Poorer outcomes for BRCA1/2 carriers after standard treatment


It is not entirely surprising to come across a paper suggesting that male carriers of the BRCA1/2 genes are at risk for worse post-treatment outcomes than non-carriers of these genes after standard forms of first-line treatment for prostate cancer.

Castro et al. looked at data from a cohort of > 1,300 men who received definitive first-line treatment for local or locally advanced prostate cancer. Their objective was to assess the outcomes of patients carrying the BRCA1/2 genes and to compare them to the outcomes of the non-carriers by looking at such outcomes as metastasis-free survival and prostate cancer-specific survival over time. Specifically, the study explored such outcomes as median survival data and survival rates at 3, 5, and 10 years post-treatment.

Here are the core study data and findings:

  • The study cohort included 1,302 men with local or locally advanced prostate cancer.
    • 535/1.302 patients (41.1 percent) were treated by radical prostatectomy.
    • 767/1,302 patients (58.9 percent) were treated by radiation therapy.
    • 67/1,302 patients (5.1 percent) were BRCA1/2 carriers.
      • 35/67 BRCA1/2 carriers were treated by radical prostatectomy.
      • 32/67 BRCA1/2 carriers were treated by radiation therapy.
  • Median patient follow-up was 64 months or just over 5 years.
  • At 3 years post-treatment,
    • 90 percent of BRCA1/2 carriers were free from metastasis.
    • 97 percent of non-carriers were free from metastasis.
    • The prostate cancer-specific survival rate among BRCA1/2 carriers was 96 percent.
    • The prostate cancer-specific survival rate among non-carriers was 99 percent.
  • At 5 years post-treatment,
    • 72 percent of BRCA1/2 carriers were free from metastasis.
    • 76 percent of non-carriers were free from metastasis.
    • The prostate cancer-specific survival rate among BRCA1/2 carriers was 76 percent.
    • The prostate cancer-specific survival rate among non-carriers was 96 percent.
  • At 10 years post-treatment,
    • 50 percent of BRCA1/2 carriers were free from metastasis.
    • 84 percent of non-carriers were free from metastasis.
    • The prostate cancer-specific survival rate among BRCA1/2 carriers was 61 percent.
    • The prostate cancer-specific survival rate among non-carriers was 85 percent.
  • BRCA mutations were an independent prognostic factor for
    • Metastasis-free survival (hazard ratio [HR] = 2.36)
    • Prostate cancer-specific survival (HR = 2.17)

It is well understood that men who carry the BRCA1 or BRCA2 genes are at high risk for more aggressive forms of prostate cancer (although we are still learning exactly why this seems to be the case). It is inevitable that this increase in risk for aggressive disease was going to turn into a long-term risk for worse clinical outcomes if such patients received only standard forms of first-line treatment and/or if they weren’t diagnosed and treated early enough.

What this study clearly shows us is the importance of identifying male carriers of the BRCA1/2 genes as part of the characterization of men who come from BRCA1/2 carrier families, individualized testing programs for such men to ensure early diagnosis, and appropriately aggressive treatment to minimize the chance of early micrometastasis leading to inevitable, evident metastatic disease among such men.

2 Responses

  1. Deleterious BRCA mutations have been implicated in about six different cancer types. (They represent a small fraction of patients in each type.) Given the role of the BRCA genes, it makes sense. They are supposed to repair mistakes in DNA replication. If they aren’t completely doing the job, more mistakes will get through and occasionally one of those mistakes will be harmful. I don’t know if this study attempted to categorize the BRCA mutations. Some are a little bad, and some are really, really bad.

    PARP inhibitors may be the hopeful news for these patients. A number of years ago when Astra Zeneca was first doing trials with their PARP inhibitor, it was tested on a group of patients without any thought given to BRCA genetic status. The results of the trial were disappointing … only a few patients were helped. (It didn’t get past statistical significance.) They were going to give up on it, but some of the researchers went back to try and find what the few patients who were helped had in common. It was deleterious BRCA gene mutations.

    There are about six PARP inhibitors currently in trials. One drug being tested by BioMarin may end up being a best in class. Independent researchers at the NIH believe this drug will be significantly more effective than all the others (based on “test tube” analysis which doesn’t always translate into actual human results). BioMarin is currently running a large, Phase III trial breast cancer patients. I don’t know if they are running any prostate cancer trials.

    [Editorial comment: Here is a link to the list of trials of the BioMarin PARP inhibitor (BMN 673) in genetically defined cancers. No current trial is specific to prostate cancer.]

  2. Chuck Ryan at UCSF proposed a PARP trial to one of my buddies this week — he will be genetically tested shortly; I will let you know what drug is being considered.

    I also heard that Larry Fong was back East discussing another PARP inhibitor this past week. I believe it was olaparib with Merck?

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