Review: Molecular Pathogenesis of Premalignancy Series Premalignancy in Prostate Cancer: Rethinking What We Know Angelo M. De Marzo 1–5 , Michael C. Haffner 1,2,4 , Tamara L. Lotan 1–5 , Srinivasan Yegnasubramanian 1–5 , and William G. Nelson 1–5 Abstract High-grade prostatic intraepithelial neoplasia (PIN) has been accepted as the main precursor lesion to invasive adenocarcinoma of the prostate, and this is likely to be the case. However, in an unknown number of cases, lesions fulfilling the diagnostic criteria for high-grade PIN may actually represent intra-acinar or intra- ductal spread of invasive carcinoma. Intriguingly, this possibility would not contradict many of the findings of previous epidemi- ologic studies linking high-grade PIN to carcinoma or molecular pathologic studies showing similar genomic (e.g., TMPRSS2-ERG gene fusion) as well as epigenomic and molecular phenotypic alterations between high-grade PIN and carcinoma. Also, this possibility would be consistent with previous anatomic studies in prostate specimens linking high-grade PIN and carcinoma in autopsy and other whole prostate specimens. In addition, if some cases meeting morphologic criteria for PIN actually represent intra-acinar spread of invasive carcinoma, this could be an impor- tant potential confounder of the interpretation of past clinical trials enrolling patients presumed to be without carcinoma, who are at high risk of invasive carcinoma. Thus, in order to reduce possible bias in future study/trial designs, novel molecular pathology approaches are needed to decipher when an apparent PIN lesion may be intra-acinar/intra-ductal spread of an inva- sive cancer and when it truly represents a precursor state. Similar approaches are needed for lesions known as intraductal carcinoma to facilitate better classification of them as true intra-ductal/acinar spread on one hand or as precursor high- grade PIN (cribriform type) on the other hand; a number of such molecular approaches (e.g., coevaluating TMPRSS-ERG fusion and PTEN loss) are already showing excellent promise. Cancer Prev Res; 9(8); 648–56. Ó2016 AACR. Introduction Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer-related death in men in the United States. While the death rate has been decreasing in some countries, including the United States, the aging population and the increasing "westernization" in a number of parts of the world is projected to produce an increasing burden of cases worldwide for the foreseeable future. Early detection, through serum pros- tate-specific antigen (PSA) screening coupled with improved treatment of localized disease, is likely responsible for much of the decrease in death rate (1). Nevertheless, as a result of the potential harmful side effects associated with radical treatment of men who do not necessarily need treatment, PSA screening is controversial (2). Thus, in addition to early detection with serum PSA screening and treatment of established disease, there has been great interest in developing strategies to prevent the disease altogether or to intercept the disease before it can progress to aggressive forms. Attempts to prevent prostate cancer were conducted in two different large prospective randomized clinical trials (RCT) employing the 5-a reductase inhibitors finasteride (the Prostate Cancer Prevention Trial or PCPT; ref. 3) and dutasteride (Reduc- tion by Dutasteride of Prostate Cancer Events or REDUCE; each vs. placebo; ref. 4). Both trials showed a reduction in the period- prevalence of prostate cancer of approximately 25%. However, in both trials, there was a small increase in the total number of patients diagnosed with higher grade disease; and, with long-term follow-up in the PCPT, there was no apparent survival advantage in patients in the treatment arm (5). Thus, neither of these agents are currently being employed widely for the chemoprevention of prostate cancer. A third large RCT (Selenium and Vitamin E Cancer Prevention Trial or SELECT) consisted of treatment with the antioxidants vitamin E and/or selenium which showed a lack of efficacy (6). A number of chemoprevention trials employed enrichment of men with high risk of cancer development because they were diagnosed with high-grade PIN, in which attempts were made to reduce the development of invasive disease with a variety of agents (reviewed in refs. 7, 8); such trials have not resulted in strong candidates for use as chemopreventative agents in any population to date (Table 1). Proposed Alternative Prostate Cancer Precursor Lesions In addition to the well-accepted lesion of high-grade PIN, a number of different histologic lesions have been proposed as potential precursor lesions for prostate cancer, such as ade- nosis (atypical adenomatous hyperplasia) and proliferative Departments of Pathology 1 , Oncology 2 and Urology 3 , The Johns Hop- kins University School of Medicine, The Sidney Kimmel Comprehen- sive Cancer Center 4 and The Brady Urological Research Institute at Johns Hopkins 5 , Johns Hopkins University, Baltimore, MD. Corresponding Author: Angelo M. De Marzo, Johns Hopkins University, 1550 Orleans Street, Koch Cancer Research Bldg., CRB II – 144, Baltimore, MD 21231. Phone: 410-614-5686; Fax: 410-502-9817; E-mail: ademarz@jhmi.edu doi: 10.1158/1940-6207.CAPR-15-0431 Ó2016 American Association for Cancer Research. Cancer Prevention Research Cancer Prev Res; 9(8) August 2016 648 Downloaded from http://aacrjournals.org/cancerpreventionresearch/article-pdf/9/8/648/2255629/648.pdf by guest on 10 June 2022