Prostatic intraepithelial neoplasia (PIN) and other prostatic lesions as risk factors and surrogate endpoints for cancer chemoprevention trials.
The most efficient strategy for chemoprevention clinical trials are short-term studies which focus on surrogate endpoint biomarkers (SEBs) in high-risk target populations. High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer, and is found in a significant number of routine contemporary needle biopsies without cancer. The frequency and extent of PIN are decreased with androgen deprivation therapy, suggesting that it is a suitable endpoint biomarker for modulation. Potential SEBs for screening chemopreventive agents for prostate cancer in short-term Phase II trials include (1) histologic premalignant lesions, such as high-grade PIN; (2) biochemical markers, including prostate-specific antigen (PSA) serum concentration; and (3) morphometric markers, including nuclear texture, shape, and roundness; size and number of nucleoli; and number of apoptotic bodies; (4) proliferation markers, including MIB-1 and PCNA; (5) genetic markers, including nuclear DNA content (ploidy), oncogene c-erbB-2 (HER-2/neu) expression, fluorescence in situ hybridization for chromosome 8; and PSA-producing cells in the blood detected by reverse transcriptase polymerase chain reaction; and (6) differentiation markers, such as microvessel density as a determinant of angiogenesis. Each of these endpoint biomarkers is measured easily and accurately in serum or in tissue specimens such as formalin-fixed, paraffin-embedded needle biopsies, and may be modifiable by intervention. The clinical utility of these biomarkers as modulatable endpoints in prostate cancer chemoprevention needs to be demonstrated in future clinical trials.
Bostwick
D G
DG
Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Aquilina
J W
JW
D015415:Biomarkers / Q000032:analysis*; D002455:Cell Division; D018890:Chemoprevention; D002898:Chromosomes, Human, Pair 8 / Q000737:chemistry; D002986:Clinical Trials as Topic; D004247:DNA / Q000032:analysis; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology; D011379:Prognosis; D011467:Prostate / Q000473:pathology*; D017430:Prostate-Specific Antigen / Q000032:analysis; D019048:Prostatic Intraepithelial Neoplasia / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D012307:Risk Factors
D015415:Biomarkers; D004247:DNA; D017430:Prostate-Specific Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases