Germline BRCA2 mutations and management of mCRPC

A newly published paper in the Journal of Clinical Oncology has confirmed — based on a prospective study (as opposed to retrospective data) — that there is a strong risk association between a germline mutation of the BRCA2 gene and risk for metastatic castration-resistant prostate cancer (mCRPC).

The new paper by Castro et al. (a Spanish clinical research group) investigated the impact on cause-specific survival (CSS) after the diagnosis of mCRPC in patients with prostate cancer who carried germline DNA damage repair (gDDR) mutations, including germline mutations of the ATM, BRCA1, BRCA2, and PALB2 genes (see also this news item on the ScienceDaily web site).

What Castro et al. have been able to show is that, among 419 eligible patients enrolled into the so-called PROREPAIR-B study,

  • 68/419 patients with mCRPC (16.2 percent) were carriers of gDDR mutations, including
    • 14 with BRCA2 mutations
    • 8 with ATM mutations
    • 4 with BRCA1 mutations
    • 0 with PALB2 mutations
  • The presence of germline BRCA2 mutations was an independent prognostic factor for CCS (hazard ratio [HR] = 2.11; P = 0.033).
  • Compared to non-gDDR carriers, CSS was halved in germline BRCA2 carriers (17.4 v 33.2 months; P = 0.027), but …
  • The difference in CSS between ATM, BRCA1, BRCA2, and PALB2 carriers and non-carriers was not statistically significant (23.3 v 33.2 months; P = 0.264).
  • Significant interactions could be observed between gBRCA2 status and treatment type (androgen signaling inhibitor vs. taxane therapy).
  • Cause-specific and progression-free survival times were greater in gBRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes.

The authors conclude that:

gBRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of gBRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.

What we have here, therefore, is additional justification for the idea that early identification of men who are gBRCA2 carriers is important in the selection of their treatment early in the course of their disease. The question that will be even more important is going to be when one should test for the presence of the BRCA2 mutation.

The “New” Prostate Cancer InfoLink thinks there are two components to this issue:

  • Any man who comes from a family in which the BRCA2 gene is known to be prevalent my be wise to determine whether he is a carrier relatively early in life, for the simple reason that it has implications for a whole spectrum of life decisions.
  • Should all men with advanced forms of prostate cancer be screened for the presence of gDDR mutations to seek out those who are carriers of the BRCA2 gene?

From a theoretical perspective, the answer to the question raised in the second bullet is clearly, “Yes.” From a more pragmatic perspective the answer is probably, “Yes, if this is financially feasible.”

As the cost of germline screening has come down, it has become more practical to conduct such screening. But making sure that every patient with advanced prostate cancer gets screened is probably not feasible yet — however good an idea it might be.

We still don’t know the very best way to treat men who carry a BRCA2 mutation and get prostate cancer. For example, should they get treated with things like a PARP inhibitor or abiraterone acetate or enzalutamide early in the course of their disease if they are high risk (i.e., adjuvant to surgery or radiation)? This is where there is still going to be a lot of work to be done.

One Response

  1. Screening for germline DNA-repair mutations is available (ordered by any doctor) from Color Genomics for $200. It is a saliva test one does at home. It’s the one Johns Hopkins uses.

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