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INTRODUCTION

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Over the past decade, insight into the biological basis of prostate cancer development and progression has influenced our approach to treating patients with the disease. While research efforts have historically focused on the prostate cancer epithelial cell, there is growing evidence that interactions between the host tissue microenvironment and the cancer epithelial cell are critical for tumorigenesis. Understanding the bidirectional cancer cell–host interaction now dominates prostate cancer research.

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Prostate cancers have recognizable clinical features that allow anticipation of their clinical behavior. Fortunately, the progression from localized, androgen-dependent disease to castration-resistant disease with bone-forming metastases occurs in only a minority of patients. To conceptualize the clinical heterogeneity displayed along this continuum, patients have historically been assigned to different “clinical states” (eg, metastatic castrate vs noncastrate) to help structure treatment recommendations and therapy development (1,2). However, this approach has been limited by the fact that patients within each state display wide biological heterogeneity and response to therapy. To address this, improved classification of the disease based on the underlying molecular mechanisms of progression is necessary. This effort will create a “marker-driven” strategy to more reliably predict prostate cancer progression, permit optimal selection of specific therapies for individual patients, and apply therapy to only those patients who need it. This strategy will favorably improve the outcome of selected patients threatened by their disease while avoiding unnecessary morbidity to the majority who are not.

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EPIDEMIOLOGY AND CLINICAL FEATURES

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Prostate cancer is a major health-care challenge in the United States (3). It is the second most common cancer in men (behind skin cancer) and the second leading cause of cancer death (behind lung cancer). There are a number of unique clinical features of prostate cancer that distinguish it from other solid tumor types:

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  1. Despite the high prevalence of prostate cancer, the majority of patients diagnosed with the disease eventually die from other causes. This is in striking contrast to lung cancer, where the majority of patients diagnosed with the disease die from it.

  2. Cancer of the prostate often has a prolonged natural history. This is evidenced by a high incidence of occult malignancy in autopsy series of men who die from nonprostate cancer causes and in clinically normal prostates of men undergoing cystoprostatectomy for bladder cancer. Therefore, over the course of a normal lifetime, most men will develop “clinically occult” prostate cancer that will never produce symptoms, require treatment, or cause death.

  3. The incidence of detected carcinoma increases with age.

  4. Androgens are a major driving force in normal prostate development and are implicated in tumorigenesis.

  5. Prostate cancer is typically multifocal, commonly presenting as synchronous carcinomas arising in multiple locations, and the malignant potential is determined by the sum of the primary and secondary grades (Gleason score). Thus, biologic heterogeneity is an inherent property of each tumor.

  6. Clinical prostate cancer is more prevalent in Western than Eastern societies, although ...

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