Why inheriting a particular gene may be important for prostate cancer patients


An important poster that your sitemaster managed to “miss” at the recent ASCO meeting (because he was at another meeting while it was being presented) has just been discussed on the MedPage Today web site.

Hearn et al. (abstract no. 5015) — but see also this report on the MedPage Today web site — have given  us an excellent example of how “individualized” or “personalized” medicine may be able to tell us how well (or how not so well) an individual patient with progressive prostate cancer might respond to standard forms of androgen deprivation therapy (ADT). Their data is based on identification of whether the patient carries the HSD3B1(1245C) allele (a non-wild-type form of the HSD3B1 gene).

It has been known for a while that selected mutations to the HSD3B1 gene are associated with an increased ability for the intratumoral synthesis of dihydrotestosterone or DHT, which is key to the stimulation of the growth of prostate cancer cells. Some of us are born with such mutations, but most of us aren’t. So Hearn et al. set out to investigate whether carriers of these mutations (who had inherited them at birth) would show signs of resistance to ADT sooner than men who do not carry such mutations. Their hypothesis was that this would prove be the case.

Basically, what Hearn et al. have shown is that not only do carriers of the HSD3B1(1245C) allele who get progressive prostate cancer indeed have greater risk for early androgen resistance; they also showed that the more such mutations one has, the greater one’s risk for early androgen resistance.

This was a complex study involving detailed genetic analysis of tissues from several different patient data sets and correlation of those data with the patients’ clinical outcomes over time. However, fundamentally, Hearn et al. have been able to show the following:

  • They looked at data from 443 patients in three different cohorts
    • A primary cohort of 118 patients
    • A post-prostatectomy validation cohort of 137 patients
    • A metastatic validation cohort of 188 patients.
  • Average (median) progression-free survival decreased as the number of variant alleles inherited increased:
    • 6.6 years in men who inherited normal, wild-type HSD3B1 from both of their parents
    • 4.1 years in men who inherited HSD3B1(1245C) from one of their two parents (heterozygotic)
    • 2.5 years in men who inherited HSD3B1(1245C) from both of their parents (homozygotic)
  • Average (median) distant, metastasis-free survival also decreased as the number of variant alleles inherited increased:
    • 9.1 years in men who inherited normal, wild-type HSD3B1 from both of their parents
    • 6.8 years in men who inherited HSD3B1(1245C) from one of their two parents (heterozygotic)
    • 3.6 years in men who inherited HSD3B1(1245C) from both of their parents (homozygotic)
  • Overall survival also decreased at 5 and 10 years with the number of variant alleles inherited:
    • 82 percent at 5 years and 55 percent at 10 years in the normal, wild-type men
    • 74 percent at 5 years and 35 percent at 10 years in the heterozygotic HSD3B1(1245C) patients
    • 58 percent at 5 years and 0 percent at 10 years in the homozygotic HSD3B1(1245C) patients
  • On multivariable analysis, the impact of HSD3B1 genotype was maintained
    • On risk for metastasis (hazard ratio [HR] = 2.8; P = 0.023)
    • On risk for death (HR = 3.3; P = 0.016)
  • The above findings from the primary cohort were independently validated by the data from the two secondary cohorts.

Hearn et al. conclude that:

Inheritance of the HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis predicts innate resistance to ADT in prostate cancer.

Now this is a potentially practice-changing finding because it means that we now know, upfront, that there seems to be a subgroup of men who are going to do significantly less well than most men on ADT because of their inherited genetic make-up. Note that not a single patient with homozygous HSD3B1(1245C) survived for 10 years.

Of course what we do not know yet is how to deal with this. Should we try to delay the use of ADT for as long as possible in such men? Should we treat them with a different type of ADT? What? We just don’t know yet.

It seems probable that not only do these data need to be confirmed by an independent group of researchers using quite different data sets (to confirm that these results are “real”). We are also going to need to start to investigate how best to treat this subgroup of men — starting with a determination of just how common this genetic risk is in the population at large and in the population of men with progressive prostate cancer specifically.

One commentator referred to in the MedPage Today article apparently found the results of this study by Hearn et al. to be “somewhat surprising”. The “New” Prostate Cancer InfoLink really does not find them surprising at all. We know all too well that adenocarcinoma of the prostate (as opposed to the rarer subtypes of prostate cancer) is not one disease but more like 25 different types of one basic disease. It is therefore hardly surprising at all that one’s basic genetic make-up may have profound impact on how one responds to certain types of treatment. Indeed, The “New  Prostate Cancer InfoLink is quite sure that as we start to learn more about how individual biology affects response to treatments over time, we are going to find many more small variations like this in how well individuals respond to treatment. We may also be able to use such data to begin to explain how it is that there are some men who can live for 2o+ years with metastatic prostate cancer and other who are likely to have a much faster demise (unless we can work out how to treat them differently and better).

3 Responses

  1. Thank you for all your valuable reports. This one has typing error.

    The sentence, “Note that not a single patient with heterozygous HSD3B1(1245C) survived for 10 years” should read: “Note that not a single patient with homozygous HSD3B1(1245C) survived for 10 years.”

  2. Thank you Richard. Mea culpa. This will be corrected in seconds!

  3. This might be a good place to plug an excellent new book by Siddhartha Mukherjee — The Gene. I’m on the last section, and have found it hard to put down. Similar to his writing about cancer in The Emperor of All Maladies, he puts the entire history of our knowledge about genes into wonderful perspective.

    With astounding advances in diagnostics and treatments (based on a rapidly growing knowledge of molecular biology) being announced almost every day, this book will help catch interested layman (such as myself) right up to date. A few months back, the UK authorized doctors to create babies with three parents. (It’s in this book.) A number of companies are testing gene therapies for blood-based diseases such as sickle cell anemia. One group, among much controversy, recently announced they they are planning on building an entire human genome from scratch. This knowledge obviously comes with some huge ethical and safety questions (explored in the book). I have no financial stake in the success of the book … just recommending a good read.

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