BRCA-2, etc, in CRPC.

[pjoshea13]

New paper below.

Nalakrats quoted some statistics 4 months ago:

"Latest statistical data from 2 studies, one said 1.2% of all Men with Prostate Cancer have this mutation. Another study indicted it was 2% of all Prostate Cancers---for those that carry the Mutated BRCA-2 Gene."

That sounds about right for familial diesease, & (to me) there doesn't seem much point in being tested unless there is a cluster of breast & prostate cancers in the family.

Lynparza (Olaparib) is a PARP inhibitor that has had some success in cases with BRCA1/2 & ATM repair gene defects

From Steve Freedland:

... we conducted "prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals."

"... aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers." 29 of 150 CRPC cases.

Together with the other aberrations that were discovered, it appears that there might be great value in being biopsied & tested once ADT has failed.

-Patrick

ncbi.nlm.nih.gov/pubmed/286...

Urol Oncol. 2017 Jun 13. pii: S1078-1439(17)30220-X. doi: 10.1016/j.urolonc.2017.05.010. [Epub ahead of print]

Commentary on "Integrative clinical genomics of advanced prostate cancer". Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM.Cell. 21 May 2015;161(5):1215-1228.

Freedland SJ, Aronson WJ.

Abstract

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. A total of 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could affect treatment decisions for these affected individuals.

Copyright © 2017 Elsevier Inc. All rights reserved.

PMID: 28623072 DOI: 10.1016/j.urolonc.2017.05.010

[Dan59]

It was my understanding that there are other germline mutations that come into play, and that the total would be 32% chance a APC patient would have one of them. When I was tested I had a clinicically insignificant hedgehog mutation. I am not sure if over time we would possibly develop a different mutation. Thank You for your advocacy Patrick.

[ctarleton in reply to Dan59]

Don't know if it applies or not, but this article addresses the types and frequencies of 20 inherited DNA-repair gene mutations among 692 men with metastatic prostate cancer. Around 11.8% had one or more of the mutations. The breakout was BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]).

nejm.org/doi/full/10.1056/N...

When I was tested, I came up negative for around 53 of the genes that were tested from this test (which now has 67 available genes for testing):

ambrygen.com/tests/customne...

The same testing company now has a ProstateNext test, which seems to closely align with most of the genes listed in the Article above. This link also has the names of those genes, plus some very useful explanatory information about their relationships to prostate and other related cancers:

ambrygen.com/tests/prostate...

Charles

[pjoshea13 in reply to ctarleton]

Charles,

When I think of familial PCa, I remember old studies with estimates, such as no more than 4%. Familial PCa is suspected when there is a PCa cluster in the family or, in the case of BRCA, a BCa cluster. If everyone in the group responded, I wonder what the percentage of familial cases would be? Nowhere near 57% I would guess.

In the link you gave:

"Prostate cancer is also among the most heritable of human cancers, with 57% ... of the interindividual variation in risk attributed to genetic factors."

Some say that PCa is a disease that almost all men would have if they lived long enough. If almost 57% of all men carry risk factors for PCa, there must be a survival advantage! LOL. Not much consolation to my son.

It's exciting to think that BigPharma might be working on gene aberration cancer treatments that might be used across a number of different cancer types. Gives them a financial incentive.

When I began reading the studies 13 years ago, there was the occasional paper that looked at gene polymorphisms. Very interesting, but how could I use such information. I have ignored all such papers & now there are over 3,000 of them. For the vitamin D receptor alone, there are 110 PCa polymorphism papers.

A polymorphism is a variation, rather than a mutation, I feel, in that a sizable percentage of the population might carry it. However, it might affect PCa (up or down). What to do about that?

As I recall, there was only one study that affected my regimen. Seemed to suggest that selenium supplementation might be most beneficial with one variation, but perhaps detrimental with another. One could play the percentages, I suppose.

-Patrick

[ctarleton in reply to pjoshea13]

That Decision Making under Risk and Uncertainty can be a real bitch, huh?

Charles

[Sisira]

Thank you Patrick for your post which also provoked the thoughts of Dan and Charles to make some worthy contributions.

For me looking at these specific Gene Mutations in the context of Prostate Cancer is something like taking a drop of water from the SEA and trying to fathom how big is the SEA!

However the following lines fiercely attracted my attention :

"Prostate Cancer is also among the most heritable of human cancers" - Patrick

I am really worried about my son!

"Some say that PCa is a decease that almost all men would have if they lived long enough" -Patrick

Finally, with all this good research work on Gene mapping etc. all of us will fall into the mouth of the DRAGON - BigPharma and pulverized to be converted to their massive profits! This I can see very clearly as the end of the story.

Sisira