In this study of primarily asymptomatic, local stage prostate cancer, pre-diagnostic serum lycopene concentration was not associated with the risk of total, low- or high-grade cancer. There were also no associations of serum lycopene with prostate cancer risk within strata defined by age, race, BMI or family history of prostate cancer. However, in the placebo arm of the trial, increasing serum lycopene was associated with reduced risk of prostate cancer that was diagnosed following either an elevated PSA test or abnormal DRE and a corresponding increased risk of cancer diagnosed at the end of the study without indication for biopsy. In the finasteride arm, increasing serum lycopene was associated only with decreased risk of low-grade cancer diagnosed for cause.
The overall lack of association between serum lycopene concentration and prostate cancer risk found in this study is consistent with previous studies(2
), which found no significant associations in unstratified analyses. Comparing our findings to previously-reported findings in subgroups requires careful evaluation of each. Two studies have reported significant inverse associations of lycopene with risk of high grade/advanced stage cancer only: In the placebo arm of the Physicians Health Study (PHS), a randomized trial of aspirin and β-carotene supplementation, there was a 60% reduction in risk of aggressive cancer comparing the highest to lowest quintiles of serum lycopene(6
); and in the European Prospective Investigation into Cancer and Nutrition (EPIC) there was a 60% reduced risk of advanced prostate cancer among men in the highest compared to lowest quintile of plasma lycopene(11
). There was a dose-response association in the PHS but an inverted J-shaped association in EPIC. Neither this nor any of the four previously-published studies that examined associations stratified by grade and/or stage have replicated these findings(4
). In the Health Professionals Follow-Up Study there were 63% and 52% reduced risks among men who, respectively, provided their serum samples at age ≥ 65 years and had no family history of prostate cancer(4
). Neither this nor any of the four previously-published studies that examined associations stratified by age(6
) or the one study stratified family history of prostate cancer(13
) replicated these findings. Our study provides no support of previous subgroup findings from serum-based studies, which with the exception of two studies finding associations for aggressive disease, have never been replicated.
Findings from cohort studies based on self-reported diet provide little additional clarity on subgroup findings in serum-based studies, specifically regarding whether associations of lycopene with prostate cancer risk are limited to older men, men with advanced disease or men without a family history of prostate cancer. In the PHS, high tomato sauce intake was associated with similar reductions in risk of organ-confined, minimally-extraprostatic and advanced disease, but larger reductions in risk for low- compared to high-grade disease(19
). In the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) there was an inverse association of lycopene intake only among men with a family history of prostate cancer(17
). Even within cohorts, no statistically significant subgroup finding has been consistent between diet- and serum-based analyses (4
). Given that both this study and the majority of previously-published cohort studies based on either serum or dietary measures of lycopene exposure have found no association either overall or in subgroups, and that a small number of subgroup findings are not consistent across or even within studies, we judge that the accumulated evidence does not support an association lycopene with prostate cancer.
This study found inverse associations of serum lycopene with cancer diagnosed for cause (following a biopsy prompt) and positive associations with cancer diagnosed not-for-cause (at the protocol-specified end of the study biopsy). Results were somewhat inconsistent across study arms; we therefore first consider the placebo arm, in which findings were similar for low-and high-grade cancer. Cancers diagnosed for-cause were more likely to be higher-grade and higher-volume (23
), as both are associated with elevated PSA. We considered whether lycopene preferentially prevented more clinically-significant cancers, however this was unlikely because findings did not differ by grade. High lycopene concentration could have delayed or prevented cancer detection if serum lycopene or a factor association with serum lycopene was inversely associated with PSA. There was a weak inverse association of serum lycopene with PSA in the placebo but not finasteride arm: controlled for age, race, family history, BMI and cholesterol: β (ng/ml PSA per 10 ug/dl lycopene) =−0.041 [95% CI −0.013 – −0.069] and −0.006 [95% CI −0.026 −0.038] in the placebo and finasteride arms, respectively; pinter
<0.03. We know of no biological explanation for this finding, however it does suggest that when using current PSA screening practices high serum lycopene could delay or prevent prostate cancer diagnosis. We next considered findings in the finasteride arm, in which there was an inverse association of lycopene with low-grade, for-cause cancers only, with no association with high-grade or not-for-cause cancer. The lack of association with high-grade disease may be due to the increase in the sensitivities of both PSA screening and DRE to detect high-grade cancer among men receiving finasteride (27
), which could attenuate any association of lycopene on the detection of high-grade cancer. We have no hypotheses to explain the inverse association of lycopene with for-cause but not not-for-cause, low-grade cancer. It is also possible that all of these subgroup findings could be due to chance, reflecting the large number of subgroup analyses completed within these data. The clinical significance of these findings is uncertain. It would be beneficial if high lycopene intake delayed or prevented the detection of local stage, low-grade cancers that were of no clinical significance. In contrast, it would be harmful if high lycopene intake delayed or prevented detection of high-grade prostate cancer, as these are generally aggressive and far more likely to metastasize and cause death.
There are unique aspects to this study that must be considered when interpreting its results. Most importantly, study participants had PSA <3 ng/ml at study entry and received annual screening (PSA plus DRE) during the 7 years of the trial and, further, almost half of the cancers were detected at the end-of-study biopsy among men without an elevated PSA or abnormal DRE. Therefore the incidence of cancer and the proportion of cancers that were low-grade and local-stage were higher in the PCPT than in other studies. We note that in the placebo arm, findings for for-cause cancers can be directly compared to studies in populations undergoing routine PSA screening. However, when considering the positive association with cancers detected by not-for-cause biopsy and the null findings for all cancers combined, it appears that the inverse associations found for screen-detected cancers were misleading. Lycopene assessment was from two samples collected approximately 3 years apart, which we believe is superior to measuring lycopene based on self-reported “usual” diet because the correlation between dietary lycopene as measured by the PCPT food frequency questionnaire (FFQ) and serum lycopene was low (0.12) and the effective reliability of the serum measure was higher (0.86) than the 6-month test-retest reliability of the PCPT FFQ (0.48). However, blood samples were not protected from light during collection and were subject to one freeze-thaw cycle in the preparation of the pooled aliquots; this will add error to the lycopene assay but there is no reason to believe that this error would be biased by case/control status.
A major strength of the PCPT is the mitigation of detection biases present in most observational cohorts in which PSA level and digital rectal examinations affect the decision to perform a prostate biopsy. Use of PSA screening is likely associated with dietary patterns(29
), such that biases due to screening may have seriously confounded previous studies. An additional strength is the availability of Gleason score based on a single, research pathologist, in contrast to other studies that have classified the aggressiveness of incident cancers using a mix of clinical and pathological (post-prostatectomy) stage, grade that is either qualitative or assigned by multiple clinical pathologists, or long-term clinical outcomes. Finally, this study, with 1,683 (461 high-grade) cases was substantially larger than the 692 (235 high-grade) in the PLCO (13
), which is the next largest study.
In conclusion, we found no evidence in this unique sample of primarily local stage, biopsy-detected cancers that serum lycopene is associated with reduced prostate cancer risk. In men not treated with finasteride, lycopene was associated with delayed detection of both low- and high-grade cancers, which was an unexpected finding of uncertain clinical significance. Overall our findings are consistent with those from most other cohort studies, which taken together do not support the use of lycopene for the prevention of prostate cancer.