Prostate cancer risk

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Hi All, It seemed, that "for fatal prostate cancer, ... taller height, higher BMI, ... and high intakes of total energy ... were associated with a statistically significant increased risk". The below paper is pdf-availed. Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC.Risk factors for prostate cancer incidence and progression in the health professionals follow-up study.Int J Cancer. 2007 Apr 20; [Epub ahead of print] PMID: 17450530 Risk factors for prostate cancer could differ for various sub-groups, such as for "aggressive" and "non-aggressive" cancers or by grade or stage. Determinants of mortality could differ from those for incidence. Using data from the Health Professionals Follow-Up Study, we re-examined 10 factors (cigarette smoking history, physical activity, BMI, family history of prostate cancer, race, height, total energy consumption,

and intakes of calcium, tomato sauce and alpha-linolenic acid) using multivariable regression in relation to multiple subcategories for prostate cancer risk. These were factors that we previously found to be predictors of prostate cancer incidence or advanced prostate cancer in this cohort, and that have some support in the literature. In this analysis, only 4 factors had a clear statistically significant association with overall incident prostate cancer: African-American race, positive family history, higher tomato sauce intake (inversely) and alpha-linolenic acid intake. In contrast, for fatal prostate cancer, recent smoking history, taller height, higher BMI, family history, and high intakes of total energy, calcium and alpha-linolenic acid were associated with a statistically significant increased risk. Higher vigorous physical activity level was associated with lower risk. In relation to these risk factors, advanced stage at diagnosis was a good surrogate for

fatal prostate cancer, but high-grade (Gleason >/= 7 or Gleason >/= 8) was not. Only for high calcium intake was there a close correspondence for associations among high-grade cancer, advanced and fatal prostate cancer. Tomato sauce (inversely) and alpha-linolenic acid (positively) intakes were strong predictors of advanced cancer among those with low-grade cancers at diagnosis. Although the proportion of advanced stage cancers was much lower after PSA screening began, risk factors for advanced stage prostate cancers were similar in the pre-PSA and PSA era. The complexity of the clinical and pathologic manifestations of prostate cancer must be considered in the design and interpretation of studies. Article Text The wide international variation in incidence rates[1][2] and increases in prostate cancer incidence and mortality rates in migrants from countries with low rates to those countries with high rates[3][4][5] demonstrate the

importance of modifiable etiologic factors for this cancer. However, the evidence for any specific factor has generally not been very consistent. The heterogeneous nature of prostate cancers, which range from relatively innocuous to highly aggressive in behavior, may contribute to inconsistent results. Because they may act on different biologic pathways, risk factors may be different for various sub-groups of prostate cancer, such as for aggressive and non-aggressive cancers, defined by grade, stage, or survival. The premise, usually implicit, that risk factors for initiation of relatively innocuous, well-differentiated prostate cancers should be the same as those that cause death from prostate cancer has little theoretical or empirical basis. Further, although many epidemiologic studies now combine cancers of advanced stage at the time of diagnosis and those with high Gleason grade to characterize aggressive prostate cancer, this practice implicitly supposes that grade -

which reflects degree of differentiation - carries the same meaning as advanced stage, but a risk factor could influence the progression of a cancer independently of an effect on tumor grade. Thus, results across studies could vary depending on the specific prostate cancer sub-type examined. In the Health Professionals Follow-Up Study, we have reported on various lifestyle and nutritional factors in relation to risk of prostate cancer. Most of the reports have addressed single factors, and focused on incident cancer, or advanced disease at diagnosis as an indicator of aggressive disease. In this report, we consider systematically 10 risk factors with cases from 1986 to 2002 in relation to various prostate cancer sub-types, specifically, total incident prostate cancer, fatal prostate cancer, advanced or non-advanced stage at presentation, high-grade or low-grade prostate cancer, and some combinations of stage and grade. We examined in

multivariable analysis 10 factors that we previously found to be predictors of prostate cancer incidence or advanced prostate cancer, and that have some support in the literature. These include cigarette smoking history,[6] race,[7] family history of prostate cancer, physical activity,[8] body mass index (BMI),[9] height,[9] total energy consumption,[10] and intakes of calcium,[11] tomato sauce[12] and -linolenic acid.[13][14] Further, we considered how alternative definitions of clinically advanced prostate cancer influenced the results. In addition, we considered the potential influence that PSA screening may have on identifying risk factors for total prostate cancer and advanced prostate cancer, because PSA screening advances the time of diagnosis and alters the spectrum of cancers that are diagnosed. Finally, we considered if risk factors differed for earlier-age onset and late-onset prostate cancer. ... The Health Professionals Follow-up

Study cohort was initiated in 1986, when 51,529 U.S. male health professionals, ages 40-75, completed a mailed questionnaire on age, marital status, height and weight, ancestry, medications, smoking history, disease history, leisure-time physical activity, diet (in the past year) and use of vitamin and mineral supplements. This cohort is predominantly Caucasian (>91%). Through biennial follow-up mailed questionnaires, we updated information on disease history, smoking history, body weight and physical activities, and every 4 years, we updated dietary information. We identified deaths in this cohort through information from family members, the postal system and the National Death Index. Through these methods, we ascertained at least 98% of the total deaths.[15] The conduct of this cohort study and these analyses was approved by the Human Subjects Committee of the Harvard School of Public Health. ... Results From 1986 to the end of the study period, January 31, 2002, in 673,706 person years, we documented 3,544 incident prostate adenocarcinoma cases after excluding 71 cases (about 2% of total) of stage T1a cancers. We documented 90% of the 3,544 cases through medical records and pathology reports, and the remaining 10% by supporting data for the diagnosis that participants provided (typically, evidence of treatment). Based on the pathology report, we had information on Gleason sum for 2,701 cases (76.2% of the total). We documented 1,110 high-grade cancers defined as Gleason </=7 (and 322 as Gleason =/>8), and 1,601 low-grade cases (Gleason </=6). Also, 523 cases were considered to be advanced stage or fatal, of which 312 cases were defined as fatal prostate cancer, having been the underlying cause of death, by January 31, 2002. Incident and fatal prostate cancerWe first examined each factor in relation to incident prostate

cancer and fatal prostate cancer. The results are displayed in Figure 1. Only 4 factors had a statistically significant association with incident prostate cancer: higher tomato sauce intake was associated with a decreased risk, and African-American race, a positive family history of prostate cancer, and higher -linolenic acid intake were associated with an increased risk. In contrast, most items were significantly associated with risk of fatal prostate cancer. Specifically, recent smoking history, positive family history of prostate cancer, taller height, higher BMI, and high intake of total energy, calcium and -linolenic acid were associated with a statistically significant increased risk, whereas higher vigorous physical activity level was associated with lower risk of fatal prostate cancer. For tomato sauce, the magnitude of the inverse association was similar for fatal as for total prostate cancer, and the smaller numbers may have prevented us from detecting a

statistically significant association with fatal prostate cancer. Advanced and non-advanced stage prostate cancerThe results for advanced and non-advanced prostate cancer were largely similar as those for fatal and incident prostate cancer respectively (see Table I). However, some differences were notable. While smoking within the past 10 years was associated with a higher risk of fatal prostate cancer, it was not significantly associated with risk of advanced prostate cancer. In addition, high tomato sauce intake was associated with a decreased risk of advanced prostate cancer, although the test for linear trend was not statistically significant (RR = 0.66; 95% CI = 0.44-1.00, for intake >/=2 vs. <0.25 servings/week; p(trend) = 0.12). Although more frequent vigorous physical activity was strongly associated with a decreased risk of advanced and fatal prostate cancer, it was associated with a modest but statistically significant

increased risk of non-advanced prostate cancer (RR = 1.19; 95% CI = 1.03-1.37, for high versus low quintile; p(trend) <0.01). For N0 M0 prostate cancers with capsular invasion alone (stage C1 or T3a), none of the risk factors was associated significantly with these cancers except for family history of prostate cancer, and suggestively for calcium (positively) and tomato sauce (inversely). Thus, this endpoint in general (except possibly for calcium intake) appears to respond to risk factors similarly to the non-advanced as opposed to advanced cancers. Table I. Multivariable Relative Risk (RR) and 95% Confidence Interval (CI) for High Versus Low Category of the Specified Variable by Stage of Prostate CancerTable I. Multivariable Relative Risk (RR) and 95% Confidence Interval (CI) for High Versus Low Category of the Specified Variable by Stage of Prostate

Cancer==========================================================Factor^1---Organ confined Minimally extraprostatic Advanced>>>>>>---T1 or T2 and N0M0 (n=2161) T3a and N0M0 (n=345) T3b or T4 or N1 or M1 (n=523)==========================================================Cigarette smoking (prior 10 y) 0.88^2 (0.77-1.01) 1.11 (0.82-1.52) 1.14 (0.90-1.45)Height 1.00 (0.79-1.28) 0.80 (0.46-1.40) 2.12^3 (1.23-3.65)Vigorous physical activity 1.19^3 (1.03-1.37) 1.25 (0.89-1.75) 0.64^2 (0.44-0.94)Body mass index 1.02 (0.76-1.36) 0.91 (0.48-1.72) 1.34^3 (0.79-2.26)Total energy intake 1.04 (0.89-1.21) 0.77 (0.52-1.14) 1.68^2 (1.20-2.36)Calcium intake 0.96 (0.68-1.34) 1.98 (1.04-3.78) 1.91^(1.20-3.03)Alpha-linolenic acid 1.12^2 (0.98-1.29) 1.18 (0.83-1.69) 1.57^3 (1.19-2.07)Tomato sauce intake 0.753 (0.61-0.92) 0.64 (0.37-1.10) 0.66 (0.44-1.00)Family history of CaP 1.77^3 (1.54-2.04) 2.43^3 (1.78-3.32) 2.27^3

(1.73-2.97)African-American 1.51^3 (1.06-2.15) 0.26 (0.04-1.87) 1.75 (0.90-3.41)========================================================== 1 Multivariable RR based on the high versus low category for each specified item (see Fig. 1 for variables in the model and cutpoints for the categories). 2 p value 0.06 <p</=0.10, for test for trend. 3 p value </=0.05, for test for trend. High-grade and low-grade prostate cancerWe next examined high-grade and low-grade prostate cancer separately. Risk factors for high-grade prostate cancer (Fig. 2) were not consistently reflected in relation to fatal prostate cancer (Fig. 1). Analyses defining high-grade as Gleason 8 gave similar results as those with high-grade defined as Gleason =/>7 but with wider confidence intervals because of the much smaller number of cases (data not shown). Only high calcium intake exhibited a close correspondence

for high-grade cancer, advanced and fatal prostate cancer. Taller height was also associated with an increased risk of high-grade prostate cancer, but the magnitude of the association was much weaker than that for fatal prostate cancer and it was non-monotonic. African-American race was associated with a significantly higher risk of high-grade prostate cancer, but not with low-grade prostate cancer. Similar to its association with non-advanced prostate cancer, vigorous activity was associated with a modest but statistically significant greater risk of low-grade prostate cancer. alpha-linolenic acid intake was positively and tomato sauce intake was inversely associated with risk of low-grade prostate cancer. In a separate analysis, we examined cancers that were high-grade but non-advanced at the time of diagnosis (n = 860 cases). None of the variables indicated a significant trend; high intake of calcium was suggestively associated with an increased risk (multivariable RR =

1.51, 95% CI = 0.95-2.41). In a case-only analysis, trends for a higher likelihood of a diagnosed cancer being high-grade versus low-grade were evident only for higher calcium intake (p = 0.002), taller height (p = 0.01), and marginally for less vigorous physical activity (p = 0.06). Low-grade, advanced prostate cancerPoor differentiation (i.e., high Gleason grade) is a well-established strong determinant of progression and fatality from prostate cancer. However, a small proportion of lower grade prostate cancers do progress to advanced stage and lead to mortality. In our data, only 83 cases were defined as low-grade and advanced stage. Higher intakes of alpha-linolenic acid (multivariable RR = 2.23, 95% CI = 1.11-4.48; p(trend) = 0.04) and tomato sauce (multivariable RR = 0.27, 95% CI = 0.10-0.96; p(trend) = 0.02), which were associated with overall low-grade prostate cancer, had especially strong relationships with low-grade advanced

prostate cancers, suggesting that these factors may influence progression of well- and moderately-well differentiated lesions into advanced stages. No other factor was associated with this endpoint. Effect modification by time period as a surrogate of PSA eraThe widespread use of PSA screening in the United States beginning around the early 1990's had a profound influence on the apparent incidence of prostate cancer, as well as the spectrum of case types being diagnosed. We examined the risk factors in relation to total and advanced prostate cancer in the pre-PSA screening era and the PSA screening era. As shown in Table II, the proportion of advanced cases decreased dramatically in the PSA era (from 27.5% to 10.4%). The association patterns for total and for advanced cancers were largely similar for the 2 time periods, with several exceptions: calcium intake was associated with increased risk of total prostate cancer in the earlier era

but not in the PSA era, and the associations with family history of prostate cancer and African-American race tended to be stronger for both total and advanced prostate cancer in the pre-PSA era. Table II. Multivariable Relative Risk (RR) and 95% Confidence Interval (CI) for High Versus Low Category of the Specified Variable in the Pre-PSA (1986-1/1992) and PSA (2/1992-1/2002) Eras ==========================================================Factor^2---Total prostate cancer---Advanced prostate cancer^1 >>>>>---Pre-PSA Era (n = 894) PSA Era (n = 2650)---Pre-PSA Era (n = 246) PSA Era (n = 277) ==========================================================Cigarette smoking (prior 10 y) 1.07 (0.89-1.28) 0.93 (0.82-1.06) 1.17 (0.84-1.64) 1.10 (0.77-1.55) Height 1.11 (0.78-1.57) 1.03 (0.83-1.29) 1.664 (0.81-3.41) 2.79^4 (1.20-6.50) Vigorous physical activity 0.95 (0.74-1.22) 1.15^4 (1.01-1.30) 0.57 (0.30-1.06)

0.69 (0.43-1.11) Body mass index 0.94 (0.61-1.47) 1.21 (0.94-1.56) 1.21^4 (0.55-2.67) 1.43 (0.70-2.91) Total energy intake 1.14 (0.88-1.47) 0.95 (0.82-1.09) 1.90^4 (1.17-3.10) 1.50 (0.93-2.42) Calcium intake 1.77^3 (1.26-2.48) 1.01 (0.74-1.39) 1.82 (0.97-3.45) 2.08 (1.05-4.10) Alpha-linolenic acid 1.12 (0.91-1.38) 1.13^3 (0.99-1.28) 1.62^4 (1.09-2.42) 1.51^4 (1.03-2.23) Tomato sauce intake 0.70^3 (0.52-0.93) 0.86^3 (0.70-1.04) 0.69 (0.40-1.20) 0.63 (0.34-1.17) Family history of CaP 2.70^4 (2.22-3.27) 1.66^4 (1.45-1.89) 3.17^4 (2.22-4.54) 1.56^4 (1.02-2.37) African-American 2.00^4 (1.25-3.22) 1.31 (0.93-1.85) 2.49^4 (1.09-5.67) 1.13 (0.36-3.54) ==========================================================>>>3 Stringent definition of advanced prostate cancer (e.g., T3b, T4 or N1 or M1).>>>2 Multivariable RR based on the high versus low category for each specified item.>>>3 p value 0.06 p </=0.10,

for test for trend.>>>4 p value </=0.05, for test for trend. Effect modification by ageWe also examined if risk differed by age group, using the median age of cases as the cutpoint (<68 years; =/>68 years). For total prostate cancer, only for BMI was there strong statistical evidence of an age interaction (p = 0.001); for younger men, an inverse association was observed (RR = 0.81, 95% CI = 0.58-1.13 for BMI =/>30 versus <21 kg/m2, p(trend) = 0.01), whereas for older men, a positive association was observed (RR = 1.47; 95% CI = 1.10-1.96, p(trend) = 0.02). For fatal prostate cancer, these respective RR's for younger and older men were RR = 0.88; 95% C = 0.41-1.91, p(trend) = 0.12 and RR = 2.73; 95% C = 1.44-5.14, p(trend) = 0.03. For physical activity, the result for interaction for fatal cancer was not statistically significant based on a test for trend, but the inverse association was stronger for older men

for the high versus low quintile (RR = 0.78, 95% CI = 0.36-1.66 for men <68 years and RR = 0.46, 95% CI = 0.21-1.00 for men 68 years). In the Health Professionals Follow-Up Study (summarized in Table III) we found only low tomato sauce and high alpha-linolenic acid intakes, a positive family history of prostate cancer, African-American race and possibly calcium intake were associated with increased incidence, but additional factors were associated with fatal prostate cancer. These results suggest that reducing mortality from prostate cancer through lifestyle and diet may generally be more feasible than preventing its occurrence. Because prostate cancers probably have a multiple decades-long induction or latent phase, initiating and early-acting factors may have occurred many years prior to our follow-up, whereas progression factors are operative late and thus are more easily identifiable in a cohort of middle-aged and elderly men. On the

other hand, tallness, presumably a surrogate of a factor acting during the growth period (e.g., adolescent IGF-1 levels) strongly predicted prostate cancer mortality but did not predict incidence; this finding suggests early-operative carcinogenic processes could affect aggressive behavior in cancers, or increase the incidence of a sub-set of prostate cancer with a greater propensity to progress. Table III. Summary of Results for Risk Factors for Prostate Cancer Endpoints^1 in Multivariable Analysis in the Health Professionals Follow-Up Study (1986-2002)^2=============================================>>>>>>>Incident Non-advanced Low-grade Fatal Advanced High-grade=============================================Vigorous activity space + + - (-) spaceBody mass index space space space + + space Calorie intake space space space + +Height space space space + + (+)Tobacco (last 10 yr) + + (-) +

space spaceTomato sauce - - - (-) space spaceAlpha-linolenic acid + (+) + (+) + spaceCalcium (+) space space + (+) +African-American + + space space space space + Family history of CaP + + + + + +=============================================>>>1 Advanced cancers are those with extension into seminal vesicle, lymph nodes, distant metastatic, or which are fatal. High grade cancers are those of Gleason grade =/>7. >>>test for trend and the comparison for extreme categories are statistically significant. (+) or (-) denotes that only one of these is statistically significant. -- Al Pater, alpater@...

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