Tomatoes, Lycopene and Prostate Cancer

Edward Giovannucci, M.D., Sc.D.

Channing Laboratory, Department of Medicine

Brigham & WomenÕs Hospital and Harvard Medical School

181 Longwood Avenue, Boston, MA 02115

Department of Nutrition, Harvard School of Public Health

In economically developed countries, prostate cancer is one of the leading causes of cancer death. Most of the established risk factors for prostate cancer are non-modifiable. These include older age, a family history of the disease, and race. Some evidence indicates that nutritional or other environmental factors influence the occurrence or progression of prostate cancer. A diet high in red meat and dairy seems to increase risk of prostate cancer. Unlike many other cancer sites, most data do not strongly support an important role of overall fruit and vegetable consumption in helping to prevent prostate cancer. Nonetheless, it is still possible that rich sources of specific bioactive compounds may be beneficial. Some micronutrients, such as selenium and vitamin E have, in fact, been shown to have potential benefits. Recently, tomatoes and tomato-based products, the major source of many of the dietary carotenoids including lycopene, have shown promise for the prevention of prostate cancer. The potential impact of tomatoes and lycopene are the focus here.

Carotenoids are a group of at least 600 compounds manufactured by plants, and account for many of the bright colors in the plant kingdom. Only about 14 carotenoids are found in appreciable levels in human tissues. The most common carotenoids in the human diet and plasma are b-carotene, a-carotene, lycopene, lutein, and b-cryptoxanthin. Carotenoids have many interesting properties in biological systems. b-carotene and a few other carotenoids can be converted to vitamin A. Additionally, carotenoids react with free radicals and singlet oxygen generated by normal cellular respiration and possibly by exogenous sources such as cigarette smoking (1). Antioxidants limit oxidative damage to the cell membrane lipid bilayer and to DNA. Cells have complex, multifaceted systems to limit oxidative damage; it is possible, but not proven, that dietary antioxidants such as carotenoids complement these antioxidant systems that are imperfect.

Of the 14 carotenoids found in human serum, tomato and tomato products contribute to 9 and are the predominant source of about half. In recent years, focus has increased on lycopene, a carotenoid that cannot be converted into vitamin A, and found primarily in tomatoes. Lycopene is the most efficient carotenoid in quenching singlet oxygen species, (2) and is likely an effective free radical scavenger in vivo (3). It inhibits proliferation of cancer cells in vitro (4), including that in prostate cell lines induced by DHT (5), and in vivo (6). In a recent human trial, dietary lycopene provided by tomato juice, spaghetti sauce and tomato oleoresin resulted in a significant reduction in lipid oxidation (7). Lycopene is the most abundant carotenoid in plasma (8, 9) and in the prostate (mean of 30% of total) (10).

Some epidemiologic studies have correlated risk of prostate cancer with intake of tomatoes and tomato-based product or lycopene, and other studies have directly measured lycopene in blood samples. Dietary-based studies have been either case-control, for which prior diet in men with prostate cancer is compared with that of a control or comparison group free of cancer, or prospective, for which diet is measured at baseline and men are followed for prostate cancer occurrence.

A case-control study conducted in Minnesota (11) found that men diagnosed with prostate cancer reported less tomato intake than men without prostate cancer, though the study was relative small and the result was not statistically significant. Another case-control study, conducted in a multi-ethnic population in Hawaii (12), found no association between consumption of "tomatoes" and prostate cancer risk. However, the actual intake levels were not reported, and it did not appear that tomato-based products such as tomato sauce were specifically considered in this study. A case-control study conducted in the United Kingdom (13) found no association between raw or cooked tomatoes and risk of prostate cancer. However, the strongest diet-prostate cancer association found was for baked beans (relative risk = 0.52; 95% CI = 0.31-0.88, for high versus low intake), and tinned baked beans, usually stored in tomato sauce, may possibly be the best source of highly bioavailable lycopene. A recent study conducted in Greece found that men with prostate cancer reported slightly less raw tomatoes (P = 0.12) but significantly less cooked tomatoes (P = 0.005).

Four dietary prospective studies (14-17) have reported on the relationship between tomato or lycopene consumption and prostate cancer risk (table 2). In a cohort of 14,000 Seventh-day Adventist men (14), higher consumption of tomatoes was statistically significantly related to lower risk of prostate cancer in a multivariate analysis. The only other food item related to a lower prostate cancer risk was intake of beans, lentils, and peas. b-carotene-rich foods were unrelated to risk. In a larger study that had a more comprehensive dietary questionnaire (16), intakes of the carotenoids b-carotene, a-carotene, lutein and b-cryptoxanthin were not associated with risk of prostate cancer, but high intake of lycopene reduced risk of prostate cancer by 21%. Also, high intake of tomatoes and tomato products, which accounted for 82% of lycopene, was associated with a 35% lower risk of total prostate cancer, and a 53% lower risk of advanced (extraprostatic) prostate cancer. Tomato sauce had the strongest inverse association with prostate cancer risk (RR = 0.66; 95% CI = 0.49-0.90; P for trend = 0.001), and weaker inverse associations were observed with tomatoes and pizza, but none with tomato juice. Of note, the degree of reduction of prostate cancer risk by the tomato-related products (tomato sauce, substantial reduction; tomatoes and pizza, moderate reduction; and tomato juice, no reduction) corresponded with the degree that these items correlated with plasma lycopene levels in a sample of men. Preliminary results from two other cohort studies (15, 17) also support an inverse association between tomato or lycopene intake and prostate cancer risk.

Three studies (18-20) have reported on the risk between prediagnostic serum carotenoids and risk of prostate cancer (table 3). The first report, a study by Hsing et al. (18), was based on serum obtained in 1974 from 25,802 persons in Washington County, Maryland. This study found a 6.2% lower median lycopene level in men with prostate cancer diagnosed during a 13-year period compared to age- and race-matched controls. The relative risk was 0.50 (95% CI = 0.20 - 1.29) between high and low quartiles of lycopene. Lycopene was the only carotenoid associated with lower prostate cancer risk in this relatively small study.

The largest blood-based study was based on an analysis from the Physicians' Health Study (19). The study design used was a nested case-control study using samples stored in 1982. In total 578 prostate cancer cases occurred over the 13 years of follow-up. Of the 578 cases, 259 were classified as "aggressive" based on high grade or advanced stage. The baseline plasma lycopene level of cases was compared with that of age-matched prostate cancer-free controls. The investigators found a lower risk of prostate cancer, particularly for aggressive prostate cancer (relative risk = 0.56 (95% CI = 0.34-0.92) when comparing high to low quintile of plasma lycopene. None of the other measured carotenoids were related to risk of prostate cancer in this study.

A study of prediagnostic serum carotenoids and prostate cancer risk, conducted between 1971 and 1993 in a Japanese-American population in Hawaii (20), did not find an association between serum lycopene levels and risk of prostate cancer. However, several characteristics of the study may have contributed to the null association. Only a single assessment of serum lycopene was used to characterize follow-up for up to a twenty-two year period (only 14 cases occurred within the first 5 years of follow-up), and the study included "low virulence" prostate cancer (28% were diagnosed incidentally during surgery for benign prostatic hyperplasia) in a low-risk population. These factors might contribute to the null results. Most importantly, the serum lycopene levels were quite low-the median serum concentration among controls was only 134 ng/ml, compared to 320 ng/ml in the Hsing et al. study (18) and 424 ng/ml in the sample of 121 health professionals (16)). The low levels may indicate either very low intake of bioavailable lycopene in this population or degradation of lycopene in stored samples, which could account for the absence of an association.

Overall, the dietary case-control and prospective studies, and the biomarker (lycopene) epidemiologic data strongly indicate that intake of tomatoes and tomato products lower risk of prostate cancer, especially aggressive prostate cancer. This benefit may be related to lycopene, but other potential beneficial substances instead of or combined with lycopene cannot be excluded. These associations cannot be considered as definitively representing cause-and-effect because they are based on observational and not randomized data. However, the consistency across different populations is striking, and the finding that cooked and processed tomato products yield greater benefit is intriguing because cooking and processing greatly enhance the bioavailability of lycopene from tomatoes (16). Moreover, it is unlikely that another healthy behavior that correlates with tomato intake accounts for the association because tomato products are quite diverse items; some are correlated positively with healthy behaviors (e.g. tomatoes) and some inversely (e.g. pizza), and some (e.g. tomato sauce) display no obvious pattern with healthy behaviors. Thus, it was remarkable that tomato sauce, pizza, and tomatoes were each associated with lower prostate cancer risk in the Health Professionals Follow-Up Study (16).

Thus, the available data suggest that adequate consumption of tomato and tomato-based products may be prudent. In the Health Professionals Follow-Up Study, even 2-4 weekly servings of tomato sauce, an excellent source of bioavailable lycopene, reduced risk of total prostate cancer by a third and aggressive prostate cancer by half. This recommendation is consistent with current guidelines to increase fruit and vegetable consumption to lower risk of cancer and other health conditions. There is unlikely to be adverse effects of tomato consumption, and perhaps other benefits may be evident (21). The specific use of lycopene-concentrated pills, however, needs to be evaluated in clinical trials before recommendations can be made. Also, the data available thus far have dealt only with tomato or lycopene intake prior to the diagnosis of cancer; the influence of tomatoes or lycopene on prognosis after the diagnosis of prostate cancer requires evaluation.

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