Kathryn M. Wilson

Lifestyle and dietary factors in the prevention of lethal prostate cancer

The prevention of lethal prostate cancer is a critical public health challenge that would improve health and reduce suffering from this disease. In this review, we discuss the evidence surrounding specific lifestyle and dietary factors in the prevention of lethal prostate cancer. We present a summary of evidence for the following selected behavioral risk factors: obesity and weight change, physical activity, smoking, antioxidant intake, vitamin D and calcium, and coffee intake.

Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels and prostate cancer risk in the Cancer of the Prostate in Sweden Study

Acrylamide, a probable human carcinogen, is formed during the cooking of many commonly consumed foods. Data are scant on whether dietary acrylamide represents an important cancer risk in humans. We studied the association between acrylamide and prostate cancer risk using 2 measures of acrylamide exposure: intake from a food frequency questionnaire (FFQ) and acrylamide adducts to hemoglobin. We also studied the correlation between these 2 exposure measures. We used data from the population‐based case‐control study Cancer of the Prostate in Sweden (CAPS). Dietary data was available for 1,499 cases and 1,118 controls. Hemoglobin adducts of acrylamide were measured in blood samples from a subset of 170 cases and 161 controls. We calculated odds ratios (ORs) for the risk of prostate cancer in high versus low quantiles of acrylamide exposure using logistic regression. The correlation between FFQ acrylamide intake and acrylamide adducts in non‐smokers was 0.25 (95% confidence interval: 0.14–0.35), adjusted for age, region, energy intake, and laboratory batch. Among controls the correlation was 0.35 (95% CI: 0.21–0.48); among cases it was 0.15 (95% CI: 0.00–0.30). The OR of prostate cancer for the highest versus lowest quartile of acrylamide adducts was 0.93 (95% CI: 0.47–1.85, p‐value for trend = 0.98). For FFQ acrylamide, the OR of prostate cancer for the highest versus lowest quintile was 0.97 (95% CI: 0.75–1.27, p trend = 0.67). No significant associations were found between acrylamide exposure and risk of prostate cancer by stage, grade, or PSA level. Acrylamide adducts to hemoglobin and FFQ‐measured acrylamide intake were moderately correlated. Neither measure of acrylamide exposure—hemoglobin adducts or FFQ—was associated with risk of prostate cancer.

Vasectomy and Risk of Aggressive Prostate Cancer: A 24-Year Follow-Up Study

PURPOSE Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. PATIENTS AND METHODS Among 49,405 U.S. men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. RESULTS Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. CONCLUSION Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely.

Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations.

PURPOSE Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. METHODS The impact of BMI (high BMI: ≥ 25 kg/m2 v low BMI: < 25 kg/m2) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. RESULTS In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). CONCLUSION High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

Dietary Acrylamide and Cancer Risk in Humans: A Review

Abstract.In April 2002, researchers from the Swedish National Food Administration reported that they had detected elevated levels of acrylamide in commonly consumed baked and fried foods. Acrylamide is known as a neurotoxin in humans and as a carcinogen in experimental animals, and it is classified as a probable human carcinogen by the International Agency for Research on Cancer (IARC, 1994). Therefore, the discovery that the compound forms naturally during high-heat cooking of starchy foods caused substantial alarm in Sweden and worldwide. Within months of the initial Swedish report, national governments and food companies began their own investigations on acrylamide in foods and discussed the potential impact of dietary acrylamide on the public’s health. The discovery also provoked public debate among scientists about the importance of the finding because of the relative lack of data in humans on the one hand and the knowledge that acrylamide in high doses is genotoxic in cell and animal studies on the other. Since 2002, researchers have engaged in a wide range of studies spanning across disciplines. In this review, we summarize the current state of knowledge on acrylamide in foods. We discuss the formation and intake of acrylamide in foods, present evidence for carcinogenicity in cell and animal studies, and examine the findings from epidemiological studies of occupational and dietary exposures. We conclude with a discussion of future directions in the field.Zusammenfassung (Redaktion).Im April des Jahres 2002 berichteten Forscher der nationalen, schwedischen Lebensmittelbehörde über den erhöhten Gehalt an Acrylamid in gebackenen oder frittierten, üblicherweise verzehrten Lebensmitteln. Acrylamid gilt in Bezug auf den Menschen als Neurotoxin und hat sich in Tierversuchen als karzinogen erwiesen; die International Agency for Research on Cancer (IARC) hat Acrylamid als potenziell karzinogen für den Menschen eingestuft. Daher hat die Entdeckung, dass sich diese Substanz natürlicherweise beim starken Erhitzen von stärkereichen Lebensmitteln bildet, erhebliche Beunruhigung in Schweden und weltweit ausgelöst. Schon wenige Monate, nachdem der schwedische Report über Acrylamid in Lebensmitteln erschienen war, wurden von den Regierungen verschiedener Staaten und auch von der Lebensmittelindustrie eigene, diesbezügliche Forschungsprogramme veranlasst. Der potenzielle Einfluss des Acrylamids in Lebensmitteln auf die Gesundheit der Bevölkerung wurde ebenso diskutiert wie die Bedeutung dieser Entdeckung angesichts der Tatsache, dass für Menschen zwar kaum Daten vorliegen, dass aber Acrylamid in hohen Dosen auf Zellkulturen und Versuchstiere genotoxisch wirkt. Seit dem Jahr 2002 ist diesen offenen Fragen im Rahmen mehrerer Disziplin-übergreifender Forschungsvorhaben nachgegangen worden. Im vorliegenden Review wird der derzeitige Wissensstand über Acrylamid in Lebensmitteln vorgestellt. Die Autoren diskutieren die Bildung von Acrylamid in und seine Aufnahme mit Lebensmitteln, besprechen seine karzinogenen Eigenschaften in Versuchen mit Zellkulturen oder Tieren und analysieren die Ergebnisse epidemiologischer Studien. Zukünftige Entwicklungen werden erörtert.

Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study

BACKGROUND High calcium intake has been associated with an increased risk of advanced-stage and high-grade prostate cancer. Several studies have found a positive association between phosphorus intake and prostate cancer risk. OBJECTIVE We investigated the joint association between calcium and phosphorus and risk of prostate cancer in the Health Professionals Follow-Up Study, with a focus on lethal and high-grade disease. DESIGN In total, 47,885 men in the cohort reported diet data in 1986 and every 4 y thereafter. From 1986 to 2010, 5861 cases of prostate cancer were identified, including 789 lethal cancers (fatal or metastatic). We used Cox proportional hazards models to assess the association between calcium and phosphorus intake and prostate cancer, with adjustment for potential confounding. RESULTS Calcium intakes >2000 mg/d were associated with greater risk of total prostate cancer and lethal and high-grade cancers. These associations were attenuated and no longer statistically significant when phosphorus intake was adjusted for. Phosphorus intake was associated with greater risk of total, lethal, and high-grade cancers, independent of calcium and intakes of red meat, white meat, dairy, and fish. In latency analysis, calcium and phosphorus had independent effects for different time periods between exposure and diagnosis. Calcium intake was associated with an increased risk of advanced-stage and high-grade disease 12-16 y after exposure, whereas high phosphorus was associated with increased risk of advanced-stage and high-grade disease 0-8 y after exposure. CONCLUSIONS Phosphorus is independently associated with risk of lethal and high-grade prostate cancer. Calcium may not have a strong independent effect on prostate cancer risk except with long latency periods.

5α-Reductase inhibitors and risk of high-grade or lethal prostate cancer.

IMPORTANCE 5α-Reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. OBJECTIVE To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study of 38,058 men followed up for prostate cancer diagnosis and outcomes between 1996 and 2010 in the Health Professionals Follow-up Study. EXPOSURES Use of 5ARIs between 1996 and 2010. MAIN OUTCOMES AND MEASURES Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. RESULTS During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high grade (Gleason sum [GS] 8-10), 1238 were GS 7, and 1600 were low grade (GS 2-6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (hazard ratio [HR], 0.77; 95% CI, 0.65-0.91). 5ARI users had a reduced risk of GS 7 (HR, 0.67; 95% CI, 0.49-0.91) and low-grade (GS 2-6) prostate cancer (HR, 0.74; 95% CI, 0.57-0.95). 5ARI use was not associated with risk of high-grade (GS 8-10) prostate cancer (HR, 0.97; 95% CI, 0.64-1.46) or lethal disease (HR, 0.99; 95% CI, 0.58-1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use, 0.95; 95% CI, 0.92-0.99), localized (HR, 0.95; 95% CI, 0.90-1.00), and low-grade disease (HR, 0.92; 95% CI, 0.85-0.99). There was no association for lethal, high-grade, or grade 7 disease. CONCLUSIONS AND RELEVANCE While 5ARI use was not associated with developing high-grade or lethal prostate cancer, it was associated with a reduction in low-grade, GS 7, and overall prostate cancer. Because the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.

Common Genetic Variation of the Calcium-Sensing Receptor and Lethal Prostate Cancer Risk

Background: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels. Methods: We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993–2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multimarker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs. Results: The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009). No individual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P < 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42–0.99): rs6438705; 0.65(0.47–0.89): rs13083990; and 1.55(1.09–2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31–0.95)]. There were no significant associations with overall or high-grade PCa. Conclusions: Our findings indicate that CaSR may be involved in PCa progression. Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted. Cancer Epidemiol Biomarkers Prev; 22(1); 118–26. ©2012 AACR.

Dietary lycopene intake and risk of prostate cancer defined by ERG protein expression

BACKGROUND There is limited evidence that supports etiologically distinct molecular subtypes of prostate cancer, the identification of which may improve prevention. Given their antioxidant properties, we hypothesized that lycopene and tomato sauce may be especially protective against diseases harboring the common gene fusion transmembrane protease, serine 2 (TMPRSS2):v-ets avian erythroblastosis virus E26 oncogene homolog (ERG). OBJECTIVE We aimed to examine associations between estimated lycopene and tomato sauce intake and the risk of prostate cancer defined by ERG protein expression subtype. DESIGN Our study population consisted of a prospective cohort of 46,719 men from the Health Professionals Follow-Up Study. TMPRSS2:ERG was assessed by ERG immunohistochemistry on tumor tissue microarrays constructed from radical prostatectomy specimens. We used multivariable competing risk models to calculate HRs and 95% CIs for the risk of ERG-positive and, separately, ERG-negative disease. We implemented inverse probability weighting to account for evaluating ERG status only in surgically treated cases. RESULTS During 23 y of follow-up, 5543 men were diagnosed with prostate cancer, among whom 884 were assayed for ERG (426 ERG-positive). With inclusion of only the latter cases, increasing cumulative average tomato sauce intake was associated with a decreased risk of prostate cancer overall (≥2 servings/wk compared with <1 serving/mo; multivariable HR: 0.70; 95% CI: 0.52, 0.95; P-trend = 0.002). With respect to molecular subtypes, cumulative average tomato sauce intake was associated with a decreased risk of ERG-positive disease (HR: 0.54; 95% CI: 0.37, 0.81; P-trend = 0.004) but not with ERG-negative disease (HR: 0.96; 95% CI: 0.62, 1.50; P-trend = 0.10) (P-heterogeneity = 0.04). Increasing quintiles of lycopene intake were associated with a decreased risk of both subtypes (P-heterogeneity = 0.79). Inverse probability weighting did not materially change the results. CONCLUSIONS Our results lend some support to the hypothesis that prostate cancers that harbor TMPRSS2:ERG may be etiologically distinct from fusion-negative cancers. In particular, tomato sauce consumption may play a role in reducing TMPRSS2:ERG-positive disease.

Ejaculation Frequency and Risk of Prostate Cancer: Updated Results with an Additional Decade of Follow-up

BACKGROUND Evidence suggests that ejaculation frequency may be inversely related to the risk of prostate cancer (PCa), a disease for which few modifiable risk factors have been identified. OBJECTIVE To incorporate an additional 10 yr of follow-up into an original analysis and to comprehensively evaluate the association between ejaculation frequency and PCa, accounting for screening, clinically relevant disease subgroups, and the impact of mortality from other causes. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of participants in the Health Professionals Follow-up Study utilizing self-reported data on average monthly ejaculation frequency. The study includes 31925 men who answered questions on ejaculation frequency on a 1992 questionnaire and followed through to 2010. The average monthly ejaculation frequency was assessed at three time points: age 20-29 yr, age 40-49 yr, and the year before questionnaire distribution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incidence of total PCa and clinically relevant disease subgroups. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS AND LIMITATIONS During 480831 person-years, 3839 men were diagnosed with PCa. Ejaculation frequency at age 40-49 yr was positively associated with age-standardized body mass index, physical activity, divorce, history of sexually transmitted infections, and consumption of total calories and alcohol. Prostate-specific antigen (PSA) test utilization by 2008, number of PSA tests, and frequency of prostate biopsy were similar across frequency categories. In multivariable analyses, the hazard ratio for PCa incidence for ≥21 compared to 4-7 ejaculations per month was 0.81 (95% confidence interval [CI] 0.72-0.92; p<0.0001 for trend) for frequency at age 20-29 yr and 0.78 (95% CI 0.69-0.89; p<0.0001 for trend) for frequency at age 40-49 yr. Associations were driven by low-risk disease, were similar when restricted to a PSA-screened cohort, and were unlikely to be explained by competing causes of death. CONCLUSIONS These findings provide additional evidence of a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa, particularly for low-risk disease. PATIENT SUMMARY We evaluated whether ejaculation frequency throughout adulthood is related to prostate cancer risk in a large US-based study. We found that men reporting higher compared to lower ejaculatory frequency in adulthood were less likely to be subsequently diagnosed with prostate cancer.