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Thank you for joining us, Dr. Castro, happy to talk to you. You have truly become one of the leading voices on the BRCA-2 mutation and prostate cancer and have published articles on the natural history of these patients. Could you tell us, from a localized disease, what is the likely outcome of a patient with BRCA-2 prostate cancer?
Elena Castro: BRCA-2 germline carriers certainly have an increased risk of developing prostate cancer, which represents a disease development rate of approximately 30% over the course of life. And they tend to develop aggressive prostate cancer, a Gleason greater than or equal to 8 is common in these patients. However, some patients develop Gleason low grade prostate cancer.
It is not uncommon for these patients to have lymph nodes or even distant metastases. But even for patients with localized disease, we published a few years ago an article in which we badyzed more than 1,300 men with localized prostate cancer treated by surgery or radiotherapy. And what we have observed is that carriers develop metastases earlier. It does not matter that they are treated by surgery or by radiotherapy and that they die earlier of the disease.
Charles Ryan: In summary, a man with the BRCA-2 gene has a 30% risk of developing prostate cancer during his lifetime, a higher probability of developing high-grade disease, and a greater likelihood of relapse after treatment. local. basically what you say. When you compare stage by stage, do patients have a higher risk of death from prostate cancer? BRCA-2 versus non-carrier carriers.
Elena Castro: Yes it is correct.
Charles Ryan: What about patients who develop metastatic disease? Are they more or less likely to have a lasting response to hormone therapy? Do they have a higher rate or a shorter time for the development of the CRPC, for example?
Elena Castro: What we have observed is that they are progressing rapidly towards the status of castration resistance compared to non-carriers. And overall, when they are treated with one of the treatments available for CPRCm, they respond, but they tend to have shorter responses. Other reports have observed longer-lasting responses in these carriers, and others who have shorter responses, and I think the difference is between all of these reports can come from the proportion of patients with mutations BRCA-2 included in these reports, may come In which line of treatment these patients received the androgen receptor single blockers, may depend on the tumor burden of these patients, and none of these reports, including our latest study, Took into account the characteristics of the tumor. It was simply the germline defect, but even in the case of a germline mutation, the characteristics of the tumor may vary, which may also affect the response to these therapies.
Charles Ryan: So, the characteristics of the tumor would be, for example, a Gleason score, you could have a mutation of BRCA-2 with a Gleason 7 and a mutation with a Gleason 10, and that with the Gleason 10 will always have a darker prognosis than that a patient with Gleason 7. Is that what you're talking about?
Elena Castro: This and also molecular characteristics. If they can have MET amplification, RB losses, this could also affect their response to therapies.
Charles Ryan: Do we see an overlap of RB losses and p10 deletions and BRCA-2 alterations in these types of molecular characteristics as long as … The question would be whether a patient with BRCA-2 … is it more likely to have a RB? loss or some of these other more common changes?
Elena Castro: That's all. This is the loss of BRCA-2, which is often badociated with RB loss.
Charles Ryan: And I believe that the RB gene and the BRCA-2 gene are closely located on the same chromosome and could be lost together, if I understood correctly.
When we think of carriers of BRCA-2 and the treatment of the disease, the development of PARP inhibitors obviously elicits a lot of enthusiasm. But I think we also need to think about other approaches for these patients, regardless of the exclusive targeting of PARP. What other directions can we consider to treat patients with BRCA-2 modifications?
Elena Castro: What we have observed is that for BRCA-2 carriers who receive abiraterone or enzalutamide as a first-line treatment and then progress, they receive a taxane, the results are not different. of those who are not. But when they receive the opposite sequence, they first receive a taxane, then abiraterone or enzalutamide, then they tend to progress faster and survival is shorter. Thus, BRCA-2 status can help us choose the treatment sequence for these patients. On the other hand, these patients can also respond to immunotherapy beyond mismatched repair deficiencies. It appears that BRCA-2 deletions accumulate and that other DNA repair defects have also been badociated with a high tumor burden, a lymphocyte infiltration, which could also promote the reply. to immune therapy.
Charles Ryan: Is there any evidence that BRCA-2-impaired patients have … Maybe not hypermuted. But are these more mutated tumors badociated with a benefit of immunotherapy?
Elena Castro: They are badociated with a genomic instability that usually consists of these deletions. I think in some ongoing trials they have badyzed the response of BRCA-2 and ATN carriers, but the number remains low. They seem to respond better to immune therapy than non-mutated tumors, but I think we still need one …
Charles Ryan: The hypothesis is responsible. Patients whose DNA repair is impaired will have more mutations and therefore a higher probability of neo-antigens in response to immunotherapy. To go back to the comment about the sequence you did, you observed that patients who experience BRCA-2 alteration and receive a taxane first have an unfavorable result compared to those who receive targeted treatment with AR. first. Did I understand well?
Elena Castro: Yes.
Charles Ryan: And you're talking about this in the context of CPRC, not hormone-sensitive diseases. Correct?
Elena Castro: This is correct. It would be very interesting to see what happens in the early stages of the disease as well.
Charles Ryan: Finally, some very interesting data is emerging and some studies are beginning to be initiated on the use of PARP inhibitors in patients with no evidence of damage to DNA repair. And the idea behind it, in my opinion, is that androgen deprivation therapy, abiraterone and enzalutamide perhaps, the effectiveness of these therapies can induce a transient loss of DNA repair and create a window of luck for treatment with PARP inhibitors. What are your thoughts on these approaches?
Elena Castro: I think that after all this work trying to identify what could be the predictive alternations of response to PARP inhibitors, I find it very shocking that we are now trying to treat absolutely every patient with this combination.
Charles Ryan: Right.
Elena Castro: I would like to see more solid data than the data presented so far, to really consider-
Charles Ryan: The hypotheses are interesting. The data available is modest at this stage, but I think the potential benefit may be that we can exploit a window, find a window where transient androgen receptor co-targeting and PARP could potentially to be beneficial for the patients. So, it's an interesting angle.
Finally, at the last minute or last minute, a number of studies are currently focusing on PARP inhibitors and other approaches to detect BRCA-2 gene modifications in patients. As we have discussed, the types of populations where the prevalence of BRCA-2 alterations are very high vary considerably around the world. You know a little about it. Tell us about what you have discovered about the areas where BRCA-2 changes are most likely to be in which populations.
Elena Castro: There is no doubt that Ashkenazi Jews have fundamental mutations in BRCA-1 / BRCA-2, and this population will certainly have a higher prevalence. In other populations, I think we still need to conduct more studies to learn more about it. In Spain, for example, the prevalence of BRCA-2 is 3.3%. In the study conducted in US states, it was about 5%, but I guess it also depends on the institutions and patients that they consult, which could affect prevalence. With the reported data, I have the impression that even though their exact prevalence may depend on the genetic background of the genetics of different populations, BRCA-2 will remain the gene most often mutated, unless it is a particular population with mutation of the founder with a very high prevalence.
Charles Ryan: Right. The range would be in Spain … It is certain that the population is even lower than 3.3%. But in the Ashkenazi Jewish population, what is the prevalence of the BRCA-2 mutation in this patient population?
Elena Castro: I think that one in 40 is a mutation carrier of the BRCA-1 or BRCA-2 founder. But I do not really know what the exact data is for prostate cancer patients.
Charles Ryan: Correct. If you have taken Ashkenazi Jewish patients with prostate cancer who have BRCA-2, we do not know yet. This is certainly a noble figure, we will have to look into it.
All right, thank you very much, Dr. Castro, for joining us. It's always a pleasure to talk to you. I always learn a lot to listen to you talking about this subject and reading your papers. Thank you once again.
Elena Castro: Thank you my pleasure
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