Editor’s Note Is prostate cancer essentially breast cancer in men?

On September 9, 1985, Richard Peto a previously obscure Oxford statistician changed cancer research forever. I have a grainy videotape of Peto's historic presentation at the NIH Consensus Conference on Early Breast Cancer, and you can see the glee in his eyes as he systematically destroys the widespread previously held belief that adjuvant tamoxifen had no effect on breast cancer mortality.

That day in Bethesda was the beginning of the mega-randomized adjuvant trial. Prior to this presentation, many individual breast cancer trials had failed to detect a mortality benefit from tamoxifen. Peto clarified this issue by explaining that to detect a significant impact of a therapy on an endpoint, it is critical for a study to have enough observed events, as opposed to enough enrolled patients or follow-up time.

Specifically, to detect an impact on mortality, enough deaths must be observed. Peto then went on to demonstrate that not enough deaths had occurred in the individual breast cancer trials to reliably evaluate whether a modest but humanly important survival benefit was present. However, when he combined these studies into a meta-analysis of virtually every randomized trial of adjuvant tamoxifen ever conducted, enough deaths were observed to detect a very substantial mortality reduction.

Over the years, I have recorded several interviews with Peto for our breast cancer audio series. In 1990 I was honored to attend a closed meeting of his breast cancer trialists' group in an ancient lecture hall in Oxford. Peto, a bit of a maverick, sent out premeeting questionnaires to the attendees to ascertain what they believed the second meta-analysis would demonstrate. For two days, he presented overhead transparencies (he still doesn't use slides or PowerPoint presentations) of the trialists' predictions and the actual results, which, of course, were vastly different.

Shortly after I started this series several years ago, I ran into Sir Richard (by this time he had been knighted for his work) at a meeting and asked why he wasn't doing a similar meta-analysis of adjuvant hormonal trials in prostate cancer. He confided in me that just such a study was ongoing, and he graciously invited me back to Oxford for his first presentation of these data in September 2002. Only two other US-based physicians were part of this small group, and I sat in the back of the room with one of them, Rowan Chleblowski, a medical oncologist who has published extensively on breast cancer but also participates in prostate cancer research.

Rowan and I were gaggle-mouthed as we watched the data unfold. The disease-free and overall survival curves for the relatively scant trials of adjuvant endocrine intervention of prostate cancer looked eerily similar to the old breast cancer graphs.

An unfortunate similarity between the breast and prostate cancer overviews is that public presentation of the actual data is embargoed until formal publication of the definitive paper. This often takes years. To this date, the only public discussion of this fascinating analysis was Peto's "Best of Oncology" lecture in Copenhagen at the 2003 ECCO meeting, during which he presented both the breast and prostate cancer overview. As a result, his presentation with slides is posted on the ECCO website (http://www.fecs.be/conferences/ecco12/virtualmeetings.shtml).

During the upcoming AUA annual meeting, our group will host a "think tank" of 12 prostate cancer research leaders. As part of the agenda for this event, we intend to show the web presentation of Peto's breast-prostate talk. This will be one of many topics discussed at the "think tank," and the proceedings will be recorded and edited into a special issue of this series. It will be extremely interesting to hear the responses of this diverse group of practitioners, which includes Edward Messing, the other American and only US-based urologist to attend the 2002 Oxford meeting.

Likely comments include the fact that Peto combined trials in which the primary local modality was surgery or radiation therapy. This methodology is based on the long-held belief in breast cancer that adjuvant therapy targets micrometas-tases irrespective of the type of local treatment. In contrast, urologic oncologists generally do not accept that premise regarding prostate cancer.

Another controversy will involve the fact that most of these adjuvant prostate trials treated patients at the onset of clinical rather than PSA progression.

Therefore, these data are not relevant to the current standard of care whereby most men are treated for biochemical failure rather than for clinically apparent disease.

The counterclaim to that argument is that no randomized trial has demonstrated that treating at PSA progression results in the same outcome as adjuvant treatment. Again, this is a long-held belief in urology that will challenge the Peto data.

To "muddy the waters" further, it is also interesting to consider that two small clinical trials in breast cancer have suggested that treating on tumor marker progression results in greater survival than waiting for clinical relapse. No breast cancer trial has ever compared adjuvant therapy to treating at biochemical relapse.

In this issue of Prostate Cancer Update, Laurence Klotz comments on the profound differences in the research cultures that exist in breast cancer and prostate cancer. He notes that his colleague at the University of Toronto, oncologist Dr Paul Goss, recently published a lead article in the New England Journal of Medicine on the use of an aromatase inhibitor in women who have completed adjuvant therapy with tamoxifen.

Dr Klotz notes that the Goss study garnered considerable attention and led to an immediate change in clinical practice of oncologists. He also points out that the benefits of therapy seen in that study were the same or perhaps less than those observed with the use of maximum androgen blockade (MAB) in prostate cancer. However, MAB has received a lukewarm reception by urologists.

Dr Klotz will also be at our "think tank," and it will be interesting to observe how this dialogue unfolds, particularly since he is presenting a paper at the AUA suggesting that the benefits of MAB using bicalutamide may be considerably greater than MAB with other antiandrogens.

In addition to the analogous research issues on endocrine therapy, many other fascinating similarities exist between breast and prostate cancer. Chemoprevention has been demonstrated to alter the natural history of both diseases, but the clinical implications are uncertain. For both types of cancer, current therapies have sexual implications, and the treatment options for local disease control have very different long-term implications.

Perhaps most encouraging is that the mortality rates for both breast and prostate cancer are significantly decreasing. Peto noted in his ECCO lecture that this reduction in mortality is likely the result of earlier diagnosis and earlier use of endocrine intervention for both tumors. Regrettably, the specialization of cancer care means that investigators in both fields rarely meet. This is unfortunate because each group might teach the other a great deal.

— Neil Love, MD