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Fred Hutchinson Cancer Research Center, Seattle, WA 98109-4686
2To whom correspondence should be addressed. E-mail: akristal{at}fhcrc.org.
KEY WORDS: • lycopene • tomato • epidemiological • prostate cancer
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Review of published literature
One way to organize the literature about lycopene and prostate cancer is by exposure measure and study design. The 3 exposure measures that are relevant are 1) consumption of high-lycopene foods, primarily concentrated, cooked tomato products and foods made with these products; 2) dietary lycopene intake; and; 3) serum lycopene concentration. The study designs are 1) case control; 2) longitudinal, including nested case-control studies examining stored serum; 3) cross-sectional studies (studies of serum lycopene comparing men with and without prostate cancer); and 4) human clinical trials focusing on intermediate end points in prostate tissue. Summarized briefly, we make the following observations. First, only one prospective cohort study has examined cooked tomatoes. The Health Professionals Cohort (HPC) found a significant 23% reduction in risk associated with high consumption, with an ordered and a significant trend across increasing consumption categories (2). Most case-control studies of cooked tomatoes report modest, statistically nonsignificant associations with reduced prostate cancer risk. Second, only 2 cohort studies have examined dietary lycopene. The HPC found a significant 16% reduction in risk associated with high lycopene intake (2), whereas The Netherlands Cohort Study found no association (3). Six cohorts have reported results of associations for prediagnostic serum lycopene concentration, and none have found statistically significant results except in subgroup analyses. In the Physicians’ Health Study cohort, high serum lycopene was associated with a 41% reduced risk among men in the placebo arm, but there was no association among those receiving the ß-carotene supplement (4). In the HPC, high serum lycopene was associated with a 53% reduced risk among men over age 65 y or with no family history of prostate cancer, but there was no association among men under age 65 y (5). Of the remaining 4 cohorts, 2 reported nonsignificant relative risks under 1.00 and 2 reported nonsignificant risks above 1.00 (6–8). Third, all 3 of the studies contrasting serum lycopene concentrations in men with and without prostate cancer reported significantly lower serum lycopene in men with cancer (9–11). Fourth, 2 very small human experimental studies have examined effects of tomato products on intermediate measures possibly related to prostate cancer risk by comparing prostate tissue collected at diagnostic biopsy (pretreatment) to tissue collected at prostatectomy (posttreatment). These studies were designed as pilot projects, yet because they have been interpreted in both the scientific and the lay press as if they were well-executed, randomized clinical trials, they deserve comment here. One study examined effects of tomato sauce and reported posttreatment increases in serum and tissue lycopene concentrations and reductions in serum prostate specific antigen (PSA) and leukocyte oxidative DNA damage (12). Oxidative DNA damage in prostate tissue collected at prostatectomy was lower in men participating in the study than in tissues collected from a convenience sample of prostatectomy tissue from men not participating in the study. This study had no control group, and none of these changes can or should be attributed to the tomato sauce intervention. A second study was a randomized trial using a tomato oleoresin supplement (13). This study reported that the supplement significantly delayed or reversed the development of multifocal disease, large tumor volume, and invasion at or beyond the prostate margins. It is not reasonable to conclude that 4 wk of tomato oleoresin supplementation could have these profound effects on prostate cancer biology. Instead, these results are due to either the failure of randomization or differential dropout between treatment arms; of the men completing the study, 67% in the intervention arm had stage T1C cancer at baseline compared with only 36% in the placebo arm.
Taken together, we do not find evidence to support a substantial association of lycopene or tomato products with reduced prostate cancer risk. Results of large cohort studies are mixed, and few serum-based or case-control studies were sufficiently large to detect modest effect sizes. Most of the studies published on lycopene and cancer have not been designed or analyzed to answer this question optimally, and key areas for advancing this research include a) improving assessments of lycopene exposure; b) incorporating information on cancer stage, grade, and screening into statistical analyses; and c) investigating interactions between oxidative stress or polymorphisms in genes affecting response to oxidative stress with lycopene intake.
Assessment of lycopene exposure
While we assume that the exposure of interest is prostate-tissue lycopene concentration, this is not a feasible measure for epidemiological research. Instead, we use either serum lycopene concentration or dietary intake as surrogate measures. There is considerable variability in the lycopene content of standard servings of lycopene-containing foods, ranging from 
1900 µg in half a pink grapefruit to almost 20,000 µg in a half cup of tomato sauce, and absorption is greatest from concentrated tomato products that are consumed or cooked in fat. Nevertheless, serum lycopene concentration correlates poorly with consumption of lycopene-rich foods, probably because measures of intake are poor and because other factors affect serum levels (14). Indeed, single-dose feeding studies may be misleading regarding the absorption of lycopene from different foods and at various concentrations. For example, although absorption may be poor from a single serving of uncooked and fat-free, high-lycopene foods, plasma lycopene does slowly increase when lycopene is fed as tomato juice or watermelon juice, and, after 2 wk, it reaches the same maximum concentration from a 20-mg and a 40-mg dose (15). Findings are similar for buccal epithelial lycopene concentration; lycopene increases rapidly when feeding lycopene beadlets or tomato oleoresin and very slowly when feeding tomato juice, but, by 4 wk, lycopene levels are the same regardless of dietary source (16). These and other studies suggest that lycopene accumulates in LDL and other tissues, where it reaches a maximum concentration at a moderate level of lycopene intake. These results may explain why dietary intake measures correlate poorly with serum concentration and, by inference, with prostate-tissue concentration as well. Therefore, serum measures are the most valid assessment of lycopene possible in epidemiological studies, but a single measure may not be optimal because of variability within individuals over time. In a small study we conducted in the Prostate Cancer Prevention Trial, serum lycopene was moderately consistent across individuals over many years and, by using the average of 3 measures collected over 7 y, we could measure lycopene concentration with a reliability of 0.82. It is likely that multiple serum measures taken over time will yield the best assessment of lycopene exposure in the prostate.
PSA screening and prostate cancer epidemiology
PSA screening has profoundly affected epidemiological studies of prostate cancer. After a near doubling of incidence after the adoption of PSA screening in the United States in the early 1990s, the incidence has dropped but remains 30% above pre-PSA era rates. The majority of men now diagnosed with prostate cancer have low-grade disease confined to the prostate, many of whom would never clinically manifest the disease. Further, it is now clear that PSA screening is neither sensitive nor specific, because 15% of men with "normal" PSA tests (94% of men over age 50 y have such "normal" values) have biopsy-detectable cancer (17). Therefore, from a large pool of men with prostate cancer, it is primarily the subset of men who undergo PSA screening who are "cases" in epidemiological studies. It is thus critical to include information on the clinical and, whenever feasible, biological characteristics of cancers that comprise the cases under investigation, including both Gleason grade and stage, in an attempt to separate clinically significant from latent disease. Another complexity in prostate cancer epidemiology introduced by PSA screening is because of the correlation of screening with other purportedly healthful behaviors, including using vitamin supplements and eating a healthy diet. This may lead to an unusual type of confounding, in which a confounding factor masks a true association. Thus, without a control for the number of PSA screening tests, a true association of lycopene with prostate cancer may be masked or even reversed in direction (18).
Genetic characteristics and diet-gene interactions
There is good inferential evidence from studies of drug metabolism that effects of some pharmacologically active dietary compounds will differ by an individual’s genetic characteristics. Data on whether effects of lycopene differ by susceptibility to or inability to repair oxidative DNA damage is sparse. Some preliminary data suggest that persons with a variant in the XRCC1 gene are at higher prostate cancer risk if their lycopene intake is low (19). The ability to pursue this research will require collaboration among cohort studies with very large sample sizes and biological specimens available for genotyping and serum lycopene assays. Such studies are needed to determine whether lycopene has chemopreventive effects only among a subset of the population.
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CONCLUSIONS |
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FOOTNOTES |
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LITERATURE CITED |
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19. van Gils, C. H., Bostick, R. M., Stern, M. C. & Taylor, J. A. (2002) Differences in base excision repair capacity may modulate the effect of dietary antioxidant intake on prostate cancer risk: an example of polymorphisms in the XRCC1 gene. Cancer Epidemiol. Biomark. Prev. 11:1279-1284.
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