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Obesity and prostate cancer incidence and survival Elizabeth A. Platz, ScD, MPH Professor and Martin D. Abeloff, MD Scholar in Cancer Prevention Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Body fatness and prostate cancer incidence and mortality 2007 2007 Methodologic issues that arise as a result of routine PSA-based screening for prostate cancer • Changing spectrum of disease due to PSA screening – Proportion of advanced vs early disease – Nature of the early cases (may never have become clinically apparent) – Use of PSA screening differs around the world • Detection bias – Differential opportunity to be PSA screened by exposure status (obese vs not obese) – Differential detection of the presence of disease due to exposure changing PSA levels (lower PSA in obese men) Influence of PSA screening on the observed association between obesity and prostate cancer risk Renehan AG et al Eur J Cancer 2010;46:2581-92. Death from prostate cancer by BMI, Cancer Prevention Study II, 1982-1998 RR 1.4 P-trend < 0.001 1.3 1.2 1.1 1 18.5-24.9 25.0-29.9 30.0-34.9 BMI (kg/m2) Calle E et al. 2003; NEJM 348:1625-1638 35.0+ Obesity and prostate cancer, Health Professionals Follow-up Study RR 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1 P-trend=0.47 P-trend=0.03 RR=1.80, 95% CI 1.10-2.93 combined Fatal < 21 21-22.9 BMI kg/m2 23-24.9 25-27.4 Incident 27.5-29.9 Giovannucci E et al. Int J Cancer 2007;121:1571-8. PMID: 17450530 >= 30 Obesity and prostate cancer risk in the NIH-AARP Diet and Health Study RR 2.12 1.08-4.15 2.3 2.1 P-trend = 0.02 1.9 1.7 1.5 1.3 1.1 0.9 < 25 25-29.9 0.7 30-34.9 >= 40 BMI (kg/m2) 0.5 Incident Wright ME et al. Cancer. 2007;109:675-84 35-39.9 Fatal 0.67 0.50-0.89 P-trend = 0.0006 Obesity and prostate cancer, Melbourne Collaborative Cohort RR 1.7 Per 5 kg/m2: RR=1.49, 95% CI 1.11-2.00 P-trend=0.01 RR=1.52, 95% CI 0.89-2.58 1.5 Per 5 kg/m2: RR=0.99, 95% CI 0.89-1.10 P-trend=0.83 1.3 1.1 0.9 Ref Ref Fatal Nonaggressive 0.7 0.5 BMI kg/m2 <23 23-24.9 25-29.9 >= 30 Bassett JK et al. Int J Cancer 2012;131:1711-9. PMID: 22213024. Weight gain since age 18 and prostate cancer, Melbourne Collaborative Cohort RR 2.1 Per 5 kg: RR=1.13, 95% CI 1.02-1.26 P-trend=0.02 RR=1.84, 95% CI 1.09-3.09 1.9 Per 5 kg: RR=0.99, 95% CI 0.81-1.22 P-trend=0.77 1.7 1.5 1.3 Ref Ref 1.1 0.9 Fatal Nonaggressive 0.7 0.5 Weight gain since age 18 kg <5 5-9.9 10-19.9 >=20 Bassett JK et al. Int J Cancer 2012;131:1711-9. PMID: 22213024. BMI and prostate cancer by grade, Prostate Cancer Prevention Trial ORmv 1.4 P-trend=0.03 P-trend=0.04 1.2 BMI 1 Q1 Q2 Q3 Q4 0.8 0.6 0.4 0.2 0 Total Low grade High grade N=1,936 N=1,300 N=521 Gong Z et al. Cancer Epidemiol Biomarkers Prev 2006;15:1977-1983 Meta-analyses • • • • • • • Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer 2001;91:421–30 MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control 2006;17:989–1003 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569–78 Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res 2011;4:486501 Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer--a dose-response meta-analysis of prospective studies. Ann Oncol 2012;23:1665-71 Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol 2013;63:800-9 Golabek T, Bukowczan J, Chłosta P, Powroźnik J, Dobruch J, Borówka A. Obesity and Prostate Cancer Incidence and Mortality: A Systematic Review of Prospective Cohort Studies. Urol Int. 2013 Aug 8. [Epub ahead of print]. “Results: The evidence from the prospective cohort studies linking obesity with PCa incidence has not been consistent. However, cumulative data is compelling for a strong positive association between obesity and fatal PCa.” Meta-analysis: BMI and prostate cancer risk, by localized and advanced disease Literature search to Oct 2011. Discacciati A et al. Ann Oncol 2012;23:1665-71. Meta-analysis: BMI and fatal prostate cancer per 5 kg/m2 increase in BMI Cao Y and Ma J. Cancer Prev Res 2011;4:486-501. PMID: 21233290. Cause versus bias? Hypotheses based on published results • Obesity – Risk (causation) • Risk of death from prostate cancer • Risk of nonaggressive prostate cancer – Detection bias • PSA (lower production, hemodilution) • Prostate volume Freedland SJ, Platz EA Epidemiol Rev 2007;29:88-97; Freedland SJ et al. Cancer Causes Control 2006;17:5-9; Freedland SJ et al. J Urol 2006;175:500-504; Bañez LL et al. JAMA 2007;298:2275-2280 If causal, what pathways mediate the obesity-prostate cancer association? • Metabolic and hormonal perturbations secondary to obesity? – Insulin regulation (and IGF-axis) – Sex steroid hormones – Others? • Bioactive factors secreted by adipocytes? – Energy regulation – Inflammatory mediators – Others? • Obesity’s influence on the detectability of prostate cancer via these same pathways? Is obesity associated with poor outcome after prostate cancer diagnosis? • Emerging support that the extent of body fatness and weight gain – Before diagnosis – Circa diagnosis • are risk factors for recurrence and prostate cancer death in men with prostate cancer. • Excellent review: Cao Y and Ma J. Cancer Prev Res 2011;4:486-501. PMID: 21233290. Meta-analysis: BMI and death from prostate cancer in men with the diagnosis per 5 kg/m2 increase in BMI Cao Y and Ma J. Cancer Prev Res 2011;4:486-501. PMID: 21233290. Meta-analysis: BMI and prostate cancer recurrence after treatment per 5 kg/m2 increase in BMI Cao Y and Ma J. Cancer Prev Res 2011;4:486-501. PMID: 21233290. Literature is not perfectly consistent for obesity and prostate cancer recurrence • Publications since Cao and Ma’s meta-analysis – No association between obesity and recurrence • Lee SE et al. BJU Int 2011;107:1250-5. PMID: 20880194. [Korea] • Narita S et al. Prostate Cancer Prostatic Dis 2013;16:271-6. PMID: 23752230. [Japan] • Tomaszewski JJ et al. Urology 2013;81:992-6. PMID: 23453649. – Positive association between obesity with recurrence • Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID: 21325564. [also weight gain] • Asmar R et al. Prostate Cancer Prostatic Dis 2013;16:62-6. PMID: 22907512. Men who gain weight have a higher risk of prostate cancer recurrence after prostatectomy, JHH 4 P for trend 0.02 3 RR OR 2 1 0 Weight Loss >2.2 kg Maintenance <2.2kg Weight Gain >2.2 kg Weight change from 5 years before to 1 year after surgery Adjusted for weight 5 years before surgery, height, physical activity 1 year after surgery, age, race/ethnicity, family history, year of surgery, stage, grade, and smoking status. Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID: 21325564. Considerations (fully or partially) specific to prostate cancer outcomes • To confirm or refute associations observed thus far • For studies going forward Consideration 1 • What is the optimal prostate cancer outcome to capture biology and import? – Biology and import: Progression to metastasis or death from prostate cancer (rather than biochemical recurrence). – Nature of outcome that can be studied may depend on the type of treatment, though. • Especially when studying men with clinically localized prostate cancer (patients selected for curability few deaths) – Surgery - biochemical recurrence – Radiation therapy or active surveillance - rising PSA Consideration 2 • Confounding - Body fatness appears to be a risk factor for advanced stage and high-grade prostate cancer AND stage and grade are prognostic factors – Thus, must take into account stage and grade in the analysis to determine whether body fatness/weight gain are associated with poor outcome in men with prostate cancer Body fatness / weight gain Advanced stage / high-grade prostate cancer Recurrence / death from prostate cancer Consideration 3 • Etiologically relevant measurement - Timing of body fatness / weight gain relative to the diagnosis / treatment of prostate cancer – Pre-diagnostic – At diagnosis / treatment – Post diagnosis / treatment Normal Body fatness / weight gain Body fatness / weight gain Precursors Organ-confined Prostate cancer Body fatness / weight gain Limited Extraprostatic Body fatness / weight gain Disseminated Fatal How can body fatness influence outcomes after treatment, especially after prostatectomy? Body fatness Body fatness Body fatness Escaped prostate cancer cells Nascent bony mets Body fatness No prostate, Prostate cancer Prostatectomy no prostate focus cancer focus Body fatness Recurrence / death from prostate cancer Consideration 4 • Does the influence of weight gain on outcome differ by starting body fatness? – – – – Lean, gain weight Obese, gain weight Lean, no weight gain Obese, no weight gain • Considerations 3 and 4 coupled: Full evaluation of body fatness and weight gain over the life course. – Requires prospective study of men without the diagnosis, followed to diagnosis (and treatment), and then followed to death – Requires repeated measures of body fatness, including circa the diagnosis /treatment Consideration 5 • Confounding and modifying effects by factors that are highly correlated with body fatness – – – – Physical inactivity Diabetes Energy intake Smoking RRobs > RRtrue Obesity + Poor outcome Physical inactivity + • Statistical analyses RRobs < RRtrue Obesity - Poor outcome Smoking + Consideration 6 • Alternative explanations to biology • Greater technical difficulty when treating obese men relative to lean men (e.g., positive surgical margins) – Lower likelihood of cure unrelated to prostate cancer biology Ho T et al. Eur Urol 2012;62:910-6. PMID: 22921964 Consideration 6 • Greater technical difficulty when treating obese men relative to lean men (e.g., positive surgical margins) Ho T et al. Eur Urol 2012;62:910-6. PMID: 22921964 Consideration 6 • Alternative explanations • Different choice of treatment by obese and nonobese men – Where the treatment may have a different likelihood of cure irrespective of extent of body fatness Consideration 7 • Hormonal therapy for men with metastatic prostate cancer causes central adiposity and metabolic perturbations. – What is the influence of this milieu on prostate cancer death (beyond obvious increase in risk of death from other causes)? – An area of active study. Consideration 8 • Surveillance for the early recurrence (e.g., postprostatectomy) – What is the influence of body fat on PSA produced by cells that have escaped from the prostate? • PSA (lower production, hemodilution) in men who are obese compared with lean – Detection bias - time to recurrences would be falsely LONGER in obese compared with lean men • Needs thorough evaluation. BMI and risk of biochemical recurrence after prostatectomy, JHH Covariates At the time of surgery Freedland SJ et al. J Urol 2005;174:919-22. PMID: 16093988. Pre-diagnostic obesity and prostate cancer death in men with prostate cancer, Physicians’ Health Study Unadjusted Ma J et al. Lancet Oncol 2008;9:1039-47. PMID: 18835745. Pre-diagnostic body mass index and prostate cancer death in men with prostate cancer, PHS P-trend=0.0042 2 1.8 1.6 RR* 1.4 1.2 *Adjusted for age at diagnosis, baseline smoking status, time interval from BMI measurement to prostate-cancer diagnosis, clinical stage, and Gleason grade. BMI 30+ vs < 25 kg/m2: Adj excluding for stage/grade – RR=2.66 Adj including for stage/grade – RR=1.95 Body fatness / weight gain Advanced stage / high-grade prostate cancer Recurrence / death from prostate cancer 1 < 25 25.0-29.9 BMI (kg/m2) Ma J et al. Lancet Oncol 2008;9:1039-47. PMID: 18835745. 30.0+ Men who gain weight have a higher risk of prostate cancer recurrence after prostatectomy, JHH 4 P for trend 0.02 3 RR OR 2 1 0 Weight Loss >2.2 kg Maintenance <2.2kg Weight Gain >2.2 kg Weight change from 5 years before to 1 year after surgery Adjusted for weight 5 years before surgery, height, physical activity 1 year after surgery, age, race/ethnicity, family history, year of surgery, stage, grade, and smoking status. Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID: 21325564. Summary • Evidence is mostly consistent that obesity is a risk factor for a more aggressive prostate cancer phenotype (e.g., high grade/advanced stage disease, prostate cancer mortality). • Evidence building that obesity/weight gain is a risk factor for poor outcome in men diagnosed with prostate cancer. • Many methodologic issues still need to be addressed for both etiology and prognosis. Important questions that remain to be addressed • Does weight loss reduce the risk of developing aggressive prostate cancer? Men who gain weight have a higher risk of recurrence after prostatectomy, JHH • Does weight loss reduce the risk of recurrence, the development of metastases, and death from prostate in men with the disease? Joshu CE et al. Cancer Prev Res 2011;4:544-51. PMID: 21325564. Take home message for men • Maintaining a healthy weight is important for good health in general, and may help prevent dying from prostate cancer.