Ok very quick notes

• Prostate cancers are known to have a wide spectrum of outcomes.

• Stage IV (metastatic) disease tends to have genetic testing. These panels tend to be on the order of a few hundred genes to 1000s of genes.

• Classically prostate cancer is driven by androgen receptor upregulation. Disease progression is often due to the disease overcoming treatment with antiandrogenic such as enzalutamide.

Correction: enzalutamide was designed to overcome castrate resistant prostate cancer. abiraterone would have been more appropriate to bring up here.

• Upon review of NCCN guidelines: there are two main genetic indicators for targeted therapies. Both of these mutations are indicated for germline and somatic contexts: BRCA1/2 for parp inhibition and dMMR/MSI-H for pembrolizumab

o Note that there are some somatic mutations with HRD pathway that are indicated for treatment. But that is only if they are somatic

• This study aims to figure out the etiology of the disease in an evolutionary manner. That is what are the key events that lead to oncogenesis.

edit note: the word that escaped me was epistasic given that we are looking into the nuts and bolts cause and effects of different mutations.

edit note 2: I'm going to be honest, most of the time I've read about prostate cancer is in the metastatic setting and thus it has already become castrate resistant. Abiraterone is also meant to aid in sensitizing castrate resistant prostate cancer. Let's just say androgen deprivation therapy for now. On the other hand, I hope this was instructive in showing how important AR is as a pathway for prostate cancer

• Quick thought: this could be useful if this matches with molecular screening in earlier stage disease. If we can reliable map out which chain of events (tumor suppressor loss of function mutations/ gain of function mutations for oncogenes, chromosomal level mutations) lead to more aggressive disease, we can inform changes in surveillance and earlier/ more aggressive treatment.

• Granted this isn’t too out there, tissues cores are taken out to begin with to get initial snapshot into how aggressive disease (it’s how you get the Gleason score after all).

• Regarding switching pathways, that’s not too crazy given neuroendocrine transformations exist in prostate + lung cancer

user:	crispycas12
created:	November 25, 2022
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