Prostate Cancer

Reviewing the Literature

RIU0263_04-20.qxd 26/4/06 3:59 Page 89 Prostate Cancer Prostate Cancer Translation Research in Prostate Cancer Reviewed by Danil V. Makarov, MD, Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2006;8(2):89-91] © 2006 MedReviews, LLC ecent publications in the area of prostate cancer have highlighted deficiencies in the use of prostate-specific antigen (PSA) as the solitary biomarker for this disease. The Prostate Cancer Prevention Trial demonstrated a significant incidence of prostate cancer (including highgrade prostate cancer) at PSA levels traditionally thought to be in the normal range; yet the problem of over-diagnosis of clinically insignificant prostate cancer still remains.1,2 A need exists to develop a test or tests with greater sensitivity for the detection of prostate cancer, as well as a test or tests to improve specificity for the detection of clinically relevant prostate cancers.3 Only recently has our knowledge of prostate cancer biology been used to develop chemotherapeutic agents able to prolong life in advanced disease.4,5 A better knowledge of molecular pathways can bring to light new potential targets for prostate cancer treatment. In two recently reported studies, investigators have used data from high-throughput gene microarray experiments to bring us closer perhaps to solving these challenges. These studies demonstrate the potential power of molecular biology to improve clinical practice and, simultaneously, how much more we have to learn. R Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer cancer outlier profile analysis on the Oncomine database (the University of Michigan database that combines the results of 132 gene expression data sets representing 10,486 microarray experiments) to determine candidate chromosomal aberrations of known causal cancer genes over-expressed in prostate cancers. Two genes encoding ETS family transcription factors, ERG and ETV1, were identified as over-expressed outliers in prostate cancer. These two genes are known to play a role by binding specific regions of deoxyribonucleic acid (DNA) and activating multiple proteins involved in regulating cell growth pathways in Ewing’s sarcoma and myeloid leukemias. The researchers next looked for ERG and ETV1 expression by quantitative polymerase chain reaction. ETV1 was demonstrated in the LNCaP cell line and two surgical specimens (a primary prostate tumor and a lymph node metastasis) from a patient with hormonerefractory disease. ERG was discovered in a lymph node from another patient and also discovered in the VCaP and DuCaP cell lines. To determine the gene immediately attached to these transcription factors, the group sequenced sequential exons “exon-walking” on the transcripts and identified recurrent gene fusions of the 5' untranslated region of TMPRSS2, an androgen-sensitive serine protease over-expressed specifically in prostate adenocarcinoma. Using fluorescence in situ hybridization to directly image the specific genes in question, the researchers found that 23 (79%) of 29 prostate cancer samples (13 localized and 16 metastatic) harbored ERG rearrangement or ETV1 gene fusion. These rearrangements might, thus, be a very frequent event in the development of prostate cancer. To explain their function, the group performed experiments measuring ERG expression in prostate cancer cell lines. They combined cells with known ERG rearrangements with various combinations of androgens and anti-androgens, and their data suggest that, in prostate cancer, TMPRSS2 mediates the over-expression of ETS family members, making these normally androgen-insensitive genes androgen responsive. Tomlins SA, Rhodes DR, Perner S, et al. Science. 2005;310:644-648. Many altered genes involved in cancer development have been identified by analyzing recurrent chromosomal rearrangements in leukemias, lymphomas, and sarcomas. Epithelial tumors, such as prostate adenocarcinoma, have many recurrent gene chromosomal rearrangements, yet few of them have been determined to be specific for these tumors. The authors used a bioinformatics technique called The truly exciting finding here is that these chromosomal rearrangements might potentially be used as future targets for therapy. These chromosomal rearrangements seem to be very widespread in prostate cancer; thus, one day these aberrations, if detected, might be correlated to disease prognosis or to the detection of extraprostatic disease. The truly VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY 89 RIU0263_04-20.qxd 26/4/06 3:59 Page 90 Prostate Cancer continued exciting finding here is that these chromosomal rearrangements might potentially be used as future targets for therapy or as biomarkers. More work will need to be done to determine this phenomenon’s frequency in a larger sample of prostate cancers, as well as to determine whether this pathway can be halted by exogenous chemotherapy. Autoantibody Signatures in Prostate Cancer Wang X, Yu J, Sreekumar A, et al. N Engl J Med. 2005;353:1224-1235. It has long been thought that as prostate epithelial cells change from benign to malignant the cells begin to produce characteristic proteins that might be detected by the host as foreign antigens, provoking an immune response. Such a response, which potentially limits the growth of the cancer, could be exploited to determine the presence of a tumor that might be difficult to detect by traditional screening methods (serum PSA assay and digital rectal examination). Wang and colleagues at the University of Michigan attempted to diagnose prostate cancer by screening patients’ sera for these autoantibodies. To determine relevant autoantibodies, a set of proteins had to be identified for screening. The researchers extracted messenger ribonucleic acid (mRNA) from 6 patients’ prostate cancer tissue (3 with organ-confined disease and 3 with stage T3). This was then reverse-transcribed into stable complementary DNA (cDNA) and inserted into a phage display library. Purified antibodies from the serum of 10 control patients were used to remove phages containing any proteins expressed in normal persons, thus decreasing “noise” from the screening proteins. Next, antibodies from the sera of 19 prostate cancer patients were used to select phages expressing proteins from prostate cancer in a process dubbed iterative biopanning; this increases the “signal” from the screening library. A total of 2304 single colonies were then spotted onto a slide treatable with serum from a test subject; antibodies from the subject would adhere to a spot expressing its complementary antigen. These clones were tested against 20 serum samples from prostate cancer patients and 11 controls. The 186 phage peptides identified as having the greatest differences in expression were used in focused microarrays. Serum samples from 119 patients with prostate cancer and 138 controls were screened with the assay. A model was developed on a training set using 22 phage proteins, only 4 of which (BRD2, eIF4G1, RPL22, and RPL13a) were derived from in-frame, named coding sequences known to be over-expressed in prostate cancer. This validated model had strong performance characteristics, able to discriminate prostate cancer from control with 88.2% specificity 90 VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY (95% confidence interval [CI] 0.78-0.95) and 81.6% sensitivity (95% CI 0.70-0.90). The area under the receiver operating curve for the autoantibody signature was 0.93 (95% CI 0.88-0.97), superior even to the PSA curve (which was very strong because these patients were identified through PSA screening), 0.80 (95% CI 0.71-0.88). Logistic regression revealed that the phage–peptide panel provided additional discriminative power over PSA (P
.001). The model was also used on alternative serum samples. Only 5 of 14 postprostatectomy samples were classified as prostate cancer, and only 3 of 11 serum samples from patients with hormone-refractory disease. Of 30 samples from patients with lung adenocarcinoma, 9 were classified as having prostate cancer, suggesting the assay has some degree of nonspecificity across tumor types. Others have voiced some major criticisms of this very important work. The assay is based on the mRNA of only 6 prostate cancer patients. Other prostate cancers might have important antigens not expressed in these 6 particular patients. Some argue that this is irrelevant because only four of the proteins are actually coded for. The rest could be mimeotypes, random sequences similar enough to significant proteins in prostate cancer that they are “detected” by antibodies in any patient serum. A random collection of phage proteins could then be used, rather than a cancer tissue–based cDNA microarray.6 Are the significant tumors actually being detected? Would more dangerous tumors not evade detection better, as in the case of hormone-refractory tumors? A common problem arising when many variables are used to predict an event based on few observances is model over-fitting. The authors even note that the predictive capability is the same regardless of This is a very strong beginning for the use of tumor immunomics in prostate cancer. whether 10 or 22 phage proteins are used. With the 95% CI as the cutoff for significance, 5% of all variables examined could be significant by pure chance. It could be that this model predicts too well in this small sample of tumors but might have limited ability when verified against other, larger tumor banks. Despite these obvious shortcomings, this is a very strong beginning for the use of tumor immunomics in prostate cancer. We anticipate more important work from this field in the future. References 1. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level
or 4.0 ng per milliliter. N Engl J Med. 2004;350:2239-2246. RIU0263_04-20.qxd 26/4/06 3:59 Page 91 Urinary Incontinence 2. 3. 4. 5. 6. Carter HB. Prostate cancers in men with low PSA levels—must we find them? N Engl J Med. 2004;350:2292-2294. Carter HB, Isaacs WB. Improved biomarkers for prostate cancer: a definite need. J Natl Cancer Inst. 2004;96:813-815. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. Finn OJ. Immune response as a biomarker for cancer detection and a lot more. N Engl J Med. 2005;353:1288-1290. Urinary Incontinence Is Estrogen for Urinary Incontinence Good or Bad? Reviewed by Dae Kyung Kim, MD,* Michael B. Chancellor, MD† logic and trial evidence has shown both beneficial and harmful effects of estrogen on UI. Does MHT really help UI? The evidence and opinions vary widely. The American College of Obstetricians and Gynecologists has stated, “for genitourinary symptoms associated with menopause, estrogen and progestin have been shown to be beneficial.” However, a recent Cochrane review assessing the effects of estrogen for the treatment of UI concluded that treatment with estrogen alone was associated with perceived improvement or cure compared with placebo but that larger trials were needed. Given the recent report that estrogen alone was shown to increase the risk of stroke with no benefit for coronary heart disease, the foundation to support the use of MHT for UI is questioned. Effects of Estrogen With and Without Progestin on Urinary Incontinence Hendrix SL, Cochrane BB, Nygaard IE, et al. *Department of Urology, Eulji University School of Medicine, Daejeon Korea; †Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA JAMA. 2005;293:935-948. [Rev Urol. 2006;8(2):91-92] Estrogen Treatment for Urinary Incontinence: Never, Now, or in the Future? © 2006 MedReviews, LLC DuBeau CE. JAMA. 2005;293:998-1001. enopausal hormone therapy (MHT) has long been used to improve various postmenopausal symptoms. Until recently, MHT was credited with many benefits well beyond the indications for symptomatic relief of hot flashes, night sweats, and vaginal dryness. Improvement of urinary incontinence (UI) was one of the well-known benefits of MHT in urology practice. MHT for the treatment of UI was based on assumptions about biological mechanisms, associations of various symptoms with menopause, and small, uncontrolled trials. The lower urinary tract shares a common embryologic origin with the genital tract and the urogenital sinus, and estrogen and progesterone receptors are present in the vaginal epithelium, urethra, and bladder trigone. Reduction of estrogen after menopause leads to significant atrophic changes in the genital tract, which might lead to itching, burning, dryness, and dyspareunia. Coexistent symptoms, including urinary frequency, urgency, UI, and recurrent urinary tract infections, were thought to be related to atrophy of the urinary tract. Because MHT has a beneficial effect on vaginal mucosa, in particular in improving symptoms of atrophic vaginitis, it was suggested that MHT might also improve UI. However, epidemio- M This large, randomized clinical trial of MHT seems to resolve the controversy around estrogen and UI. The primary aim was to determine the effects of MHT (estrogen plus progestin or estrogen alone) on the 1-year incidence and severity of symptoms of stress, urge, and mixed UI in healthy postmenopausal women. Treatment with daily tablets of 0.625 mg of conjugated equine estrogen (CEE) alone or 0.625 mg of CEE plus 2.5 mg of medroxyprogesterone acetate increased new-onset UI among continent women and worsened the characteristics of UI among already-incontinent women. This effect persisted through 3 years. The results of this study consistently demonstrate that there is no role for estrogen in the prevention or treatment of UI, and this is the first randomized trial to demonstrate that estrogen alone increased UI. Although the definition of UI used in this study was somewhat different from the International Continence Society definition and led to more “yes” responses, the baseline prevalence was consistent with more recent studies that also defined UI broadly as any leakage of urine in the last 12 months. Because these findings are based on one specific type, route of administration, and dosage of estrogen (with or without VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY 91