In the Health Professionals Follow-Up Study (summarized in ) we found only low tomato sauce and high α-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.
SUMMARY OF RESULTS FOR RISK FACTORS FOR PROSTATE CANCER ENDPOINTS1 IN MULTIVARIABLE ANALYSIS IN THE HEALTH PROFESSIONALS FOLLOW-UP STUDY (1986–2002)2
We speculate that pathways through which specific factors may influence death from prostate cancer may be quite diverse, and may involve: (i) increasing incidence (e.g. high α-linolenic acid, low tomato sauce intake, family history of prostate cancer, African–American race), (ii) increasing the likelihood of poor differentiation (as assessed by Gleason score) in a prostate cancer (e.g. calcium, and possibly tallness and African–American race), (iii) increasing promotion or progression preferentially of better differentiated prostate cancers (e.g. high α-linolenic acid, low tomato sauce intake) into advanced stages, and (iv) by increasing mortality independently of incidence and grade (e.g. high BMI, physical inactivity, cigarette smoking). If all or even a sub-set of these patterns whereby risk factors increase risk are causal, one would predict substantial heterogeneity in the prostate cancer literature. Different susceptibility to risk factors based on age may additionally contribute to heterogeneity.
Potential mechanisms underlying these associations have been discussed in our previous publications, and we consider here in general terms the plausibility of mechanisms acting through these endpoints. That any factor that increases the incidence of a cancer could ultimately increase the mortality is intuitive, unless the factor only increased risk of a sub-set of lesions that are defined as cancers histologically, but that could not progress further. The existence of such a sub-set of tumors is entirely plausible, in view of the natural history of prostate cancer and the enormously high prevalence of apparently innocuous disease at older ages. Influencing cancer risk by affecting differentiation status is also a plausible mechanism. For example, such a role has been suggested for vitamin D, a differentiation agent.26,27
In contrast, some risk factors may preferentially influence the promotion or progression of well-differentiated lesions. Interestingly, as for tomato sauce and α-linolenic acid, in the Physicians’ Health Study we had previously shown that high circulating IGF-1 levels were preferentially associated with increased risk of low-grade but advanced prostate cancers,28
a finding confirmed in preliminary analyses in the Health Professionals Follow-Up Study and by others.29
A possible explanation is that growth in poorly differentiated cancers may be more autonomous because these cancers may have extensive mutations in the IGF-1 growth factor signaling pathway.30,31
In contrast, better-differentiated cancers may have a relatively intact signaling pathway responsive to circulating IGF-1 levels. Finally, that some factors would influence survival (and thus mortality) independently of incidence or tumor grade would not be surprising; examples may be through effects on angiogenesis, or on progression of metastatic clones.
The findings for BMI illustrate the complexity of studying prostate cancer. Our current findings are consistent with our previous reports of no overall association with total prostate cancer, but with an indication of an inverse association in younger men and a suggestive positive association in older men.9,32
In previous analyses, we did not have adequate power to study fatal prostate cancer; in the current analysis, we found BMI positively associated with risk of fatal prostate cancer, especially in older men. Most studies have not shown an association between BMI and incident prostate cancer,33,34
but an association with fatal prostate cancer has been observed more frequently.35–38
The mechanisms underlying the heterogeneity by age are unknown, but may relate to specific hormones, such as testosterone, estrogen, insulin, and IGF-1, that change in concentration over the lifespan and that are influenced by BMI or influence BMI.32
Chance seems unlikely as the primary explanation because each factor considered has been consistently associated with risk in multiple time periods throughout our follow-up period. For bias, differential detection through PSA screening is of most concern, as groups with more frequent screening may be more likely to have a cancer detected, especially at an earlier stage. In general, PSA screening intensity is very high in this population and fairly equal across categories of various exposures; the percentage of men reporting having had a PSA test in the prior 2 years asked biennially from 1994 to 2000 for the low and high categories, respectively, for the following exposures are: height: 74 and 75%; BMI: 70 and 73%; vigorous activity: 74 and 77%; calories: 77 and 72%; calcium: 71 and 76%; α-linolenic acid: 74 and 75%; tomato sauce: 74 and 75%; 75% for never smokers and 70% for current smokers; family history, no: 74% and family history yes: 81%; Caucasian: 75% and African–American: 77%. These modest differences in PSA screening were unlikely to produce substantial bias. Perhaps the most compelling argument against detection bias is that the associations with advanced and fatal prostate cancer were observed prior to widespread PSA screening, or before PSA screening could plausibly affect mortality. Finally, confounding cannot be ruled out in observational studies. An advantage of our cohort is that detailed data on many factors allowed us to consider confounding carefully. However, residual or uncontrolled confounding could still occur, especially with error in measuring exposures and covariates. Yet, even if confounding did account for some of our findings (for example, if α-linolenic acid were acting as a marker of another type of fat), our general conclusions regarding the differential effects of risk factors on various endpoints would remain valid. The possibility that bias or confounding may have contributed to our findings has been further considered in detail for each factor in our previous publications.
A limitation of our study is that to assess Gleason score, we relied on pathology reports, which may result in measurement error. Further, Gleason grading may have undergone secular changes.39
However, our results were similar when we excluded cases with Gleason score of 7, and when we considered cancers with scores of 8 or greater as high-grade. More importantly, one of our major goals for this analysis was to assess the utility of various endpoints in epidemiologic studies, so our findings are directly relevant to epidemiologic studies that use pathology reports to assign Gleason score. Both inherent limitations in the Gleason score to predict death, as well as measurement error in assigning the Gleason score, ultimately are relevant factors regarding its utility.
The findings have important implications for the design and interpretations of studies of prostate cancer. First, in cancer epidemiology, incidence has typically been considered as a more relevant endpoint than mortality, but this may not be true for prostate cancer. Studies focusing primarily on incidence may miss important associations with fatal prostate cancer. This limitation of total prostate cancer incidence as an endpoint is exacerbated by PSA screening, leading mainly to diagnosis of non-advanced prostate cancer cases, with few deaths. These include a small proportion of cases that are not advanced at time of diagnosis, but have lethal potential if untreated. Such cases cannot be readily distinguished from innocuous cancers. Second, results from analyses of cancers with strong indicators of disease progression at the time of diagnosis (e.g. seminal vesicle or lymph node involvement) parallel results for fatal prostate cancer, but these clinical manifestations are also becoming rare in the PSA era. Extension beyond the prostate but not into adjacent organs does not appear to be an adequate marker of aggressive prostate cancer; in many studies conducted in the PSA era, these may comprise a substantial proportion of lesions that are defined as advanced.
Third, some factors may act on the progression of well-differentiated prostate cancers, but may not influence poorly-differentiated lesions. This finding, if confirmed, could have some important practical implications. Well-differentiated prostate cancers (for example, Gleason score of 6 or lower) have a relatively good prognosis, but a proportion of these do progress leading to difficult decisions regarding treatment. Some interventions, such as tomato sauce or lycopene, could potentially act to reduce progression of low-grade cancers. Finasteride may be an example of an agent that inhibits (or even regresses) growth in better differentiated lesions, but not for poorly differentiated lesions.40
If the propensity for progression could be further reduced in these cancers, perhaps treatment could be deferred or even averted. However, treatments that influence incidence or progression of primarily well-differentiated cancers may do little to prevent mortality from poorly differentiated cancers, which account for the majority of fatal cancers.
A fourth implication is that although high-grade, non-advanced prostate cancers are relatively common in the PSA era, and are often used as an endpoint to characterize aggressive prostate cancer, the pattern of most risk factors for high-grade, non-advanced cancers is not the same as that for fatal prostate cancer. Even though high-grade cancers are more likely to progress than low-grade cancers, the majority of high-grade cancers are not fatal, especially those diagnosed in the PSA era. Moreover, lesions that do progress may take many years to do so, and the endpoint of organ-confined, high-grade cancers does not necessarily help identify most risk factors for progression. Calcium intake, the factor most strongly associated with high-grade vs
. low-grade cancer, was associated with advanced prostate cancer in both the pre-PSA and the PSA eras, but with total prostate cancer only in the pre-PSA era (). A possible reason is that in the pre-PSA era, a much higher proportion of cancers were diagnosed due to clinical progression, for which high-grade is an important determinant. In the PSA era, these cancers may have been largely diluted by the high prevalence of PSA-detected cancers. Interestingly, we had previously shown that high calcium intake was associated with a non-significant inverse association with organ-confined, low-grade prostate cancer in the PSA era.41
A fifth implication is that heterogeneity by age at risk may occur for some risk factors, most notably BMI and possibly physical activity. Other sources of heterogeneity that we did not assess are possible.
The etiology of prostate cancer remains enigmatic. Results of many studies have been conflicting, especially in the PSA era. Currently, studies relying solely on incidence may have limited applicability to identifying means to prevent dying from prostate cancer. Using Gleason sum to characterize aggressiveness may be informative in some contexts, but generally does not seem useful in pointing to risk factors that influence disease progression. Fatal and advanced stage prostate cancer may be informative endpoints, although advanced stage should be based on clear indicators, such as invasion into the seminal vesicle or other regional structures or metastasis to the lymph nodes, bone, or other organs. The complexity of the clinical and pathologic manifestations of prostate cancer must be considered in the design and interpretation of studies.