Lycopene and Cancer : A Review of the Evidence

Prepared by David Heber, MD, PhD, FACP, FACN

INTRODUCTION

The evidence for the statement that lycopene intake can reduce the risks of certain common forms of cancer is derived from a combination of epidemiological, basic science and limited human intervention trials. There are over 70 studies including studies that have reported on the intake of tomatoes, tomato-based products, and lycopene or blood or tissue levels of lycopene and risk of a cancer site. All of the studies have been reviewed in preparation of this report. Among the many studies, none refute the selected ones analyzed below. The ones below build a significant and strong base of scientific evidence linking tomato product and lycopene intake to reduction in the risks of common forms of cancer. Evidence is strongest for reduction in the risks of cancers of the prostate and lung but the evidence is suggestive for cancers of the colon, stomach, cervix, breast, oral cavity, pancreas, and esophagus. The studies providing the evidence base are grouped below by type of cancer.

The population-based studies are not all of equal weight, and the non-supportive studies are often in smaller populations. Clearly, the most comprehensive and supportive studies of an association are the Harvard Physicians’ Study and Health Professional Follow Up Study. Those large cohort studies clearly demonstrate an association not only between dietary intake of tomatoes and tomato products with prostate cancer risk reduction but also clearly establish an association with blood levels of lycopene. Studies of lycopene absorption from the diet and metabolism clearly establish a link between tomato product and lycopene intake with blood levels of lycopene. Taken together with the limited human intervention data in which administration of 30 mg lycopene supplement capsules or an equivalent amount of tomato paste led to beneficial changes in prostate cancer cell biomarkers in prostate cancer patients, the studies provide credible scientific evidence for the assertion that intake of tomato products or lycopene reduces prostate cancer risk. Non-supportive studies of dietary intake and prostate cancer risk are included below but these were generally smaller studies where the failure to find an association is not credible evidence in contradiction to the larger population-based studies reviewed.

1. Prostate Cancer

Summary

Prostate cancer is the most common cancer in American men. Preventable measures for this malignancy are not well established. Among potentially beneficial natural compounds is the carotenoid lycopene, which is derived largely from tomato-based products. Recent epidemiologic studies have suggested a potential benefit of this carotenoid against the risk of prostate cancer, particularly the more lethal forms of this cancer. Five studies support a 30% to 40% reduction in risk associated with high tomato or lycopene consumption, three are consistent with a 30% reduction in risk (but the results in those three were not statistically significant), and seven were not supportive of an association. The largest well-designed relevant dietary study, a prospective study in male health professionals found that consumption of two to four servings of tomato sauce per week was associated with about a 35% risk reduction of total prostate cancer and a 50% reduction of advanced (extraprostatic) prostate cancer. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study. In the largest plasma-based study, very similar risk reductions were observed for total and advanced prostate cancer for the highest versus lowest quintile of lycopene. Other studies, mostly dietary case-control studies, have not been as supportive of this hypothesis. The reasons for these inconsistencies are unclear, but in three of the seven null studies, tomato consumption or serum lycopene level may have been too low to observe an effect. Because the concentration and bioavailability of lycopene vary greatly across the various food items, dietary questionnaires vary markedly in their usefulness of estimating the true variation in tissue lycopene concentrations across individuals. To optimize the interpretation of future findings, the usefulness of the questionnaire to measure lycopene levels in a population should be directly assessed. Although not definitive, the available population-derived data suggest that increased consumption of tomatoes and tomato-based products may be prudent. There have also been two small-scale human intervention trials in which lycopene given as a supplement was found to increase serum lycopene levels and to result in beneficial changes in prostate tissues. Finally, in terms of biological rationale, there are a number of studies in cell culture which document anti-cancer effects of lycopene working through multiple pathways. This review will first consider the epidemiological studies summarized above and then review the clinical and basic studies.

1. A. Supportive Epidemiologic or Population-based Studies

Mills PK, Beeson WL, Phillips RL, Fraser GE.Positive associations between dietary intake of lycopene and prostate cancer. Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer 1989;64:598-604.

Dietary and lifestyle characteristics were evaluated in relation to subsequent prostatic cancer risk in a cohort of approximately 14,000 Seventh-day Adventist men who completed a detailed lifestyle questionnaire in 1976 and who were monitored for cancer incidence until the end of 1982. During the 6-year follow-up period, 180 histologically confirmed prostatic cancers were detected among some 78,000 man-years of follow-up. Increasing educational attainment was associated with significantly decreased risk of prostate cancer in this study; age at first marriage was also inversely associated with risk, although this was not significant. There was no relationship between body mass index (as measured by Quetelet's Index) and risk. A history of prostate "trouble" was associated with a 60% increase in risk which was highly significant. Although there were suggestive relationships between increasing animal product consumption and increased risk, these results did not persist after accounting for the influence of fruit and vegetable consumption. Nor was exposure to the vegetarian lifestyle during the childhood years associated with alterations in subsequent risk. However, increasing consumption of beans, lentils and peas, tomatoes , raisins, dates, and other dried fruit were all associated with significantly decreased prostate cancer risk.

Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.Cancer Res 1999 ;59:1225-30

This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. In this nested case-control study, plasma samples were obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. The five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol were quantitated using high-performance liquid chromatography. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide strong evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer since in this study blood levels of lycopene confirmed earlier associations of dietary intake of tomato products and lycopene with reduced prostate cancer risk.

Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC.A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002 ;94:391-8.

Findings from the Health Professionals Follow-Up Study (HPFS) from 1986 through January 31, 1992, suggest that frequent intake of tomato products or lycopene, a carotenoid from tomatoes, is associated with reduced risk of prostate cancer. This prospective study evaluated additional data from the HPFS to determine if the association would persist. Prostate cancer cases from 1986 through January 31, 1998, among 47,365 HPFS participants who completed dietary questionnaires in 1986, 1990, and 1994 were analyzed utilizing pooled logistic regression to compute multivariate relative risks (RR) and 95% confidence intervals (CIs). All statistical tests were two-sided. From 1986 through January 31, 1998, 2481 men in the study developed prostate cancer. Results for the period from 1992 through 1998 confirmed the previous findings---that frequent tomato or lycopene intake was associated with a reduced risk of prostate cancer. Similarly, for the entire period of 1986 through 1998, using the cumulative average of the three dietary questionnaires, lycopene intake was associated with reduced risk of prostate cancer (RR for high versus low quintiles = 0.84; 95% CI = 0.73 to 0.96; P(trend) =.003); intake of tomato sauce, the primary source of bioavailable lycopene, was associated with an even greater reduction in prostate cancer risk (RR for 2+ servings/week versus <1 serving/month = 0.77; 95% CI = 0.66 to 0.90; P(trend)<.001), especially for extraprostatic cancers (RR = 0.65; 95% CI = 0.42 to 0.99). These associations persisted in analyses controlling for fruit and vegetable consumption and for olive oil use (a marker for Mediterranean diet) and were observed separately in men of Southern European or other Caucasian ancestry. Frequent consumption of tomato products is associated with a lower risk of prostate cancer. The magnitude of the association was moderate enough that it could be missed in a small study or one with substantial errors in measurement or based on a single dietary assessment.

1B. Human Intervention Studies

Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, Khachik F, Banerjee M, Bertram JS, Wood DP Jr.Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med 2002 ;227:881-5.

In this clinical trial, the biological and clinical effects of lycopene supplementation were examined in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.

Bowen P, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, Kim HS, Christov-Tzelkov K, van Breemen R.Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med 2002 ;227:886-93.
As part of a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage in men with prostate cancer, a nonrandomized 5th arm using tomato sauce was included and reported in this study. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical prostatectomy. Prostate tissue was obtained as biopsies at baseline and as resected tissue at the time of the prostatectomy. Serum and Prostate lycopene, serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH-deoxyguanosine/deoxyguanosine (8OHdG) were measured at baseline and at the end of the intervention. Cancer cells in paraffin sections of prostate biopsies and postintervention resected tissue were compared for 8OHdG staining and for apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6% of the intended dose, and serum and prostate lycopene concentrations increased 1.97- and 2.92-fold (P < 0.001), respectively. Mean serum PSA concentrations decreased by 17.5% (P < 0.002) and leukocyte 8OHdG decreased by 21.3% (P < 0.005) after tomato sauce consumption. Resected tissues from tomato sauce-supplemented patients had 28.3% lower prostate 8OHdG compared with the nonstudy control group (P < 0.03). Cancer cell 8OHdG staining of Gleason Score-matched resected prostate sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic index was higher in hyperplastic and neoplastic cells in the resected tissue after supplementation. These data taken as a whole indicate significant uptake of lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and prostate tissue. Whether reduction in DNA damage to prostate cancer cells is beneficial awaits further research, although reduction in serum PSA concentrations is promising.
Van Breemen RB, Xu X, Viana MA, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Bowen PE, Sharifi R.Liquid chromatography-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce. J Agric Food Chem 2002 ;50:2214-9.
Men with clinical stage T1 or T2 prostate adenocarcinoma were recruited (n = 32) and consumed tomato sauce based pasta dishes for 3 weeks (equivalent to 30 mg of lycopene per day) before radical prostectomy. Prostate tissue from needle biopsy just before intervention and prostectomy after supplementation from a subset of 11 subjects was evaluated for both total lycopene and lycopene geometrical isomer ratios. A gradient HPLC system using a C(18) column with UV-vis absorbance detection was used to measure total lycopene. Because the absorbance detector was insufficiently sensitive, HPLC with a C(30) column and positive ion atmospheric pressure chemical ionization mass spectrometric (LC-MS) detection was developed as a new assay to measure the ratio of lycopene cis/trans isomers in these samples. The limit of detection of the LC-MS method was determined to be 0.93 pmol of lycopene on-column, and a linear response was obtained over 3 orders of magnitude. Total lycopene in serum increased 2.0-fold from 35.6 to 69.9 microg/dL (from 0.664 to 1.30 microM) as a result of dietary supplementation with tomato sauce, whereas total lycopene in prostate tissue increased 3.0-fold from 0.196 to 0.582 ng/mg of tissue (from 0.365 to 1.09 pmol/mg). All-trans-Lycopene and at least 14 cis-isomer peaks were detected in prostate tissue and serum. The mean proportion of all-trans-lycopene in prostate tissue was approximately 12.4% of total lycopene before supplementation but increased to 22.7% after dietary intervention with tomato sauce. In serum there was only a 2.8% but statistically significant increase in the proportion of all-trans-lycopene after intervention. These results indicate that short-term supplementation with tomato sauce containing primarily all-trans-lycopene (83% of total lycopene) results in substantial increases in total lycopene in serum and prostate and a substantial increase in all-trans-lycopene in prostate but relatively less in serum.
Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr 1997;66:116-22.

Lycopene bioavailability from a single dose of fresh tomatoes or tomato paste (23 mg lycopene) ingested together with 15 g corn oil was compared by analyzing carotenoid concentrations in the chylomicron fraction. The lycopene isomer pattern was the same in both fresh tomatoes and tomato paste. The triacylglycerol response in chylomicrons was not significantly different after both treatments. Ingestion of tomato paste was found to yield 2.5-fold higher total and all-trans-lycopene peak concentrations (P < 0.05 and P < 0.005, respectively) and 3.8-fold higher area under the curve (AUC) responses (P < 0.001) than ingestion of fresh tomatoes. The same was calculated for lycopene cis-isomers, but only the AUC response for the cis-isomers was significantly higher after ingestion of tomato paste (P < 0.005). No difference was observed in the alpha- and beta-carotene response. Thus, in humans, the bioavailability of lycopene is greater from tomato paste than from fresh tomatoes. This is likely due to the liberation of lycopene from the chromoplast structure to which it is bound in raw tomatoes by heat processing. This is further evidence that lycopene is the bioactive constituent in tomato products and lycopene supplements.

1B. Non-supportive studies on the association of prostate cancer and lycopene:

Le Marchand L, Hankin JH, Kolonel LN, Wilkens LRVegetable and fruit consumption in relation to prostate cancer risk in Hawaii: a reevaluation of the effect of dietary beta-carotene.Am J Epidemiol 1991;133:215-9.

This is a further analysis of a case-control study of 452 prostate cancer cases and 899 population controls that was conducted in 1970-1983 among the multiethnic population of Hawaii. Because a previous analysis had shown a positive association with intake of beta-carotene, a nutrient presently being tested for chemoprevention, the authors reexamined the data for consistency among the main food sources of beta-carotene. Vegetables and fruits containing other phytochemicals suspected to be cancer inhibitors were also examined. With the exception of papaya, which was positively associated with risk among men aged 70 years and older, consumption of other yellow-orange fruits and vegetables, tomatoes, dark green vegetables, and cruciferous vegetables was not associated with prostate cancer risk. These results suggest that: 1) the positive association with beta-carotene intake among older men that the authors previously reported was essentially due to the greater papaya consumption of cases compared with controls; and 2) intake of beta-carotene, lycopene , lutein, indoles, phenols, or other phytochemicals was not associated with prostate cancer risk.
This study cannot be considered contradictory of the Heath Professional Follow Up Study which was much larger considering some 2481 cases of prostate cancer and of essentially a different design. The Harvard study is known as a prospective cohort study design in which a very large population is tested at a point in time and then over many years as they develop disease, the risk of developing the disease over time is related to that initial blood sampling. So that, for instance, lycopene blood levels and tomato intake at a reduced beginning and during the study can be followed. When this was done, both tomato product intake and blood lycopene levels correlated with the risk of prostate cancer development. In the Le Marchand study, a case-control design was used. In this method cases of cancer are identified and then controls in the same population are identified. Both groups are tested, but the prostate cancer patients are asked about their diets and have their blood samples drawn after the occurrence of cancer. This introduces bias and is considered an inferior method to the cohort study design of the Harvard study which began with a population of over 80,000 individuals to identify 2481 incident cases of prostate cancer. The failure of the above smaller study to identify an association because the sample size was inadequate or because it was designed as a case-control study does not prove the absence of an association.
Key TJ, Silcocks PB, Davey GK, Appleby PN, Bishop DT.A case-control study of diet and prostate cancer. Br J Cancer 1997;76(5):678-87

A total of 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched population controls were interviewed. The principal hypotheses were that risk would increase with a high intake of total or saturated fat and would decrease with a high intake of carotene (beta-carotene equivalents) or lycopene. We also examined the associations of other nutrients and foods with risk. There was no evidence for an association between fat intake and risk, although the average fat intake was high and the range of fat intakes was narrow (medians of lower and upper thirds of percentage of energy from fat among controls were 34.3% and 42.9% respectively). Risk was lower in subjects with higher carotene intake: odds ratios 0.65 (95% CI 0.45-0.94) and 0.76 (0.53-1.10) in the middle and upper thirds of carotene intake respectively (P for trend = 0.150). Lycopene was not associated with risk. Among 13 other nutrients examined, the odds ratios in the top third of intake were below 0.8 for: potassium, 0.74 (0.51-1.09; P for trend = 0.054); zinc, 0.73 (0.49-1.08; P for trend = 0.126); iodine, 0.75 (0.51-1.11; P for trend = 0.077); vitamin B6 food only, 0.77 (0.53-1.12; P for trend = 0.077); and vitamin B6 including supplements, 0.70 (0.48-1.03; P for trend = 0.029). Among 18 foods examined, statistically significant associations were observed for: garlic as food, > or = 2/week vs never, 0.56 (0.33-0.93); garlic including supplements, > or = 2/week vs never, 0.60 (0.37-0.96); baked beans, > or = 2/week vs < 1/month, 0.57 (0.34-0.95); and garden peas, > or = 5/week vs < or = 3/month, 0.35 (0.13-0.91). This study does not support the hypothesis that fat increases risk and is equivocal in relation to carotene. The possible relationships of vitamin B6, garlic, beans and peas with risk for prostate cancer should be further investigated.
The same criticisms apply to this study as to the Le Marchand study. This study was also a case-control study design in a relatively small number of cases. The failure to identify an association because the study was too small or designed as a case-control study does not prove the absence of an association.
Hsing AW, Comstock GW, Abbey H, Polk BF Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 1990;82:941-6.

The associations of serum retinol, the carotenoids beta-carotene and lycopene, and tocopherol (vitamin E) with the risk of prostate cancer was investigated in a nested case-control study. For the study, serum obtained in 1974 from 25,802 persons in Washington County, MD, was used. Serum levels of the nutrients in 103 men who developed prostate cancer during the subsequent 13 years were compared with levels in 103 control subjects matched for age and race. Although no significant associations were observed with beta-carotene, lycopene , or tocopherol, the data suggested an inverse relationship between serum retinol and risk of prostate cancer. Data was analyzed to calculate odds ratios for prostate cancer based on the distribution of serum retinol by quartiles, using the lowest quartile as the reference value. Odds ratios were 0.67, 0.39, and 0.40 for the second, third, and highest quartiles, respectively.
This study may have been too small to pick up the association. There were only 103 men with prostate cancer in this nested case-control study compared to 2481 men in the Harvard study. Often an association is not evident until many more individuals are studied because there is a variation in how lycopene from the diet is handled in different individuals. To overcome this variation and the poor correlation between recalled intake of lycopene in the diet, many more subjects should have been studied.

Cohen JH, Kristal AR, Stanford JL.Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst 2000;92:61-8.

The associations of fruit and vegetable intakes with prostate cancer risk were examined in a population-based, case-control study of men under 65 years of age. Case participants were 628 men from King County (Seattle area), WA, who were newly diagnosed with prostate cancer. Control participants were 602 men recruited from the same underlying population and frequency matched to case participants by age. Self-administered food-frequency questionnaires were used to assess diet over the 3- to 5-year period before diagnosis or recruitment. Daily nutrient intakes were calculated by use of a nutrient database with recently updated analytic values for carotenoids. Odds ratios for prostate cancer risk associated with foods and nutrients were calculated by use of unconditional logistic regression. No associations were found between fruit intake and prostate cancer risk. The adjusted odds ratio (ORs) for the comparison of 28 or more servings of vegetables per week with fewer than 14 servings per week was 0.65 (95% confidence interval [CI] = 0.45-0.94), with a two-sided P for trend =.01. For cruciferous vegetable consumption, adjusted for covariates and total vegetable intake, the OR for comparison of three or more servings per week with less than one serving per week was 0.59 (95% CI = 0.39-0.90), with a two-sided P for trend =.02. The OR for daily intake of 2000 microg or more lutein plus zeaxanthin compared with an intake of less than 800 microg was 0.68 (95% CI = 0.45-1.00). These results suggest that high consumption of vegetables, particularly cruciferous vegetables, is associated with a reduced risk of prostate cancer.
The failure to find an association with lycopene intake in this study has been attributed to its sample size and study design as a case-control study. In addition, the selection of men below age 65 with cancer may have selected for the less common and more aggressive forms of prostate cancer. Prostate cancer incidence increases with age and it may well be that this study failed to identify an important association for prostate cancer in men over age 65 which is a much more common age for prostate cancer. Since prostate cancer in humans develops more commonly over age 60, this study by including only men under 65 missed a large portion of the at-risk population. This reduces the generalizability of the findings.

2. Lung Cancer
Fourteen studies have reported specifically on tomato or lycopene consumption and lung cancer risk. Of these, ten suggest either a statistically significant or a suggestive inverse association. These studies were mostly case-control comparisons which were adjusted for smoking. Among these various studies there were only a few that specifically considered lycopene. One study found an inverse association between tomato intake and squamous cell and small cell lung cancer but not with other histologic types (Kvale G, Bjelke E, Gart Jj. Dietary Habits and lung cancer risk Int J Cancer 1983;31:397-405.). A case-control study in Hawaii by LeMarchand et al.(Le Marchand L, Yoshizawa CN, Kolonel LN, Hankin JH, Goodman MT. Vegetable consumption and lung cancer risk : a population-based case-control study in Hawaii. J Natl Cancer Inst. 1989;81:1158-64) found that tomato intake related to a substantially reduced risk of lung cancer. The same cohort studied for lycopene intake several years later (Le Marchand L, Hankin JH, Kolonel LN, Beecher GB,Wilkens LB, Zhao LP. Intake of specific carotenoids and lung cancer risk. Cancer Epidemiol Biomarkers Prev 1994;3:523) showed only a modest inverse association that was not statistically significant. In this population, tomatoes accounted for only 29% of the reported lycopene intake.
3. Colorectal Cancer
Five studies have reported on tomato intake in relation to colorectal cancer risk. Case-control studies in Italy (Franchesi S., Bidoli E , La Vecchia C, Talamini R, D'Avanzo B, Negri E. Tomatoes and Risk of Digestive-tract Cancers. Int J Cancer 1994;59:181-4.) (Francheschi S, Favero A, a Vecchia C, Negri E, Conti E, Montella M, et al. Food Groups and Risk of Colorectal Cancer in Italy. Int J Cancer 1997;72:56-61.) and China (Hu JF, Liu YY, Yu YK, Zhao TZ, Liu SD, Wang QQ. Diet and cancer of the colon and rectum: a case-control study in China. Int J Epidemiol 1991;20:362-7.) reported about a 60% reduction in the risk of both colon and rectal cancers associated with higher tomato consumption. In rodents, there is a lesion called aberrant crypt foci which are induced in the colon by intrarectal infusion of a carcinogenic material. This is considered by experimental nutrition scientists to be a premalignant lesion that has been used extensively to screen for both drugs and nutrients that may protect against colon cancer. In this model, both lycopene and lutein in relatively small doses led to inhibition of the lesion formation, while administration of beta-carotene had no effect. One study in the United States ( Freudenheim JL, Graham S, Marshall JR, Haughey BP, Wilkinson G. A case-control study of diet and rectal cancer in western New York. Am J Epidemiol 1990;131:612-24.) reported significant inverse associations between tomato consumption and colorectal cancer risk for men and women. A study in Belgium (Tuyns AJ, Kaaks R, Haelterman M. Colorectal cancer and the consumption of foods: a case-control study in Belgium. Nutr Cancer 1988;11:189-204.) found no overall association but did find a suggestion of an inverse association between the consumption of tomato puree and colon cancer. The data in this study were analysed in an unusual fashion. In all the studies reviewed above tomato product intake is estimated and both patients and controls using dietary questionnaires. Based on these data, patients and controls are classified into a number of groups (usually five as quintiles) so that those consuming the most tomato products (highest quintile) can be compared to those consuming the least tomato products (lowest quintile). In this study, the overall consumption of tomato products was low, and the researchers took the unusual step of comparing those who never consumed tomato products to those who had consumed any amount of tomato products. While this makes sense in smoking studies, it is unusual to see this in a nutritional study. This method of analyais considered together with the lower overall consumption of tomato products by comparison to other studies weakens any conclusions drawn from this study and may explain why only a non-significant association was seen, albeit in the direction of protection between tomato puree intake and cancer risk.

4. Head and Neck Cancers
Three case-control studies ( Zheng T, Boyle P, Willett WC, Hu H, Dan J, Evstifeeva TV, et al. A case-control study of oral cancer in Beijing, People's Republic of China. Associations with nutrient intakes, foods and food groups. Eur J Cancer B Oral Oncol 1993;29B:45-55.) (Zheng W, Blot WJ, Shu XO, Gao YT, Ji BT, Ziegler RG, et al. Diet and other risk factors for laryngeal cancer in Shanghai, China. Am J Epidemiol 1992;136:178-91.) (Franceschi S, Bidoli E, Baron AE, Barra S, Talamini R, Serraino D, et al. Nutrition and cancer of the oral cavity and pharynx in north-east Italy. Int J Cancer 1991;47:20-5.) have reported on tomato intake in relation to oral cancers. One study in China (Graham S, Haughey B, Marshall J, Brasure J, Zielezny M, Freudenheim J, et al. Diet in the epidemiology of gastric cancer. Nutr Cancer 1990;13:19-34.) reported that high consumption of tomatoes reduced the risk of oral cancer by half. A similar result was found in a study of cancers of the oral cavity and pharynx performed in Italy (Franceschi S, Bidoli E, Baron AE, Barra S, Talamini R, Serraino D, et al. Nutrition and cancer of the oral cavity and pharynx in north-east Italy. Int J Cancer 1991;47:20-5.) A study of tomato intake and laryngeal cancer in China did not find an association (Zheng W, Blot WJ, Shu XO, Gao YT, Ji BT, Ziegler RG, et al. Diet and other risk factors for laryngeal cancer in Shanghai, China. Am J Epidemiol 1992;136:178-91.)

5. Esophageal Cancer and other Digestive Tract Cancer
A study in Iran (Cook-Mozaffari PJ, Azordegan F, Day NE, Ressicaud A, Sabai C, Aramesh B. Oesophageal cancer studies in the Caspian Littoral of Iran: results of a case-control study. Br J Cancer 1979;39:293-309.) showed a 39% statistically significant reduction in esophageal cancer among men who consumed tomatoes frequently, but no such relationship was found among women. Tomato consumption showed a consistent inverse relation with the risk of digestive tract neoplasms in Italy in an integrated series of studies conducted in the 1980s (La Vecchia C. Tomatoes, lycopene intake, and digestive tract and female hormone-related neoplasms. Exp Biol Med 2002; 227 :860-3). Another series of case-control studies was conducted between 1992 and 1999 in different areas of Italy. Cases were patients below age 80 with incident, histologically confirmed cancer of the oral cavity and pharynx (n = 754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n = 1031). The comparison group involved, overall, over 5000 patients below age 80 with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term diet modifications and admitted to the same network of hospitals. Information was collected in hospital by trained interviewers using a validated food frequency questionnaire, including 78 foods or groups of foods, various alcoholic beverage, and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal, and esophageal cancer decreased across subsequent levels of lycopene intake to reach 0.7 (95% confidence interval [CI] 0.4-1.0) for oral and pharyngeal, and 0.7 (95% CI 0.4-1.1) for esophageal cancer in the highest quintile of intake. This is equivalent to a 30% decrease in risk, but both trends in risk were of borderline statistical significance. With reference to colorectal, breast, and ovarian cancer, although no consistent association was observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary in the highest quintile), tomato intake was inversely and significantly related with colorectal cancer (RR = 0.8). The inverse relation between lycopene and upper digestive tract neoplasms was not explained by alcohol or tobacco, sociodemographic factors, or total energy intake. The interpretation of such an inverse relation, however, remains open to discussion because it may be related to an effect of lycopene due to its antioxidant effect and/or a potential role of lycopene in decreasing insulin growth factor I, which is a promoter in the process of carcinogenesis.
6. Pancreatic Cancer
Four studies have examined tomato or lycopene intake and the risk of pancreatic cancer. All of these studies support an inverse association. Two studies (La Vecchia C, Negri E, Decarli A, D'Avanzo B, Franceschi S. A casecontrol study of diet and gastric cancer in northern Italy. Int J Cancer 1987;40:484-9.) (Baghurst PA, McMichael AJ, Slavotinek AH, Baghurst KI, Boyle P, Walker AM. A case-control study of diet and cancer of the pancreas. Am J Epidemiol 1991;134:167-79.) reported an inverse association but did not provide estimates of relative risk. The two that reported relative risk found a fourfold to fivefold increased risk among low consumers of tomatoes
(Bueno de Mesquita HB, Maisonneuve P, Runia S, Moerman CJ. Intake of foods and nutrients and cancer of the exocrine pancreas: a population-based case-control study in The Netherlands. Int J Cancer 1991;48: 540-9) or in those with low levels of serum lycopene (Burney PG, Comstock GW, Morris JS. Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer. Am J Clin Nutr 1989;49:895-900.) It is unlikely that the low lycopenes in this study were due to effects of the cancer, since the relationship was found in bloods drawn 9 to 12 years before the diagnosis of pancreatic cancer which is a rapidly growing cancer.

7. Bladder Cancer
Four studies of tomato or lycopene consumption and bladder cancer
(Bruemmer B, White E, Vaughan TL, Cheney CL. Nutrient intake in relation to bladder cancer among middle-aged men and women. Am J Epidemiol 1996;144:485-95.) (Riboli E, Gonzalez CA, Lopez-Abente G, Errezola M, Izarzugaza I, Escolar A, et al. Diet and bladder cancer in Spain: a multi-centre case-control study.Int J Cancer 1991;49:214-9.) ( Nomura AM, Kolonel LN, Hankin JH, Yoshizawa CN. Dietary factors in cancer of the lower urinary tract. Int J Cancer 1991;48:199-205.) failed to find any statistically significant associations but tendencies for inverse associations were noted in these studies.


8. Breast Cancer
Few studies have examined lycopene or tomato intake associations with breast cancer risk. Dietary- based studies [ (Jarvinen R, Knekt P, Seppanen R, Teppo L. Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett 1997;114:251-3.) (Levi F, La Vecchia C, Gulie C, Negri E. Dietary factors and breast cancer risk in Vaud, Switzerland. Nutr Cancer 1993;19:327-35.) (Ewertz M, Gill C. Dietary factors and breast-cancer risk in Denmark. Int J Cancer 1990;46:779-84.) (Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88:340-8.) ] do not support an association. However, among four studies based on blood biomarkers [ (Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, et al. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 1997;66:626-32.) ( Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, et al. Relationships of serum carotenoids, retinol, -tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 1998;9:89-97.) (London SJ, Stein EA, Henderson IC, Stampfer MJ, Wood WC, Remine S, et al. Carotenoids, retinol, and vitamin E and risk of proliferative benign breast disease and breast cancer. Cancer Causes Control 1992;3: 503-12.) (84. Potischman N, McCulloch CE, Byers T, Nemoto T, Stubbe N, Milch R, et al. Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A. Am J Clin Nutr 1990;52:909-15.)], three support a benefit and two are statistically significant
[( Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, et al. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 1997;66:626-32.) (Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, et al. Relationships of serum carotenoids, retinol, -tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 1998;9:89-97.)] The small study based on adipose tissue levels of lycopene did find lower levels of lycopene in cases than in controls but an effect of the cancer cannot be excluded. Lycopene also has been shown to have antiproliferative effects against breast cancer cells in culture [(Levy J, Bosin E, Feldman B, Giat Y, Miinster A, Danilenko M, et al. Lycopene is a more potent inhibitor of human cancer cell proliferation than either -carotene or ß-carotene. Nutr Cancer 1995;24:257-66.)] Rats treated with tomato oleoresin developed fewer breast tumors (Sharoni Y, Giron E, Rise M, Levy J. Effects of lycopene-enriched tomato oleoresin on 7, 12 dimethylbenz
[ a ]anthracene-induced rat mammary tumors. Cancer Detect Prev 1997;21:118-23.)

9. Cervical Cancer
Cervical Cancer is due to a gene-environment interaction in which various Human Papilloma Virus types infect the cervix. The cervix when inflamed is particularly susceptible to depletion of carotenoids and other antioxidants since it has no blood supply. Instead, it depends on diffusion from the bloodstream through thick layers of tissue to supply the cervical epithelial surface. One study of cervical cancer precursor lesions (cervical intraepithelial neoplasm or CIN) found a fourfold increased risk in women with low serum lycopene levels and a fivefold excess dietary risk in women with low dietary lycopene intake from tomato products (VanWenwyk J, Davis FG, Bowen PE Dietary and serum carotenoids and cervical intraepithelial neoplasia. Int J Cancer 1991;48:34-38.). Another study found a borderline association between between serum lycopene and risk of invasive or pre-invasive cervical cancer (Baticha AM, Armenian HK, Norkus EP, Morris JS, Spate VE. Comstock GW. Serum micronutrients and the subsequent risk of cervical cancer in a population-based nested case-control study. Cancer Epidemiol Biomarkers Prev 1993; 2;335-339). In that study, total serum carotenoids were also related to reduced risk but in the prior referenced study (Baticha et.al.), benefits were found only for lycopene. A study in the Netherlands (deVet HC, Knipschild PG, Grol ME, Schouten HJ, Sturmans F. The role of beta carotene and other dietary factors in the etiology of cervical dysplasia: results of a case-control study. Int J Epidemiol. 1991;20:603-610) found women who consumed tomatoes three or more times a week had a 40% reduction in the risk of cervical dysplasia. Thus, three of three studies found an inverse association with tomato intake or serum lycopene.

Conclusion
In sum, based on all of the publicly available scientific evidence, I conclude that significant and credible scientific evidence supports the conclusion that:
• Lycopene may reduce the risk of certain forms of cancer.

• Lycopene may reduce the risk of prostate cancer.

• Lycopene may reduce the risk of lung cancer.

• Tomatoes and tomato-based products may reduce the risk of certain forms of cancer.

• Tomatoes and tomato-based products may reduce the risk of prostate cancer.

• Tomatoes and tomato-based products may reduce the risk of lung cancer.

• There is no known toxicity for lycopene, and there is no established upper limit for lycopene intake.

Respectfully submitted,

_________________________
David Heber M.D.,Ph.D.

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