THE BIOLOGY OF HORMONE REFRACTORY PROSTATE CANCER: Why Does It Develop?

Since the pioneering studies of Huggins nearly 60 years ago, it has been known that prostate cancer cells, like certain normal prostate epithelial cells, can chronically depend on a critical level of androgenic stimulation for their net continuous growth and survival. It is on this basis that androgen ablation has been used as standard systemic therapy for metastatic prostate cancer. During this year, 41,000 men will die of prostate cancer in the United States.29 Essentially all of these patients will have received treatment with a variety of androgen ablation techniques. There are a multitude of excellent means of ablating serum androgens, including chronic treatment with luteinizing hormone releasing hormone analogues alone and in combination with antiandrogens, surgical orchiectomy, or both. A recent, large, randomized prospective clinical trial compared the effectiveness of gold standard androgen ablation (i.e., surgical orchiectomy) as monotherapy with a combination approach of orchiectomy plus concomitant antiandrogen treatment in patients with metastatic prostate cancer.13 The data suggest that there is no additional advantage of combination approaches when compared with orchiectomy alone in terms of the time to progression or overall survival.13 None of the patients with definitive metastatic disease were cured by such androgen ablation therapy regardless of how aggressively it was given.13 Thus, androgen ablation therapy is not curative for metastatic prostate cancer because it does not eliminate the portion of prostate cancer cells within a patient with metastatic disease that no longer depend on the effects of androgen for stimulation of their continuous growth and survival. These cancer cells are androgen-independent and thus hormone refractory.

The entire issue of the development of resistance to androgen ablation therapy is based on the fact that at least a portion of the cells present within a patient with prostate cancer before therapy is begun depend on androgenic stimulation for their proliferative growth and survival. If a tumor does not have at least some cells that initially require androgen stimulation for their survival, no response to subsequent androgen ablation therapy would be observable clinically. Indeed, the only detectable clinical response to androgen ablation therapy that allows a tumor to be defined as responsive is that, following such therapy, the cancer either stops increasing in size or partially or completely regresses. This response requires the presence of some cells within the tumor that will stop proliferating and die as a result of androgen ablation therapy. If a tumor is composed of cells that either are not androgen-dependent for growth and survival (i.e., androgen-independent) or are only androgen-sensitive (i.e., faster growing in the presence of androgen but do not die when androgen stimulation is inhibited), treatment of such a cancer with androgen ablation therapy will not affect a clinically detectable response because such therapy will either have no effect or will only slow the continuing growth of the cancer. Such a cancer would be clinically defined as an unresponsive (i.e., hormone-refractory) tumor even though it could contain androgen-sensitive cancer cells. A discussion of the development of clinical resistance to androgen ablation therapy a priori must take into account, regardless of the mechanism, the process of the emergence of androgen-independent or sensitive cancer cells in a tumor that before androgen ablation therapy had at least a significant number of androgen-dependent cancer cells present. To understand how such androgen-independent or sensitive (i.e., hormone refractory) prostate cancer cells develop, an appreciation of how normal prostatic epithelial cells (i.e., cells of origin for prostate cancer) are organized and respond to androgen is required.