years ago, That explains why it came back four times. I’ve been on Orgovyx and Nubeqa For almost 3 years and I’ve been undetectable for 29 months. Those two drugs work real well together.

There’s a clinical trial going on now for people that have PTEN. I’m not sure your husband would qualify, but he may even though you have this other genetic problems.

Here are some links to the actual study
https://www.annalsofoncology.org/article/S0923-7534(25)04936-1/fulltext
https://pubmed.ncbi.nlm.nih.gov/41120017/
https://clinicaltrials.gov/study/NCT04493853
This study will assess the efficacy and safety of capivasertib plus abiraterone (+prednisone/prednisolone) plus androgen deprivation therapy (ADT) versus placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC whose tumours are characterised by PTEN deficiency. The intention of the study is to demonstrate that in participants with mHSPC, the combination of capivasertib plus abiraterone (+prednisone/prednisolone) plus ADT is superior to placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC characterised by PTEN deficiency with respect to radiographic progression-free survival (rPFS) per 1) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for soft tissue and/or Prostate Cancer Working Group (PCWG3) for bone as assessed by the investigator 2) death due to any cause

@scary1
This Thursday there is An online meeting for people who that have inherited genetic issues.

You have three different issues that you probably have a lot of questions about. There are experts here that can help you with answers. Please attend this meeting. You do need to install the free GoTo Meeting software/app On your device. It works on every different type of platform, Phone, tablet or computer.
https://connect.mayoclinic.org/discussion/inherited-mutations-virtual-support-group-april-9th-8pm-eastern/