“Tracking the clonal origin of lethal prostate cancer”

In a scientifically fascinating paper by Haffner et al. (with the title given above), just published in the Journal of Clinical Investigation, the authors report having been able — for the very first time — to track the clonal origin of a specific, lethal case of prostate cancer over a 17-year time frame, from the patient’s initial diagnosis to his death. The full text of this paper is currently available on line, as are the full text of the associated editorial by Brannon and Sanders, and  a summary of the paper on the Medscape Oncology web site.

The patient in question was initially diagnosed at age 47 with TxN1M0 disease. The details of the patient’s initial diagnosis (PSA, clinical stage, number of positive biopsy cores, etc.) are not provided in this paper — presumably to ensure the anonymity of the patient and his family, since he may well have been a very “public” patient in terms of his contributions to the patient discussion boards and/or other advocacy activities.

Over time the patient received an initial radical prostatectomy, followed 5 years later (when his cancer initially recurred) by other treatments such as localized radiation therapy, aggressive androgen deprivation therapy, systemic chemotherapy, and the investigational prostate cancer vaccine GVAX. Alas, the patient subsequently died of metastatic, castration-resistant prostate cancer at age 64.

What surprised the research team, however, was that the lethal clone of prostate cancer, in this case, appears to have originated from a small focus of low-grade cancer in the primary tumor — not from a larger higher-grade primary tumor or from the lymph node metastasis found at the time of surgery and removed at that time. The researchers were able to show this through the use of a series of tissue samples taken throughout the progression of the patient’s disease  and at the time of death.

The authors are careful to point out that a key limitation to the interpretation of this study is that,

… since this is the first prostate cancer case for which it was possible to carry out such detailed longitudinal characterization of the lethal cell clone from the primary cancer to distant metastases, the extent to which these findings are generalizable is unclear. Nonetheless, this case is in many regards highly typical of prostate cancer in a clinical and molecular sense, which may indicate that these findings could be more generalizable. Future studies with additional cases will be needed to test this notion.

Brannon and Sanders also emphasize this point in their editorial.

The “New” Prostate Cancer InfoLink notes that Haffner et al., in their acknowledgements, state that,

This manuscript is dedicated to the gentleman and his family, whose commitment to advancing prostate cancer research and generous tissue donation made this study possible.

That is a dedication that The “New” Prostate Cancer InfoLink would like to fully concur with and endorse.

6 Responses

  1. So, what is this paper saying, that suddenly 3+3=6 RPP patients are not as low risk as we have been lead to believe? This also flies in the face fo the study Walsh put out about his 30-year history of RRP, in which he stated that none of his organ-confined Gleason 6 patients died of prostate cancer or developed progression in his 30-year history of performing RRP.

    Just when I had put this behind me, as I was organ-confined G6, at age 42, had surgery at Johns Hopkins by Partin, and had received an e-mail from Walsh saying I didn’t have to worry about this for 30 years, I am freaked by this paper. Great!

  2. Dear Chris:

    (1) We don’t know what this paper is saying yet. Don’t over-react.

    (2) The patient described in this paper certainly did not have organ-confined disease (because he had a postive lymph node at diagnosis).

    (3) We also don’t know either his PSA level or his pathological Gleason score.

  3. Time for some research on whether low-grade cancer can spread via the biopsy process.

  4. Arch,

    I completely don’t understand how you are drawing that conclusion from this article? Not to mention the fact there has been absolutely no evidence that biopsies spread prostate cancer Did you miss the part about the patient being lymph node positive after RRP?

    What is the basis for your comment?

  5. This is data from the supplement to the reference.

    “Here we resent the clinical history of a man who was diagnosed with prostate cancer at age 47 years after presenting with a serum prostate-specific antigen (PSA) value > 40 ng/mL (Figure S1) and no evidence for distant metastases. A radical retropubic prostatectomy revealed a Gleason 4 + 4 = 8 prostate adenocarcinoma with capsular penetration, with one of seventeen sampled pelvic lymph nodes harboring a microscopic metastatic deposit. Three months following surgery, the serum PSA was 0.13 ng/mL. Five years later, despite a lack of symptomatic or imaging evidence of progressive prostate cancer, the serum PSA rose to above 6 ng/mL, and treatment with an investigational prostate cancer vaccine (GVAX) was initiated.”

    Seems to me that this is a classic case of recurrent cancer after RP treated with alternative therapies (GVAX) and delayed androgen deprivation as is the preferred way of John Hopkins. Interesting that the clonal lineage was derived from a low-grade lesion. How common would this be for other patients? Given Johns Hopkins’ own research I would say very uncommon. I wonder what would have been this patient’s results if he had been treated with early androgen deprivation.

  6. Thanks Ralph … missed that link to the appendix!

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