Prevention, Complementary Therapies, and New Scientific Developments in the Field of Prostate Cancer

16th International Prostate Cancer Update

RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S9 16TH INTERNATIONAL PROSTATE CANCER UPDATE Prevention, Complementary Therapies, and New Scientific Developments in the Field of Prostate Cancer Philip Kantoff, MD Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Prostate cancer prevention and therapies were reviewed in a recent update. Finasteride, a 5
reductase inhibitor, shows promise as a preventative; however, it may increase the incidence of high-grade cancer. There are ongoing studies regarding the positive effects of antioxidant therapy (vitamin E, selenium, and lycopene) on the prevention of prostate cancer; initial results are promising. Lipid-lowering drugs are associated with a statistically significant reduction in prostate cancer incidence, a 46% reduction in risk of high-grade or high-stage prostate cancer, and a 66% reduction in mortality from prostate cancer. Overexpression of transcription factors is caused by translocation of the promoter of the TMPRSS2 gene, which may be a primary event in prostate cancer. Immunomic profiling with use of autoantibodies directed against prostate-specific antigens may be used to identify cases of prostate cancer. [Rev Urol. 2006;8(suppl 2):S9-S14] © 2006 MedReviews, LLC Key words: Prostate cancer • 5a reductase inhibitors • Prostate-specific antigens • Antioxidants here are a number of agents that have been studied for the purpose of prostate cancer prevention. The agents furthest along clinical development are the 5
reductase inhibitors, in particular, finasteride. In the Prostate Cancer Prevention Trial (PCPT) Thompson and colleagues1 randomized 18,882 men older than 55 years who at trial entry had no evidence of prostate cancer (prostate-specific antigen [PSA]  3.0 ng/mL and normal results on digital rectal T VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S9 RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S10 Prostate Cancer Prevention, Therapies, and Developments continued S10 VOL. 8 SUPPL. 2 2006 versus 6.2  1.4 ng/mL for men with a testosterone greater than 300 ng/mL (P  .001). Finally, Platz and colleagues4 studied 460 cases and 460 age-matched controls in the Health Professionals Follow-up Study and found that plasma total testosterone concentration was positively associated with low-grade disease (Gleason sum  7: odds ratio [OR], 1.91; 95% did not change for the duration of the study. In fact, there were no differences in high-grade cancers at the mandated end of study biopsy (Figure 1). Thus the effect on grading occurred entirely at the beginning of the study, perhaps suggesting that this was not biologically meaningful. Second, Dr. Lucia compared the characteristics of the high-grade tumors Plasma total testosterone concentration was positively associated with low-grade disease and inversely associated with high-grade disease. confidence interval [CI], 0.89-4.07; Ptrend  0.02) and inversely associated with high-grade disease (Gleason sum  7: OR, 0.26; 95% CI, 0.10-0.66; Ptrend  0.01). Together these studies support that higher-grade cancer can be seen in the influence of lower levels of testosterone. Dr. M. Scott Lucia, Associate Professor of Pathology, Director, Prostate Diagnostic Laboratory, and Co-Director, Prostate Cancer Research Laboratories at the University of Colorado Health Sciences, presented important data that suggested that some of the upgrading found in the PCPT trial may be artifactual. First, most of the differences in the number of highgrade cancers were detected very early in the trial, and the hazard ratio Number of cancers examination) to either placebo or to finasteride (5 mg/day) for 7 years. Prostate biopsies were mandated if the PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng/mL or if the digital rectal examination results were abnormal or at the end of 7 years on study. The principle findings in this study were that the rates of prostate cancer in the control arm were much higher than anticipated (24.4%). Second, there were fewer cancers detected in the finasteridetreated group (18.8%), thus resulting in a 24.8% reduction in the number of cancers (P  .001). The third finding in this study was an unanticipated increase in the number of high-grade prostate cancers (Gleason 7-10) in the finasteride arm (6.4% vs 5.1%; P  .005). Although there was great enthusiasm for the primary result, physicians have been reluctant to recommend finasteride because of the reported increased incidence of highgrade prostate cancer associated with its administration in the preventive setting. The clinical implications of this apparent upgrading of cancer remain uncertain. The extent to which this finding is real or artifactual is under investigation. Data from several other studies have suggested that higher-grade prostate cancers may be more frequent in men in whom prostate cancer develops in the context of lower testosterone levels. Hoffman and colleagues2 measured free and total testosterone in 117 consecutive patients with prostate cancer. Defining a free testosterone cutoff between high and low of 1.5 ng/mL, 11% of those men with a low free testosterone versus 0 with a high testosterone had Gleason 8-10 cancers (P  .025). Schatzl and colleagues3 studied 157 newly diagnosed prostate cancer patients. The average Gleason score for men with a total testosterone less than 300 ng/mL was 7.4  1.2 ng/mL REVIEWS IN UROLOGY 200 180 160 140 120 100 80 60 40 20 0 from both arms of the study. Most importantly, the finasteride-treated high-grade tumors tended to be smaller; fewer cores positive with less tumor present in the involved cores. In those patients who underwent prostatectomy for high-grade tumors, there were no differences in clinical stage (ie, no greater likelihood of non–organ-confined disease). Dr. Lucia did not discuss the possibility of selection bias involved in the choice of patients for surgery, which might have skewed these findings. Finally, Dr. Lucia made a theoretical case that with the gland shrinkage caused by finasteride, the ability to detect highgrade cancer was enhanced. Despite Dr. Lucia’s outstanding presentation, the issue and concerns regarding the Figure 1. Grade 7 to 10 cancers diagnosed in Prostate Cancer Prevention Trial. EOS, end of study. Data from Thompson et al.1 188 148 Finasteride Placebo 92 For cause 89 EOS RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S11 Prostate Cancer Prevention, Therapies, and Developments 10 Figure 2. Risk of prostate cancer by MnSOD polymorphism and antioxidant score. OR, odds ratio; V, valine; A, alanine. Adapted, with permission, from Li et al.5 AA VV/ VA 2.5 (1.2–5.2) OR generation of high-grade cancers remain and await further study. Another area discussed was that of antioxidants as potential chemopreventive agents. A great deal of preclinical work has suggested that prostate cancer may in part result from oxidative stress to the prostate gland. Small studies have supported the protective effects of antioxidants. A large prospective double-blinded study (SELECT) of 35,534 healthy men, which was randomized in a 2x2 factorial design to vitamin E and selenium, was completed in June 2004. The endpoint in this study was prostate cancer diagnosis and the analysis will be completed in several years. Dr. Philip Kantoff, Professor of Medicine, Harvard Medical School and Chief of the Division of Solid Tumor Oncology at the Dana-Farber Cancer Institute in Boston, described a nested case-control study conducted in the context of the Physicians’ Health Study (PHS), which may shed some early light on the effects of antioxidants. The PHS was a prospective study started in 1982 of aspirin and -carotene in healthy men. Blood was obtained at baseline (1982) in approximately two thirds of men. Health status questionnaires were sent out every couple of years. Dr. Kantoff described a nested case (567) control (764) study5 analyzing both the effect of antioxidants (vitamin E, selenium, and lycopene) on the development of prostate cancer and the effect of a functional polymorphism of manganese superoxide dismutase (MnSOD), a mitochondrial enzyme involved in detoxifying oxygen free radicals. In this study, individuals in the highest quartile of antioxidant level had a 42% reduction (P  .02) in prostate cancer risk serum antioxidant level. For those individuals with high-grade or high-stage prostate cancer, the effect was more robust with a 59% reduction (P  .001) in 5-fold 1 Ptrend  .002 0.1 I II III IV I II III IV Antioxidant status (Pinteraction  .02) the lowest quartile of antioxidant level (Figure 2). The effect again was more robust for those with high-grade or high-stage prostate cancer. In this group, there was a tenfold lower risk of prostate cancer associated with higher versus lower antioxidant level. prostate cancer risk. When MnSOD genotype was considered, the effect of antioxidants was only seen in the 25% of individuals in the study with the AA genotype. In these individuals, there was a fivefold reduction in risk for individuals in the highest versus Figure 3. Two TMPRSS2/ETV1 translocations. Reprinted, with permission, from Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644-648. Copyright 2005 AAAS. ETV1 TMPRSS2 71 142 1 2 365 3 132 3194 14 1 TMPRSS2:ETV1a 1 220 268 2 3 4 4 71 322 6154 12 MET26-LN 12 269 AG C G C G G C A G C T C A G G T A C C TMPRSS2 71 1 142 2 ETV1 365 3 3194 132 14 TMPRSS2:ETV1b 1 1 2 142 220 2 4 268 3 12 322 4 6154 12 MET26-LN 269 T T T G A A C T CA C T CA G G T A C C VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S11 RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S12 Prostate Cancer Prevention, Therapies, and Developments continued These results support a protective role of antioxidants, which is most pronounced in the subgroup of individuals with the MnSOD AA genotype. Dr. Kantoff advised that these were preliminary findings that need to be confirmed in other studies, including the SELECT trial. The next class of agents discussed as potential chemoprotective agents is lipid-lowering drugs. Mark A. Moyad, MD, MPH, the Phil F. Jenkins Director of Complementary/Preventive Medicine, University of Michigan Medical Center, discussed reasons to consider statins as potential agents. Dr. Moyad emphasized that the “heart-healthy diet and lifestyle” would also be of benefit to patients with prostate cancer. He cited a large case (3129) control (16,976) study from The Netherlands of Graaf and colleagues,6 which demonstrated a 20% reduction in total cancers associated with statin use including a 63% reduction in prostate cancer risk. Dr. Moyad also cited a study presented in abstract form by Platz and colleagues7 from the Health Professionals’ Follow-up Study. In this large case-control study, the use of lipid-lowering drugs was associated with a statistically significant reduction in prostate cancer incidence, a 46% reduction in risk of high-grade or high-stage prostate cancer, and a 66% reduction in mortality from prostate cancer. Dr. Moyad also presented the results of an abstract by Katz and colleagues,8 which looked retrospectively at a cohort of 905 patients who had been treated with androgen deprivation therapy. Those who were treated concomitantly with a statin had a higher freedom from recurrence than those who were not (88.8% vs 71.2%). The conclusion from Dr. Moyad’s lecture was that further study of statins in prostate cancer is warranted, including potentially a large chemoprevention study. S12 VOL. 8 SUPPL. 2 2006 Figure 4. Immunomic profiles of prostate cancer. (A) Hierarchical clustering of phage epitopes. (B) Tumor-normal comparison. Reprinted from Wang X, Yu J, Sreekumar A, et al. Autoantibody signatures in prostate cancer. N Engl J Med. 2005;353:1224-1235. Copyright © 2005 Massachusetts Medical Society. All rights reserved. Dr. Michael K. Brawer, Professor of Surgery at the Northwest Prostate Institute in Seattle, WA, discussed interesting preclinical and clinical data with the agent lonidamine. Lonidamine REVIEWS IN UROLOGY is a derivative of indazole-3-carboxylic acid, which was originally used as an antispermatogenic agent and is a selective inhibitor of aerobic glycolysis through inhibition of tumor RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S13 Prostate Cancer Prevention, Therapies, and Developments cell mitochondria-bound hexokinase, the entry enzyme into glycolysis. The theory behind its in vitro activity is that normal cells derive most of their energy from the citric acid cycle, whereas certain diseased cells derive their energy from glycolysis. Preclinical studies with lonidamine have seen in the absence of any appreciable side effects. Further studies of lonidamine are planned in BPH and in prostate cancer. Dr. Kantoff briefly reviewed 2 very exciting developments in the field of prostate cancer that may be groundbreaking. In work led by Arul Chin- Preclinical studies with lonidamine have demonstrated that it decreases cell proliferation and induces apoptosis in LNCaP cells. demonstrated that it decreases cell proliferation and induces apoptosis in LNCaP cells. The administration of lonidamine to mice showed a significant reduction in prostate weight. This led to a phase II clinical trial of lonidamine in men with benign prostatic hyperplasia (BPH). In this phase II study, the drug was administered at a dosage of 150 mg/d for 28 days to 60 men with BPH; there was a 14% reduction in prostate volume, a statistically significant improvement in urinary flow rate, and a reduction in post-void residual. These effects were naiyan, MD, PhD,9 from the University of Michigan, a new and highly prevalent translocation was found in early prostate cancer. Using a novel bioinformatic strategy, Dr. Chinnaiyan’s group noted that members of the ETS family of transcription factors were frequently overexpressed in many expression profiling databases. Using this information, they searched for a mechanism and found that the overexpression was a result of a translocation of the promoter of the TMPRSS2 gene, which has androgen response elements in it to several members of the ETS family of transcription factors (Figure 3). They found that 70% to 80% of primary prostate cancers possess this translocation, which suggests that it is an early and possibly primary event. The possibility that an androgen-regulated promoter drives this has potential implications on the mechanism of androgen deprivation therapy. It also suggests that this translocation may be a new target for therapy. In another exciting development,10 Dr. Chinnaiyan’s team developed phage libraries derived from prostate cancer tissue. The antigens displayed a large number of prostate-specific antigens. Using this library, the investigators discovered a set of autoantibodies directed at a subset of these antigens in patients with prostate cancer (Figure 4). This “immunomic profile” could be used effectively to distinguish men with prostate cancer from healthy men. Preliminarily, it seems that the sensitivity and specificity were better than those with PSA (Figure 5). These results need to be validated. 1.00 1.00 0.75 0.75 0.75 0.50 0.25 Epitope profiling PSA 0 Sensitivity 1.00 Sensitivity Sensitivity Figure 5. Performance of the immunomic profile relative to prostate-specific antigen (PSA). AUC, area under the curve. Reprinted from Wang X, Yu J, Sreekumar A, et al. Autoantibody signatures in prostate cancer. N Engl J Med. 2005;353:1224-1235. Copyright © 2005 Massachusetts Medical Society. All rights reserved. 0.50 0.25 0.25 Epitope profiling PSA 0.25 0.50 0.75 1 - specificity Entire PSA range n  115 AUC (PSA)  0.796 AUC (epitope)  0.927 1.00 Epitope profiling PSA 0 0 0 0.50 0 0.25 0.50 0.75 1 - specificity 4–10 ng/mL PSA range n  41 AUC (PSA)  0.562 AUC (epitope)  0.931 1.00 0 0.25 0.50 0.75 1 - specificity 1.00 2.5–10 ng/mL PSA range n  50 AUC (PSA)  0.496 AUC (epitope)  0.939 VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S13 RIUS0004(Watson)_04-24.qxd 24/4/06 12:35 Page S14 Prostate Cancer Prevention, Therapies, and Developments continued Diet and Complementary Therapies The final 2 presentations involved diet and complementary therapies. Dr. Moyad discussed diet, and his main message once again was that a hearthealthy diet and lifestyle was likely to be a prostate cancer-healthy diet and lifestyle. A great deal of his focus was on obesity. He pointed to 2 studies, those of Amling and colleagues11 and Freedland and colleagues,12 in which obesity was a significant predictor of higher Gleason score, higher rate of biochemical recurrence, and higher rates of positive surgical margins after radical prostatectomy. Dr. Moyad emphasized the importance of not only reducing fat intake but also using monounsaturated and polyunsaturated fats and soy in the diet. He described the results of a recently published prospective randomized intervention study by Hercberg and colleagues13 in which 13,017 people (5141 men; age, 45-60) were randomized to receive either 120 mg vitamin C  30 mg vitamin E + 6 mg -carotene  100 g selenium  20 mg zinc or placebo. After 7.5 years, a protective effect of antioxidants was seen in men (relative risk, 0.69 [95% CI, 0.53-0.91]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.420.93]) in men. Finally, Dr. Anne R. Simoneau, Associate Clinical Professor of Urology at the University of California, Irvine, discussed complementary therapies. She pointed out the quantity and quality of health information accessible to the public on the Internet. She searched for information on cancer and 16.2% of hits displayed complementary and alternative medicine information. Interestingly, she showed that using established instruments, the mean score for quality was 22.12 with a maximum score of 50, and a mean safety score was 13.26 with maximum score of 30. Commercial sites had the most inaccurate or misleading information, emphasizing only the positive aspects of the use of herbs, with little or no evidence.14 She also pointed out the importance of the use of “scientese” on persuasiveness on the Web.15 6. 7. 8. 9. 10. 11. 12. References 1. 2. 3. 4. 5. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349: 215-224. Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol. 2000;163:824-827. Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001;47: 52-58. Platz EA, Leitzmann MF, Rifai N. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. CEBP 2005;14: 1262-1269. Li H, Kantoff PW, Giovannucci E, et al. Manganese superoxide dismutase (MnSOD) polymor- 13. 14. 15. phism, prediagnostic plasma antioxidants and prostate cancer risk. Cancer Res. 2005;65: 2498-2504. Graaf MR, Beiderbeck AB, Egberts AC, et al. The risk of cancer in users of statins. J Clin Oncol. 2004;22:2388-2394. Platz EA, Leitzmann MF, Rifai N, et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol Biomarkers Prev. 2005;14: 1262-1269. Katz MO, Zelefsky MJ, Marion C, et al. Statin use is associated with improved biochemical outcome after high-dose radiotherapy for clinically localized prostate cancer [abstract 1016]. Int J Radiat Oncol Biol Phys. 2003;57:S271. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310:644-648. Wang X, Yu J, Sreekumar A, et al. Autoantibody signatures in prostate cancer. N Engl J Med. 2005;353:1224-1235. Amling CL, Riffenburgh RH, Sun L, et al. Pathologic variables and recurrence rates as related to obesity and race in men with prostate cancer undergoing radical prostatectomy. J Clin Oncol. 2004;22:439-445. Freedland SJ, Aronson WJ, Kane CJ, et al. Impact of obesity on biochemical control after radical prostatectomy for clinically localized prostate cancer: a report by the Shared Equal Access Regional Cancer Hospital database study group. J Clin Oncol. 2004;22:446-453. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335-2342 [erratum in Arch Intern Med. 2005;165:286]. Molassiotis A, Xu M. Quality and safety issues of web-based information about herbal medicines in the treatment of cancer. Complement Ther Med. 2004;12:217-227. Haard J, Slater MD, Long M. Scientese and ambiguous citations in the selling of unproven medical treatments. Health Commun. 2004; 16:411-426. Main Points • Physicians are reluctant to recommend finasteride because of the reported increased incidence of high-grade prostate cancer associated with its administration in the preventive setting. • Higher-grade prostate cancers may be more frequent in men in whom prostate cancer develops in the context of lower testosterone levels. • Small studies have supported the protective effects of antioxidants against prostate cancer. • Further study of statins in prostate cancer is warranted, including a large chemoprevention study. • Further studies of lonidamine are planned in benign prostate hypertrophy and in prostate cancer. • Translocations may be identified that affect androgen responsiveness, targeting prostate cancer. S14 VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY