Genotyping in Prostate Cancer

Transcript:Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: So now we’re going to talk about DNA repair defects, and PARP [poly (ADP ribose) polymerase] inhibitors, which is an exciting area of prostate cancer therapeutics. Nick, can you discuss the role of BRCA1 and BRCA2 mutations in DNA repair in prostate cancer?

Nicholas James, MD: This is an emerging field. We know that the BRCA genes are predisposed to prostate cancer in men, just as they are predisposed to various malignancies in women; this has been known for a long time. The trial that kick-started the interest in this was the TOPARP trial, which took all comers and characterized their DNA damage-repair profile. What they found was that…about 30% of men who responded were exclusively men with DNA damage-repair mutations—most frequently being the BRCA1 and BRCA2 mutations. There were no responses in men without DNA damage-repair mutations.

This kick-started the concept that you could genotype these men’s tumors and treat them with PARP inhibitors. It also seems to predict response to platinum-based chemotherapy, which is something that’s got quite a long track record in prostate cancer. We stopped doing this, but all of us who were around during the predocetaxel time will remember that some patients had good responses to platinum-based chemotherapy. Outside of a trial for men with BRCA1 and BRCA2 mutations, these populations do well on carboplatin, which is the agent I use. They are interesting, emerging data, and there are lots of different PARP inhibitors chasing this particular space.

In terms of what the proportion is in newly diagnosed men, we’ve been looking at this in the context of the STAMPEDE trial, because we were interested in starting a PARP inhibitor randomization. But the overall percentages of men with the relevant DNA damage-repair mutations is relatively low. It’s not high enough in the STAMPEDE recruitment to populate the trial in a reasonable time frame, particularly once you’ve already found cases. Sometimes you’ve got to sequence all of them to find the ones with the mutations.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes, there’s a lot of work to do.

Nicholas James, MD: Only about half of the men, give or take, have a germline mutation. So you couldn’t do the cheaper thing, which is to take a saliva sample, with which you would find only half the cases.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Germlines and mutations within the tumor are an interesting occurrence. Noel, do you want to comment on the mutations that you see: the germline mutations that people are born with? This seems to be a very interesting area in prostate cancer?

Noel Clarke, MBBS, FRCS, ChM: I think it calls for a bit of reading from a number of clinicians who I’m sure will understand the difference between germline and somatic. There are a lot of people out there who don’t.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes.

Noel Clarke, MBBS, FRCS, ChM: Germline mutation is one you’re born with and a somatic mutation occurs in the cancer because of dedifferentiation, and so on. It could possibly take us back a frame or 2, which is the importance of understanding germline mutations in diagnosis, in family history, and in the risk profiling of prostate cancer patients in relation to who gets tested, and so on, because there’s a lot of misunderstanding out there. What we know is that about 5% of prostate cancer patients will have a BRCA mutation—BRCA2 in particular is important. A patient with a family history of breast cancer with BRCA mutation—the males especially—needs to be tested by a urologist.

The second thing is that there are certain histological types that are associated with somatic mutations. There has been a body of work put out looking at cribriform architecture, which is associated with a high somatic mutation load. Additionally, the germline mutations treated with either surgery or radiotherapy behave rather paradoxically.

There’s an intermediately powered study being conducted at the Institute of Cancer Research in Royal Marsden, London, that has shown a paradox in patients who have had surgery—ie, patients with BRCA mutation and germline mutation, who were treated with surgery. They seemed to fare better than those treated with radiotherapy, which has surprised everybody because you would expect it to work the other way around.

Transcript Edited for Clarity.