Julie L. Kasperzyk

Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort

PURPOSE To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa. PARTICIPANTS AND METHODS We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis. RESULTS From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively. CONCLUSION In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients.

Milk and Dairy Consumption among Men with Prostate Cancer and Risk of Metastases and Prostate Cancer Death

Background: Whether milk and dairy intake after a prostate cancer diagnosis is associated with a poorer prognosis is unknown. We investigated postdiagnostic milk and dairy intake in relation to risk of lethal prostate cancer (metastases and prostate cancer death) among participants in the Health Professionals Follow-Up Study. Methods: The cohort consisted of 3,918 men diagnosed with apparently localized prostate cancer between 1986 and 2006, and followed to 2008. Data on milk and dairy intake were available from repeated questionnaires. We used Cox proportional hazards models to calculate HRs and 95% CIs of the association between postdiagnostic milk and dairy intake and prostate cancer outcomes. Results: We ascertained 229 prostate cancer deaths and an additional 69 metastases during follow-up. In multivariate analysis, total milk and dairy intakes after diagnosis were not associated with a greater risk of lethal prostate cancer. Men with the highest versus lowest intake of whole milk were at an increased risk of progression (HR = 2.15, 95% CI: 1.28–3.60; Ptrend < 0.01). Men in the highest versus lowest quintile of low-fat dairy intake were at a decreased risk of progression (HR = 0.62; 95% CI: 0.40–0.95; Ptrend = 0.07). Conclusions: With the exception of whole milk, our results suggest that milk and dairy intake after a prostate cancer diagnosis is not associated with an increased risk of lethal prostate cancer. Impact: This is the first larger prospective study investigating the relation between postdiagnostic milk and dairy intake and risk of lethal prostate cancer. Cancer Epidemiol Biomarkers Prev; 21(3); 428–36. ©2012 AACR.

Milk Intake in Early Life and Risk of Advanced Prostate Cancer

The authors investigated whether early-life residency in certain areas of Iceland marked by distinct differences in milk intake was associated with risk of prostate cancer in a population-based cohort of 8,894 men born between 1907 and 1935. Through linkage to cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality from study entry (in waves from 1967 to 1987) through 2009. In 2002-2006, a subgroup of 2,268 participants reported their milk intake in early, mid-, and current life. During a mean follow-up period of 24.3 years, 1,123 men were diagnosed with prostate cancer, including 371 with advanced disease (stage 3 or higher or prostate cancer death). Compared with early-life residency in the capital area, rural residency in the first 20 years of life was marginally associated with increased risk of advanced prostate cancer (hazard ratio = 1.29, 95% confidence interval (CI): 0.97, 1.73), particularly among men born before 1920 (hazard ratio = 1.64, 95% CI: 1.06, 2.56). Daily milk consumption in adolescence (vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer (95% CI: 1.25, 8.28). These data suggest that frequent milk intake in adolescence increases risk of advanced prostate cancer.

Dietary zinc and prostate cancer survival in a Swedish cohort

BACKGROUND Zinc is involved in many essential cellular functions, including DNA repair and immune system maintenance. Although experimental evidence supports a role for zinc in prostate carcinogenesis, epidemiologic data are inconsistent; no data on cancer-specific survival have been reported. OBJECTIVE Our objective was to determine whether dietary zinc assessed near the time of prostate cancer diagnosis is associated with improved disease-specific survival. DESIGN This population-based cohort consists of 525 men aged <80 y from Örebro County, Sweden, with a diagnosis of prostate cancer made between 1989 and 1994. Study participants completed self-administered food-frequency questionnaires, and zinc intake was derived from nutrient databases. Cox proportional hazards regression was used to estimate multivariate hazard ratios (HRs) and 95% CIs for time to death from prostate cancer as well as death from all causes through February 2009 by quartile (Q) of dietary zinc intake. Models were also stratified by disease stage at diagnosis (localized or advanced). RESULTS With a median follow-up of 6.4 y, 218 (42%) men died of prostate cancer and 257 (49%) died of other causes. High dietary zinc intake was associated with a reduced risk of prostate cancer-specific mortality (HR(Q4 vs Q1): 0.64; 95% CI: 0.44, 0.94; P for trend = 0.05) in the study population. The association was stronger in men with localized tumors (HR: 0.24; 95% CI: 0.09, 0.66; P for trend = 0.005). Zinc intake was not associated with mortality from other causes. CONCLUSION These results suggest that high dietary intake of zinc is associated with lower prostate cancer-specific mortality after diagnosis, particularly in men with localized disease.

Dietary Fatty Acid Intake and Prostate Cancer Survival in Örebro County, Sweden

Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989-1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (P(trend) = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; P(trend) = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.

Consumption of Fish Products across the Lifespan and Prostate Cancer Risk

Objective To examine whether fish and fish oil consumption across the lifespan is associated with a lower risk of prostate cancer. Design The study was nested among 2268 men aged 67–96 years in the AGES-Reykjavik cohort study. In 2002 to 2006, dietary habits were assessed, for early life, midlife and later life using a validated food frequency questionnaire. Participants were followed for prostate cancer diagnosis and mortality through 2009 via linkage to nationwide cancer- and mortality registers. Adjusting for potential confounders, we used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for prostate cancer according to fish and fish oil consumption. Results Among the 2268 men, we ascertained 214 prevalent and 133 incident prostate cancer cases, of which 63 had advanced disease. High fish consumption in early- and midlife was not associated with overall or advanced prostate cancer. High intake of salted or smoked fish was associated with a 2-fold increased risk of advanced prostate cancer both in early life (95% CI: 1.08, 3.62) and in later life (95% CI: 1.04, 5.00). Men consuming fish oil in later life had a lower risk of advanced prostate cancer [HR (95%CI): 0.43 (0.19, 0.95)], no association was found for early life or midlife consumption. Conclusions Salted or smoked fish may increase risk of advanced prostate cancer, whereas fish oil consumption may be protective against progression of prostate cancer in elderly men. In a setting with very high fish consumption, no association was found between overall fish consumption in early or midlife and prostate cancer risk.

One-carbon metabolism–related nutrients and prostate cancer survival

BACKGROUND Folate and other one-carbon metabolism nutrients may influence prostate cancer pathogenesis. Prior studies of these nutrients in relation to prostate cancer incidence have been inconclusive, and none have explored prostate cancer survival. OBJECTIVE The objective was to assess whether dietary intakes of folate, riboflavin, vitamin B-6, vitamin B-12, and methionine measured around the time of prostate cancer diagnosis are associated with prostate cancer survival. DESIGN This population-based prospective study comprised 525 men from Orebro, Sweden, who received a diagnosis of incident prostate cancer between 1989 and 1994 and completed a self-administered food-frequency questionnaire. Record linkages to the Swedish Death Registry enabled all cases to be followed for up to 20 y after diagnosis, and the cause of death was assigned via medical record review. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% CIs. During a median of 6.4 y of follow-up, 218 men (42%) died of prostate cancer and 257 (49%) of other causes. RESULTS A comparison of the highest with the lowest quartile showed that vitamin B-6 intake was inversely associated with prostate cancer-specific death (HR: 0.71; 95% CI: 0.46, 1.10; P for trend = 0.08), especially in men with a diagnosis of localized-stage disease (HR; 0.05; 95% CI: 0.01, 0.26; P for trend = 0.0003). However, vitamin B-6 intake was not associated with improved prostate cancer survival among advanced-stage cases (HR: 1.04; 95% CI: 0.64, 1.72; P for trend = 0.87). Folate, riboflavin, vitamin B-12, and methionine intakes were not associated with prostate cancer survival. CONCLUSION A high vitamin B-6 intake may improve prostate cancer survival among men with a diagnosis of localized-stage disease.

Polymorphic Variation in NFKB1 and Other Aspirin-Related Genes and Risk of Hodgkin Lymphoma

We found that regular use of aspirin may reduce the risk of Hodgkin lymphoma (HL), a common cancer of adolescents and young adults in the United States. To explore possible biological mechanisms underlying this association, we investigated whether polymorphic variation in genes involved in nuclear factor-κB (NF-κB) activation and inhibition, other inflammatory pathways, and aspirin metabolism influences HL risk. Twenty single nucleotide polymorphisms (SNP) in seven genes were genotyped in DNA from 473 classical HL cases and 373 controls enrolled between 1997 and 2000 in a population-based case-control study in the Boston, Massachusetts, metropolitan area and the state of Connecticut. We selected target genes and SNPs primarily using a candidate-SNP approach and estimated haplotypes using the expectation-maximization algorithm. We used multivariable logistic regression to estimate odds ratios (OR) for associations with HL risk. HL risk was significantly associated with rs1585215 in NFKB1 (AG versus AA: OR, 2.1; 95% confidence interval, 1.5-2.9; GG versus AA: OR, 3.5; 95% confidence interval, 2.2-5.7, Ptrend = 1.7 × 10−8) and with NFKB1 haplotypes (Pglobal = 6.0 × 10−21). Similar associations were apparent across categories of age, sex, tumor EBV status, tumor histology, and regular aspirin use, although statistical power was limited for stratified analyses. Nominally significant associations with HL risk were detected for SNPs in NFKBIA and CYP2C9. HL risk was not associated with SNPs in IKKA/CHUK, PTGS2/COX2, UDP1A6, or LTC4S. In conclusion, genetic variation in the NF-κB pathway seems to influence risk of HL. Pooled studies are needed to detect any heterogeneity in the association with NF-κB across HL subgroups, including aspirin users and nonusers. (Cancer Epidemiol Biomarkers Prev 2009;18(3):976–86)

Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer.

Background: Overexpression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but none of the studies have assessed its association with disease-specific mortality. Methods: We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two U.S.-based cohorts (n = 902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable HRs and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n = 95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers. Results: During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1 = 2.42; Ptrend < 0.01). This association was attenuated and nonsignificant (multivariable-adjusted HRQ4vs.Q1 = 1.01; Ptrend = 0.52) after further adjusting for Gleason score and prostate-specific antigen (PSA) at diagnosis. High PSMA expression was significantly (P < 0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ets-related gene (ERG) expression. Conclusions: High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis. Impact: PSMA is not a strong candidate biomarker for predicting prostate cancer–specific mortality in surgically treated patients. Cancer Epidemiol Biomarkers Prev; 22(12); 2354–63. ©2013 AACR.

A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer

Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45–0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40–0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36–0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02). Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612–9. ©2013 AACR.