Based on my review of the reliable and credible scientific literature regarding the effects of tomato and tomato-based food product consumption and of dietary supplementation with lycopene on various cancers, I conclude that there is significant scientific agreement in support of the following health claims:

• Lycopene may reduce the risk of cancer.
• Lycopene may reduce the risk of prostate cancer.
• Lycopene may reduce the risk of lung cancer.
• Lycopene may reduce the risk of gastric cancer.
• Lycopene may reduce the risk of colorectal cancer.
• Lycopene may reduce the risk of breast cancer.
• Lycopene may reduce the risk of cervical cancer.
• Lycopene may reduce the risk of endometrial cancer.
• Lycopene may reduce the risk of ovarian cancer.
• Lycopene may reduce the risk of pancreatic cancer.
• Tomatoes may reduce the risk of cancer.
• Tomatoes may reduce the risk of prostate cancer.
• Tomatoes may reduce the risk of lung cancer.
• Tomatoes may reduce the risk of gastriccancer.
• Tomatoes may reduce the risk of colorectal cancer.
• Tomatoes may reduce the risk of breast cancer.
• Tomatoes may reduce the risk of cervical cancer.
• Tomatoes may reduce the risk of endometrial cancer.
• Tomatoes may reduce the risk of ovarian cancer.
• Tomatoes may reduce the risk of pancreatic cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cancer.
• Lycopene-containing tomato-based foods may reduce the risk of prostate cancer.
• Lycopene-containing tomato-based foods may reduce the risk of lung cancer.
• Lycopene-containing tomato-based foods may reduce the risk of gastric cancer.
• Lycopene-containing tomato-based foods may reduce the risk of colorectal cancer.
• Lycopene-containing tomato-based foods may reduce the risk of breast cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cervical cancer.
• Lycopene-containing tomato-based foods may reduce the risk of endometrial cancer.
• Lycopene-containing tomato-based foods may reduce the risk of ovarian cancer.
• Lycopene-containing tomato-based foods may reduce the risk of pancreatic cancer.

I. Lycopene

A. Chemistry
Lycopene (C₄₀H₅₆) is a natural fat-soluble pigment found in plants where it serves as an accessory light-gathering pigment and free radical quencher. This carotenoid is an open chain polyisoprenoid with 11 conjugated double bonds. Lycopene occurs in food sources predominantly as all-trans-lycopene. Various cis-isomers also are found in human blood and tissues, suggesting post-ingestive isomerization. Because lycopene is acyclic it does not serve as a substrate for ß-carotene 15,15’-dioxygenase and therefore cannot be converted to vitamin A.^1-4

B. Food Sources
The major food sources of lycopene are raw red or pink grapefruit (1419 mcg of lycopene per 100 g edible fruit), raw watermelon (4532 mcg of lycopene per 100 g edible fruit), raw tomatoes (year-round average: 2573 mcg of lycopene per 100 g edible fruit) and processed food products containing tomatoes (tomato juice, 9037 mcg of lycopene per 100 g juice; canned whole tomatoes, 4035 mcg of lycopene per 100 g edible portion; tomato sauce, 15152 mcg of lycopene per 100 g sauce; tomato puree, 21754 to 28764 mcg of lycopene per 100 g puree; tomato paste, 29330 mcg of lycopene per 100 g paste; tomato soup, 14596 mcg of lycopene per 100 g soup; catsup, 17007 mcg of lycopene per 100 g of catsup).⁵ Little lycopene is lost during heat processing; for example, the six-fold concentration of tomatoes during the conversion of whole tomatoes into tomato paste is accompanied by a six-fold concentration of lycopene.⁶ Similarly, between 90% and 95% of the total lycopene in tomatoes is in the form of trans-lycopene, with the remainder as various cis-isomers; the ratio of trans– to cis-isomers is not affected by the conversion of raw tomatoes into tomato paste.^2,7-10

Lycopene in foods and food products is extraordinarily stable.¹¹ Estimates of losses in total lycopene content during the heat processing of tomatoes into tomato juice, paste, soup or sauce have ranged from nil to less than 15% ; ^9,12-14 Further cooking on a stove for 1 hour did not affect the product’s total lycopene content,^12,14 although the ratio of trans-lycopene to cis-lycopene was decreased slightly.¹² Storage of processed tomato juice at 25o C or 37o C for 12 months had no effect on total lycopene content, while storage at 4o C for 12 months reduced total lycopene content by 3%.¹²

C. Bioavailability
Lycopene naturally occurs in plants and is closely associated with the organic matrix of plant cells.^15,16 It appears that lycopene must be released from this matrix in order for absorption to occur.^16,17 This release is effected by gastric acidity^18,19 and by thermal processing of foods containing lycopene prior to their ingestion.^8,11,20 Several investigators have reported that the bioavailability of lycopene (assessed from analysis of acute and subacute changes in post-ingestive circulating total lycopene concentrations) is increased following the conversion of raw tomatoes into juice, paste or puree.^8,20-23 Others have reported that the bioavailability of lycopene in the tomato oleoresin extracts supplied as dietary supplements is greater than is the bioavailability of the lycopene in raw tomatoes but is not different from the bioavailability of lycopene in tomato juice.²⁴

Following release from its native organic matrix, or after ingestion as an extract, free lycopene is absorbable only after its incorporation into micelles.² Cis-isomers maybe more readily absorbed than trans-isomers (as has been found in ferrets¹⁹) as a consequence of the greater solubility in mixed micelles of cis-isomers.2 Any conditions or factors (such as hypochlorhydria, achlorhydria, biliary insufficiency, liver failure, the consumption of a fat-free diet, etc.) that interfere with or reduce postprandial micellar formation will decrease the absorbability of ingested lycopene.^16,25 Conversely, conditions that promote the solubility of lycopene in mixed micelles, such as the presence of monounsaturated fatty acids, will increase the absorbability of ingested lycopene (although low-fat diets appear to have no effect ^26,27).^21,28 Micellar dispersal at the brush border releases lycopene to enter enterocytes via passive diffusion; within enterocytes, lycopene is incorporated into chylomicrons for secretion into the mesenteric lymph system 2 to 6 hours after the consumption of lycopene-containing foods.^2,8 Acting on chylomicrons in the circulation, lipoprotein lipase releases lycopene for uptake by peripheral tissues and organs, including the liver, which repackages lycopene into lipoproteins that are secreted into the circulation 12 to 48 hours later.⁸

In the only study reporting quantitative data on lycopene absorption obtained through the application of compartmental modeling techniques to serum appearance and disappearance data, healthy men were reported to absorb an average of 4.7 mg of total lycopene from daily intakes ranging from 10 to 120 mg.²⁹ The amount of lycopene absorbed was independent of intake, suggesting the possibility of the potential for saturation of lycopene absorptive mechanisms. Mean efficiencies of absorption of oral lycopene ranged from 34% (10 mg of lycopene consumed) to 5% to 7% (60 mg to 120 mg of lycopene consumed). These estimates of lycopene absorption are greater than that obtained through the use of an invitro model, which produced an estimate that about 3% of the total lycopene in a stir-fried meal of fresh vegetables was incorporated into micelles (and therefore absorbable),³⁰ an in vivo model of human micellar formation in situ, which produced an estimate of the efficiency of lycopene absorption of about 2%³¹ and an in vivo model of lycopene absorption through association with triglycerides, which resulted in an estimate of the efficiency of lycopene absorption of about 2.5%.³²

The bioavailabilities of synthetic lycopene preparations have been compared to the bioavailabilities of the lycopene in raw tomatoes and processed tomato products. The bioavailabilities of the synthetic lycopene in microencapsulated beadlets (Lycopene 5% TG, D.S.M. N.V., Heerlen, The Netherlands; LycoVit 10%, BASF, Ludwigshafen, Germany; containing isomeric distributions of lycopene similar to that found in raw tomatoes^23,33), the extracted “natural source” lycopene in a bead formulation (Lyc-O-Mato™ 6%, LycoRed Natural Products Industries Ltd., Beer-Sheva, Israel) and lycopene in cooked tomato soup have been found to be nearly identical.23,34 Consistent with the differences in the bioavailabilities of lycopene in raw and processed tomato-based foods,^8,20-23 the bioavailability of synthetic lycopene has been reported to be significantly greater than the bioavailability of lycopene in unprocessed (raw) tomato juice.²³
II. The Relationships among the Consumption of Tomatoes and Tomato-Based Foods Containing Lycopene, Dietary Supplementation with Lycopene and Typical Circulating Lycopene Concentrations in Humans

The measured serum or plasma total lycopene concentrations of over 95% of the subjects in a vast array of studies have ranged between 0.1 x 10-⁶ M and 2 x 10-⁶ M.^{7,10,12,22,29,33-148} These reports are consistent with population survey data that have produced the estimates of serum total lycopene concentrations in the U.S. summarized in Table 1.

		Serum Total Lycopene Concentration
		Mean		1st Percentile		99th Percentile
Sex and Age		mcg/dL	x 10-6 M	mcg/dL	x 10-6 M	mcg/dL	x 10-6 M
Males and females:
	4 – 8 years	23.3	0.43	7.1	0.13	46.7	0.87
Males:
	9 – 13 years	25.0	0.47	8.2	0.15	50.7	0.94
	14 – 18 years	25.3	0.47	10.2	0.19	48.9	0.91
	19 – 30 years	26.8	0.50	9.2	0.17	51.4	0.96
	31 – 50 years	26.0	0.48	6.9	0.13	54.6	1.05
	51 – 70 years	22.0	0.41	4.2	0.08	51.0	0.95
	over 70 years	15.5	0.29	2.7	0.05	39.5	0.74
Females:
	9 – 13 years	24.4	0.45	9.7	0.18	50.7	0.94
	14 – 18 years	23.4	0.44	8.7	0.16	46.0	0.86
	19 – 30 years	24.8	0.46	7.9	0.15	53.2	0.99
	31 – 50 years	22.9	0.43	6.5	0.12	47.8	0.89
	51 – 70 years	20.9	0.39	4.3	0.08	50.1	0.93
	over 70 years	17.0	0.32	2.9	0.05	45.9	0.85
All		23.4	0.44	5.6	0.10	50.8	0.95

 

Data from several studies confirm that circulating total lycopene concentrations decline among older adults.^43,121,145 In one study, the mean serum total lycopene concentration of a cohort of men with a mean age of 73 years was only 57% of the mean serum total lycopene concentration of a cohort of men with a mean age of 24 years.¹²¹

Table 2. Daily lycopene intakes estimated from data obtained in the National Health and Nutrition Examination Survey III (NHANES III) between 1988 and 1994.¹⁵⁴

		Daily Lycopene Intake (mcg per day)
Sex and Age		Mean	Median	10th	25th	75th	99th
Males and females:
	2 – 6 months	164	0	0	0	0	2707
	7 – 12 months	1873	0	0	0	780	21577
	1 – 3 years	5278	1361	0	0	6366	43262
	4 – 8 years	6951	2902	0	780	9125	52255
Males:
	9 – 13 years	10111	4301	0	242	12771	89687
	14 – 18 years	11547	5211	0	133	15355	123299
	19 – 30 years	12656	5079	0	511	16000	110395
	31 – 50 years	9882	2902	0	0	11832	76642
	51 – 70 years	6635	1625	0	0	6853	60917
	over 70 years	6666	1376	0	0	5627	83429
Females:
	9 – 13 years	8262	2902	0	0	11482	50216
	14 – 18 years	7980	2902	0	0	10179	72465
	19 – 30 years	7438	2420	0	0	9709	62806
	31 – 50 years	5972	1836	0	0	7053	57600
	51 – 70 years	5388	1361	0	0	4877	47917
	over 70 years	4332	842	0	0	3409	52255
	Pregnant	8713	3802	0	696	13467	71038
	Lactating	9513	3969	0	1625	12058	48076
All:
	not including pregnant or lactating females	7753	2141	0	0	9152	65522
	including pregnant or lactating females	7774	2167	0	0	9226	65517

 

Data from the National Health and Nutrition Examination Survey III (NHANES III) indicate that cigarette smokers have significantly lower serum total lycopene concentrations than do nonsmokers.150 This conclusion is consistent with data obtained from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.³⁸

Less data are available concerning lycopene intake. Several surveys (1986 Continuing Survey of Food Intake by Individuals;¹⁵¹ 1992 National Health Interview Survey;¹⁵² Nutritional Factors in Eye Disease Study¹⁴⁶) have suggested that mean daily lycopene intake in the U.S. is between 1.6 and 2.6 mg.¹⁴⁹ However, data obtained from the 83,234 participants in the Nurses’ Health Study indicates that those women consumed more lycopene on a routine basis (median intake: 6077 mcg).¹⁵³ Data obtained from the participants in the NHANES III study (Table 2) contradict these reports, with mean daily lycopene intakes for adults ranging from 4332 mcg to 12656, and median daily lycopene intakes for adults ranging from 842 mcg to 5211 mcg, depending on sex and age.¹⁵⁴ Interestingly, both mean and median daily lycopene intakes were greater among pregnant and lactating adult women than among nonpregnant and nonlactating premenopausal adult women. However, with the exception of men aged 19 to 30 years, over 25% of the participants in the NHANES III study reported no consumption of lycopene-containing foods (and between 10% and 25% of men aged 19 to 30 years reported no consumption of lycopene-containing foods).

Daily lycopene intakes estimated from USDA nutrient composition⁵ and food consumption data¹⁵⁵ suggest that lycopene intakes may well average 3- to 10-fold higher than is indicated by other estimates. According to USDA data, per capita consumption of fresh tomatoes averaged 23.3 g daily in 2002 (providing about 0.6 mg of lycopene daily) and is forecast to average 23.7 g daily in 2003 (providing about 0.6 mg of lycopene daily). The consumption of all other tomato-containing foods averaged 87.8 g daily in 2002 (equivalent to 0.7 tomatoes daily⁵) providing between 9 and 27 mg of lycopene daily, depending upon the specific foods and food products consumed) and is forecast to average 89.4 mg daily in 2003 (providing between 9 and 27 mg of lycopene daily, depending upon the specific foods and food products consumed). These data indicate that total daily lycopene consumption averaged between 9 and 28 mg daily in the U.S. in 2002 and 2003. According to these same USDA data, the consumption of tomatoes, tomato-containing foods and food products and lycopene have not changed since 1990.

Data from the 38,445 women participating in the Women’s Health Study indicate that lycopene intake is determined primarily by the consumption of tomatoes and tomato-based food products.¹⁵⁶ Among 946 women participating in the Women’s Health Initiative, serum total lycopene concentration was independently significantly correlated with the consumption of fresh tomatoes, cooked tomatoes, tomato juice, tomato sauce and tomato salsa.⁴³ The results of several human studies have demonstrated that serum or plasma total lycopene concentration is significantly correlated with lycopene intake in healthy men and women^{43,65,68,141,144,146} and is unvarying within individuals over a number of years (probably reflecting the relative stability of adult dietary habits).^{60,66,77,92,98,111} Therefore, it has been asserted that the measurement of circulating total lycopene concentration in single blood samples provides predictors of long-term lycopene intakes that are sufficiently valid for epidemiologic studies.¹¹¹

In contrast, intentional reduction in lycopene intake produces a significant decrease in circulating lycopene concentrations.^124,125,157 Furthermore, increasing lycopene intake has produced significant increases in serum or plasma total lycopene concentrations in healthy men and women.^{12,22,24,34,77-79,85,89,124-126,138} Similarly, increased consumption of tomatoes and tomato-containing foods and food products significantly increased serum or plasma total lycopene concentrations in healthy men and women^{23,24,36,43,47,51,69,70,78,79,85,89,91,109,110,122-125,130,134,158} as well as in women with breast cancer,^66,92 men and women with colorectal adenomas,⁹⁸ men with prostate cancer,¹⁰⁵ men and women with diabetes,¹³⁶ male and female renal transplant recipients,¹⁰⁰ male and female cancer survivors⁶³ and lactating women.³⁸

 

III. Cancer

A. Cancer Mortality
Cancer is the second leading cause of death in the U.S.¹⁵⁹ The American Cancer Society forecast 556,500 deaths from cancer in 2003.¹⁵⁹ Overall, the 5-year relative survival rate is 62%.159 The rate of survival is drastically reduced by the presence of malignancy. Between 60% and 65% of the estimated 285,900 men dying from cancer in 2003 will die from lung, bronchial, prostate or colorectal cancers. About 75% of the estimated 270,600 women dying from cancer in 2003 will die from cancers of the lungs, bronchi, breast, colon or rectum. In addition to the termination of these cases by death, about 675,300 men and 658,800 women are predicted to become newly-diagnosed with cancer during 2003, resulting in a net increase of about 10% in the number of individuals in the U.S. with cancer. Total cancer-related health care costs during 2002 were approximately 171.6 billion dollars (approximately 61 billion dollars for direct medical expenditures).¹⁵⁹

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
Mouse C3H/10T1/2 embryonic fibroblasts are well-studied and are known to undergo neoplastic transformation in response to many chemical and physical carcinogens in a dose-dependent manner.^160,161 Following pretreatment of cultures of C3H/10T1/2 cells with the cell transformation inducing agent, methylcholanthrene, the addition of lycopene (3 x 10-6 M) to the culture medium significantly inhibited the generation of foci of transformed cells, producing about 50% inhibition.¹⁶¹ This inhibition occurred only upon exposure to lycopene during the postinitiation period; lycopene (10 x 10-6 M) exposure concurrent with exposure to methylcholanthrene did not affect transformation. The neoplastic transformation-inhibiting activity of lycopene was strongly correlated with lycopene-induced upregulation of expression of connexin 43¹⁶²and stimulation of intercellular gap junctional communication.163 In various cancers, including human prostate cancer, the expression of connexin 43 is inversely proportional to the degree of disease progression and the induction of increased connexin 43 expression in epithelial cells from prostate tumors has been accompanied by deceleration of proliferation and the induction of cellular differentiation (i.e., reversal of disease progression).164 Lycopene (3 x 10-⁶ M) also has significantly stimulated expression of connexin 43 and intercellular gap junctional communication while significantly inhibiting proliferation in cultures of human KB-1 oral tumor cells.165 Similarly, lycopene (0.1 x 10-⁶ M) significantly stimulated gap junctional communication in cultures of human fetal skin fibroblasts, although in that cell culture system lycopene did not affect connexin expression.¹⁶⁶

Gap junction channels consist of apposed cylindrical aggregates of six subunits each in adjacent cell membranes and are found throughout the body.^167,168 Extracellular loops that extend from the transmembrane-spanning domains of each of the six protein subunits across intercellular space interact with similar loops extending from an adjacent cell and establish the junction. At each gap junction, each cell contributes a hemiconnexon consisting of six identical protein units (connexins) assembled radially to encircle and enclose a water-filled pore that allows direct cytoplasmic-to-cytoplasmic communication of ions and low molecular weight water-soluble compounds (such as cyclic AMP) via passive diffusion down concentration gradients between the two cells without loss to the extracellular space. A variety of connexins exist within the human body; connexin 43 is the most widely distributed.

An important function of gap junctions is to serve as conduits for antiproliferative signals generated by proliferation-inhibited normal cells and that act to suppress the proliferation of carcinogen-initiated cells thereby preventing their transformation into tumor cells.^169,170 Cells deficient in the ability to receive or respond to such signals originating from proliferation-inhibited normal cells as a result of reduced or absent expression of connexin genes (as occurs in most human tumor cell lines) are at a relative proliferative advantage. Conversely, agents that increase gap junctional communication between cells deficient in this function and proliferation-inhibited normal cells should produce inhibition of the proliferation of previously-deficient cells. However, increased gap junctional communication between cells deficient in this function and proliferation-inhibited normal cells requires that the functionally deficient cells not have progressed from the initiation or promotion stages of carcinogenesis to the gap junctional communication-resistant stage of cell transformation into tumor cells.^169,171 This apparent requirement is consistent with reports that many tumor promoting substances inhibit gap junctional communication and that potency as tumor promoter is correlated with potency as inhibitor of connexin expression and gap junctional communication.¹⁶⁸ In addition, reduced expression of connexin genes may be a required precursor lesion preceding cell transformation and stimulation of connexin gene expression with resultant increase in gap junctional communication may be a key cancer-preventing property of connexin-inducing agents.^167,168

C. Human Studies Provide Scientific Support for the Conclusion that Risk of Developing Cancer is Reduced by the Consumption of Lycopene, or Tomatoes or Tomato-Based Foods Containing Lycopene
Oxidative damage to DNA can produce genetic changes associated with the initiation and progression of cancer.^172,173Oxidative damage to DNA has been proposed as a biologically significant contributor to the development of colon, breast, rectum and prostate cancers.^174,175 Several products of DNA base oxidation, including 8-hydroxyguanine, 2-hydroxyadenine, 5-hydroxycytosine, 5-hydroxyuracil and formyluracil, are known to be mutagenic in concentrations that mimic their frequency in endogenous DNA.^176-179 It has been reasoned that, based on the available experimental evidence, the extent of oxidative DNA damage in human cells is a biomarker with some ability to predict risk for the development of cancer and reduction in the extent of oxidative DNA damage in human cells is consistent with reduced risk for the development of cancer.¹⁸⁰

Lycopene has been demonstrated to be the most potent free radical antioxidant among the carotenoids.^51,181,182 The potential for the consumption of foods providing significant amounts of dietary lycopene to exert chemoprotection against oxidative damage to DNA was examined in healthy nonsmoking men.¹⁸³ Compared to the end of a 2-week period of intentional lycopene depletion, after 2 weeks of dietary supplementation with tomato juice containing 40 mg of lycopene daily, the number of endogenous DNA strand breaks was significantly reduced in circulating lymphocytes. Although endogenous DNA strand breaks was significantly reduced, this short-term consumption of additional lycopene-containing tomato-based food product was insufficient to produce a statistically significant decrease in the physiologic effector of DNA strand breaks, oxidative base damage. In contrast, the ingestion of a single serving of fresh tomatoes (8 g per kg body weight) by healthy men and women significantly reduced the endogenous production of oxidized DNA base adducts in circulating lymphocytes and leukocytes.⁷

Consistent with the conclusion that increased lycopene intake reduces endogenous damage to DNA, 2 weeks of dietary supplementation with tomato puree containing 7 mg of lycopene daily significantly reduced the number of exogenously-induced DNA strand breaks in circulating lymphocytes harvested from healthy women.⁸⁵ This chemopreventive effect was accompanied by significant increases in plasma total lycopene concentration and lymphocyte lycopene content. Both plasma total lycopene concentration and lymphocyte lycopene content were significantly inversely correlated with the extent of exogenously-induced oxidative damage to DNA. In another experiment in which total supplemental lycopene exposure was similar, lymphocytes harvested from healthy men and women whose diets were supplemented with semi-purified lycopene (15 mg daily) for 1 week exhibited significantly increased resistance to exogenously-induced oxidative damage to DNA.¹⁸⁴ The magnitude of effect was reflective of the extent to which dietary supplementation with lycopene produced increase in plasma total lycopene concentration. Similarly, lymphocytes harvested from healthy women supplemented with tomato puree containing 16.5 mg of lycopene exhibited significantly greater resistance to exogenously-induced DNA oxidation than was exhibited by lymphocytes harvested from healthy women whose diets were not supplemented,¹⁵⁸ and the consumption of a single serving of fresh tomatoes (8 g of tomatoes per kg body weight) significantly reduced the frequency of oxidative DNA base damage in circulating white blood cells.¹⁸⁵

In an in vitro test system, both hydrophilic and lipophilic extracts of fresh tomatoes, tomato paste and tomato puree significantly inhibited oxidative reactions catalyzed by xanthine oxidase and neutrophil-derived myeloperoxidase, major in vivo physiologic producers of superoxide, hydrogen peroxide and hypochloric acid.¹⁸⁶ In addition, the lipophilic extracts significantly inhibited copper-catalyzed oxidation of linoleic acid (lipid peroxidation). In confluent cultures of mouse C3H/10T1/2 embryonic fibroblasts, lycopene (1 x 10-⁶ M) significantly inhibited lipid peroxidation.¹⁶³

The published scientific evidence strongly supports the conclusion that the risk of developing any cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.

D. Human Studies Provide Significant Scientific Support for the Conclusion that Risk for Dying from Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
The findings of three studies support the conclusion that tomato and tomato-based food product consumption or dietary supplementation with lycopene reduce the risk of dying of cancer.^57,58,187 The results of a 5-year prospective study of 1,271 men and women aged 66 years or older indicated that the age-adjusted risk of dying from any cancer was significantly reduced by 50% (95% CI: 0.3, 0.8) in individuals who consumed an average of more than 1 serving of tomatoes weekly, compared to the risk of dying from any cancer of individuals who consumed an average of less than 1 serving of tomatoes weekly.¹⁸⁷ In another 8-year prospective study of 929 men and 1,424 women, the geometric mean serum total lycopene concentration of the subjects who died from cancer (0.28 x 10-⁶ M) was significantly lower than the geometric mean serum total lycopene concentration of the subjects who did not die during the study (0.37 x 10-⁶ M).⁵⁸

In a 9-year prospective study of 949 men and 1,495 women, 48 men and 28 women died from cancers.⁵⁷ Among these 2,444 subjects, the geometric mean serum total lycopene concentrations of the subjects who died from cancer (men: 0.16 x 10-⁶ M; women: 0.22 x 10-⁶ M) were significantly lower than the geometric mean serum total lycopene concentrations of the subjects who did not die during the study (men: 0.21 x 10-⁶ M; women: 0.31 x 10-⁶ M). The application of Cox’s proportional hazard model to the data from the entire cohort revealed that the multivariate-adjusted risk of death from any cancer was significantly reduced among those subjects with serum total lycopene concentrations in the highest tertile of serum total lycopene concentrations, compared to the risk among those subjects with serum total lycopene concentrations in the lowest tertile of serum total lycopene concentrations (hazard ratio: 0.37; 95% CI: 0.19, 0.72). This relationship was strengthened when only deaths occurring after the first three years of the study were included (hazard ratio: 0.36; 95% CI: 0.21, 0.61), when the analysis was restricted to only non-smoking subjects and only deaths occurring after the first three years of the study were included (hazard ratio: 0.33; 95% CI: 0.12, 0.90) and when the analysis was restricted to only subjects with serum total cholesterol concentrations greater than 250 mg/dL and only deaths occurring after the first three years of the study were included (hazard ratio: 0.33; 95% CI: 0.12, 0.90).

The published scientific evidence strongly supports the conclusion that the risk for dying from any cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
IV. Prostate Cancer

Prostate cancer is the leading cause of newly-diagnosed cancer in males in the US.¹⁵⁹ About 220,900 new cases of prostate cancer were forecast for the US for the year 2003, while nearly 30,000 men in the US were expected to die from this disease that year.¹⁵⁹ When all stages of prostate cancer are combined, the 5-year relative survival rate is 97%, 10-year relative survival is 79% and 15-year relative survival is 57%.¹⁵⁹

A. Pathogenesis of Prostate Cancer
Prostate cancer results from the proliferation of epithelial cells located predominantly in the peripheral zone of the prostate gland.^188,189 Carcinogenesis in the prostate occurs in a multistage process involving a series of genetic alterations with progression through a variety of pathways from precancerous lesions, including proliferative inflammatory atrophy and low-grade prostatic intraepithelial neoplasia, to a high-grade focus of accelerated proliferation without invasion of the basement membrane (“high-grade prostatic intraepithelial neoplasia”; HGPIN) through the development of a small latent androgen-dependent carcinoma to higher-grade androgen-independent metastatic disease.^188-194 HGPIN is recognized as a reversible precursor to prostate cancer.^188-194

Reactive oxygen species (such as the hydroxyl radical OH?) may be implicated in the pathogenesis of prostate cancer. A common early event in both HGPIN and prostate cancer is inactivation of the GSTP1 gene coding for the glutathione S-transferase P1 detoxification enzyme that catalyzes the conjugation of reactive oxygen species to glutathione within the prostate; elevated reactive oxygen activity results.¹⁹³ Evidence from two human studies suggests that oxidative changes in prostate tissue DNA (mutagenic lesions of adenine and guanine residues typical of those induced by hydroxyl radicals) are significantly increased in cancerous prostate tissue.^195,196 In addition, the extent of carcinogenic change was significantly correlated with the extent of hydroxyl radical-induced DNA damage.¹⁹⁵

The insulin-like growth factors (IGF-I and IGF-II) are circulating mitogens that interact with target cells via the cell membrane-bound IGF-receptor to influence the regulation of cell proliferation, differentiation, apoptosis and neoplastic transformation.^197,198 In particular, IGF-I is a potent mitogen that stimulates DNA synthesis and the progression of the cell cycle from the G1 phase to the S phase while also stimulating the expression of proapoptotic Bcl proteins and suppressing the expression of antiapoptotic Bax proteins.199 Epithelial cells harvested from noncancerous human prostate glands have demonstrated an abundance of IGF-I receptors²⁰⁰ and the in vivo proliferation of normal murine prostate epithelial cells appears to be IGF-I-dependent.²⁰¹

There is evidence that the risk of neoplastic transformation within a cell population increases as the proliferation rate of cells within the population increases,^202,203 suggesting that IGF-I availability to IGF-I-dependent tissues (such as the prostatic epithelium) contributes to risk of developing tissue-specific cancer.²⁰¹ Furthermore, increased IGF-I availability may accelerate the proliferation and clonal expansion of epithelial undergoing the process of neoplastic transformation.²⁰¹The dependence of human prostate cancer on IGF-I is suggested by the results of transplantation studies in which the proliferation of human androgen-independent PC-3 prostate cancer cells was curtailed following transplantation into IGF-I deficient mice but not after transplantation into normal mice.²⁰¹ Human prostate epithelial cells in primary culture proliferate in response to the addition of IGF-I to the culture medium; maximal response was observed with medium IGF-I concentration of 10 ng/ml and half-maximal response was observed at 1 ng/ml.²⁰⁰ There is evidence that prostate-specific antigen acts to increase circulating and perhaps local concentrations of free IGF-I by cleaving IGF-binding protein-3 (IGF-BP-3) and thereby reducing its affinity for IGF-I; the addition of prostate-specific antigen to culture medium containing both IGF-I and IGF-BP-3 restored the rate of proliferation of human prostate epithelial cells to that of cells in medium containing only IGF-I.¹⁹⁸

The findings of three retrospective case-control epidemiologic human studies support the hypothesis that increased systemic circulating concentrations of IGF-I increase the risk of developing prostate cancer.^204-206 In an examination of 152 men with prostate cancer and 152 randomly-selected cancer-free men nested within the prospective Physicians’ Health Study, men with plasma IGF-I concentrations greater than 293 ng/ml were at significantly greater risk of developing prostate cancer than were men with plasma IGF-I concentrations less than 185 ng/ml (multivariate-adjusted Relative Risk Ratio (RR): 4.32; 95% confidence interval (CI): 1.76, 10.6; adjusted for height, weight, body mass index, the presence or absence of androgen receptor CAG polymorphisms, and plasma concentrations of IGF-I, IGF-binding protein-3 and prostate-specific antigen).²⁰⁴ Other investigators found that when 52 men with prostate cancer were age-matched to 52 cancer-free men, the risk of developing prostate cancer was significantly correlated with serum IGF-I concentration; every increase in serum IGF-I concentration of 60 ng/ml was accompanied by a doubling of the multivariate-adjusted odds ratio (OR) for the development of prostate cancer (adjusted for age, height, body mass index, years of schooling and serum concentrations of testosterone, estradiol, dihydrotestosterone, dehydroepiandrosterone sulfate and sex hormone-binding protein).²⁰⁵ In another case-control study of 224 men with prostate cancer and 224 age-matched men without cancer, the mean serum IGF-I concentration of men with prostate cancer was significantly greater than that of men without prostate cancer.²⁰⁶ Among the 90 men younger than 70 years of age with prostate cancer and the 84 men younger than 70 years of age without prostate cancer, the risk of developing prostate cancer was significantly correlated with serum IGF-I concentration; every increase in serum IGF-I concentration of 100 ng/ml was accompanied by a tripling of the multivariate-adjusted odds ratio (OR) for the development of prostate cancer (adjusted for age, height and body mass index). This relationship was not statistically significant among the men 70 years of age or older.

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
Lycopene in physiological concentrations has been found to inhibit significantly the rates of proliferation of various human prostate carcinoma cell lines in culture. In concentrations as low as 10-⁸ M, lycopene has been observed to inhibit significantly the proliferation of human LNCaP prostate carcinoma cells in culture.²⁰⁷ In concentrations as low as 10-⁶ M, lycopene has been observed to reduce significantly the viability of cultures of PC-3, DU-145 and LNCaP human prostate carcinoma cells.²⁰⁸ In the presence of 50 x 10-⁶ M alpha-tocopherol, 10-⁶ M lycopene significantly inhibited (by 50% to 90%) the proliferation of PC-3 and DU-145 human prostate carcinoma cells in culture.²⁰⁹

C. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
The hypothesis that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of a randomized placebo-controlled clinical trial^62,210 and an uncontrolled clinical trial,^44,115,211 the findings of five prospective observational studies^212-216and ten retrospective case-control studies,^{64,67,90,107,114,215-211} a case series²²² and a case report.²²³

In a randomized placebo-controlled clinical trial, men with newly diagnosed localized prostate cancer received daily dietary supplementation (one capsule twice daily) with a commercially available tomato oleoresin extract (Lyc-O-Mato® capsules, LycoRed Natural Products Industries, Beer-Sheva, Israel) containing, per capsule, 14.5 to 15.5 mg of lycopene, 1.45 to 1.55 mg of phytoene, 1.25 to 1.5 mg of phytofluene, 0.25 to 0.5 mg of ß–carotene, 17.25 to 19.25 mg of total mixed carotenoids, 3.75 to 6.25 mg of total tocopherols, 35 to 40 mg of total phospholipids, 1.25 to 1.75 mg of total phytosterols and 182.5 to 190 mg of tomato oil (average total daily supplemental lycopene intake: 30 mg).^62,210 Daily supplementation was begun 3 weeks before the study subjects underwent radical prostatectomy with removal of the entire prostate gland, the seminal vesicles and the surrounding soft tissues. Examination of tissue and blood samples obtained during radical prostatectomy revealed that dietary supplementation with tomato oleoresin extract was associated with significantly less cancerous invasion of surgical margins and extra-prostatic tissues (cancer was confined to the prostate in 73% of the supplemented patients and in only 18% of the unsupplemented men) and significantly less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia, the precursor of prostate cancer^188-194 (cancer was limited to focal involvement in 33% of the supplemented patients but was multifocal and diffuse in all of the unsupplemented men). However, average Gleason tumor score, tumor volume, plasma concentrations of prostate-specific antigen (PSA), IGF-1, IGFBP-3 and total lycopene, malignant prostate tissue content of connexin 43, bcl-2 and bax proteins and total lycopene, benign prostate tissue content of connexin 43, bcl-2 and bax proteins and total lycopene, and peripheral blood lymphocyte 5-OHmdU concentrations were not affected by 3 weeks of daily dietary supplementation with tomato oleoresin extract. The results of this small preliminary study suggest that even short-term dietary supplementation with an amount of tomato oleoresin extract providing the lycopene equivalent of only 4 to 6 fresh tomatoes or 200g of tomato sauce⁵ may effectively interrupt the progression of the precursor lesion, HGPIN, to prostate cancer, even in the absence of statistically significant changes in putative biomarkers of risk for prostate cancer.

In an uncontrolled study, 32 patients (60 to 74 years old) with localized prostate adenocarcinoma (clinical stage T1 or T2) consumed tomato sauce-based pasta dishes containing 200 g of Hunt’s Spaghetti Sauce (Hunt-Wesson, Inc., Irvine, CA) daily for 3 weeks prior to radical prostatectomy.^44,115,211 These foods added an additional 30 mg of lycopene daily to a prescribed diet providing 40% of energy as fat and 15% of energy as protein. Daily consumption of tomato-based foods averaged 81.6% of the intended amount. During the 3 weeks of dietary supplementation, these men experienced significant increases in mean serum total lycopene concentration (96% increase; 95% confidence interval (CI): 42%, 151%; p = 0.0029), mean serum all-trans-lycopene concentration (119% increase; 95% CI: 56%, 183%; p = 0.0019), mean prostate tissue total lycopene content (196% increase; 95% CI: 68%, 323%; p = 0.0071), mean prostate tissue all-trans-lycopene content (310% increase; 95% CI: 92%, 527%; p = 0.0105), mean ratio of all-trans-lycopene to total cis-isomers in prostate tissue (85% increase; 95% CI: 22%, 148%; p = 0.0134) and mean proportion of total lycopene as all-trans-lycopene in prostate tissue (69% increase; 95% CI: 17%, 121%; p = 0.0154). However, the mean ratio of all-trans-lycopene to total cis-isomers in serum and the mean proportion of total lycopene as all-trans-lycopene in serum were not affected by dietary supplementation with tomato sauce. Serum total lycopene concentration and prostate total lycopene content were significantly correlated (r =- 0.51; p = 0.005). In contrast, dietary supplementation with tomato sauce significantly reduced mean serum PSA concentration by 17.5% (p = 0.002) and mean circulating leukocyte 8OHdG concentration by 21.3% (p = 0.005). Prostate tissues obtained at surgery exhibited significantly lower mean 8OHdG content than did an historical control group (28.3% decrease; p = 0.03). Similarly, mean cancer cell 8OHdG staining of Gleason Score-matched resected prostate sections was significantly reduced in mean nuclear density (by an average of 40.5%; p = 0.005) and in mean area (by an average of 36.4%; p = 0.018) compared to tissues obtained via biopsy prior to the study. In contrast, the apoptotic indices of both hyperplastic and neoplastic prostate epithelial cells were significantly increased. These data indicate that the daily consumption of foods containing at least 30 mg of lycopene significantly increased the lycopene contents of blood and prostate tissue, which was accompanied by significant reductions in DNA damage in leukocytes and prostate tissue and significant increases in anticarcinogenic apoptosis among both hyperplastic and neoplastic prostate epithelial cells.^44,115,211

The findings of five prospective observational studies^212-216 have confirmed the beneficial relationship between lycopene consumption (whether as a dietary supplement or consumed as tomatoes or tomato-based foods) and reduced risk for developing prostate cancer. In the 6-year Health Professionals Follow-Up Study, a prospective study of 47,894 men who initially were prostate cancer-free, the daily consumption of more than 6.5 mg of lycopene significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed less than 2.3 mg of lycopene daily (RR: 0.79; 95% CI: 0.64, 0.99; adjusted for age and daily dietary total energy intake).²¹² Similarly, the consumption of tomatoes more than once a week significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed tomatoes an average of one or fewer times a week (RR: 0.74; 95% CI: 0.58, 0.93; adjusted for age and daily dietary total energy intake). The consumption of tomato sauce once weekly significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed tomato sauce an average of less than once weekly (RR: 0.77; 95% CI: 0.62, 0.95; adjusted for age and daily dietary total energy intake). In contrast, tomato juice consumption appeared in this study to have no effect on the risk for developing prostate cancer.

In a further 6-year extension of the Health Professionals Follow-Up Study, it was determined that the multivariate-adjusted risk for prostate cancer was significantly decreased in men with routine daily lycopene intakes greater than 18.8 mg at the end of the study compared to the risk in men with routine daily lycopene intakes less than 3.4 mg at the end of the study (RR: 0.84; 95% CI: 0.74, 0.96; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid).²¹³ Similarly, the multivariate-adjusted risk for prostate cancer was significantly decreased in men with average estimated cumulative 12-year daily lycopene intakes greater than 18.8 mg compared to the risk in men with average estimated cumulative daily 12-year lycopene intakes less than 3.4 mg (RR: 0.84; 95% CI: 0.73, 0.96; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). However, estimated lycopene intake at the beginning of the study was not associated with risk for prostate cancer. Risk for prostate cancer also was significantly decreased in men consuming two or more servings of tomato sauce (a strong determinant of plasma lycopene concentration⁶⁸) weekly compared to the risk in men consuming less than one serving of tomato sauce monthly, at the beginning of the study (RR: 0.75; 95% CI: 0.64, 0.88; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid), during the 12 years of the study (RR: 0.77; 95% CI: 0.66, 0.90; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid) and at the end of the study (RR: 0.84; 95% CI: 0.72, 0.99; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). The prostate cancer-preventing properties of two or more weekly servings of tomato sauce were evident in men of Southern European ancestry (RR: 0.66; 95% CI: 0.47, 0.93; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid) and men of other Caucasian ancestry (RR: 0.79; 95% CI: 0.65, 0.98; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). The prostate cancer-preventing properties of two or more weekly servings of tomato sauce remained statistically significant when additionally adjusted for olive oil preference (RR: 0.77; 95% CI: 0.66, 0.91) or fruit and vegetable intake (RR: 0.78; 95% CI: 0.66, 0.91).

These investigators detected no evidence that “detection bias,” changes in the relative frequency of diagnosis of prostate cancer during the study that might result from advances in diagnostic and screening practices and technologies that may have occurred during the 12 years of the study, influenced the evidence that the consumption of the highest quintile of lycopene intake, and in particular, of two or more servings of tomato sauce weekly, significantly reduced the risk of developing prostate cancer.

In another prospective study, dietary and lifestyle characteristics were evaluated in relation to subsequent prostatic cancer risk in approximately 14,000 Seventh-day Adventist men who were observed for 6 years (some 78,000 man-years of observation).²¹⁴ Among these men, the consumption of one or more tomatoes weekly significantly decreased their age-adjusted risk for prostate cancer, compared to the risk among men who consumed tomatoes less than once a week (RR: 0.62; 95% CI: 0.40, 0.96). This reduction in relative risk was not affected by age, education, or intakes during the sixth year of the study of meat, poultry, fish, beans, legumes, peas, citrus fruit, dry fruit or nuts.

In a 5- to 8-year prospective observational study of 1,575 cancer-free men aged 40 to 86 years at the beginning of the study, the risk for developing prostate cancer was significantly reduced among the men with the highest tertile of daily dietary lycopene intake, compared to the risk among men with the lowest tertile of daily dietary lycopene intake (RR: 0.5; 95% CI: 0.3, 0.9; adjusted for age and dietary daily total energy intake).²¹⁵ The reduction in risk for the development of advanced prostate cancer reportedly was even greater (data not given).

In an ecologic epidemiologic study of diet and prostate cancer worldwide it was found that, in 28 those countries where tomatoes were consumed regularly, mortality from prostate cancer was significantly inversely correlated with tomato intake.²¹⁶

The findings of four retrospective case-control studies^217-220 also support the conclusion that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based products containing lycopene. In a study of 223 men with prostate cancer and 446 matched cancer-free men, the consumption of tomatoes or tomato-based products 14 or more times a month significantly reduced the risk for developing prostate cancer, compared to the risk among men consuming tomatoes or tomato-based products less than 3 times monthly (odds ratio (OR): 0.71; significantly different from OR = 1.0, p < 0.05).²¹⁷ Similarly, in a study of 320 men with prostate cancer and 246 cancer-free men, the consumption of cooked tomatoes at least 4 times weekly significantly reduced the risk for the development of prostate cancer, compared to the risk among men who consumed cooked tomatoes twice weekly (OR: 0.85; 95% CI: 0.75, 0.97; adjusted for age, height, education and daily dietary total energy intake).²¹⁸

In a study of 617 men with prostate cancer and 636 men without prostate cancer, daily consumption of more than 110 g of tomatoes significantly reduced the risk for developing prostate cancer, compared to the risk for men consuming less than 9 g of tomatoes daily (OR: 0.64; 95% CI: 0.45, 0.91; adjusted for vasectomy status, age, cigarette smoking status, marital status, study area, body mass index, education, current or recent use of multivitamin dietary supplements, and dietary intakes of total energy, grains, fruit, vegetables, all plants, all carotenoids, folate and folic acid, dietary fiber, conjugated linoleic acid, vitamin E, vitamin C, retinol, total fat and linoleic acid).²¹⁹ Among these men, lycopene intake was not associated with the multivariate –adjusted risk for developing prostate cancer, even though 25% of these men consumed over 12.7 mg of lycopene daily. However, in a study of 77 men with prostate cancer and 183 cancer-free men, the median daily lycopene intake of the men with prostate cancer (0.817 mg) was significantly less than the median daily lycopene intake of the men without prostate cancer (1.120 mg).²²⁰

The findings of six retrospective case-control studies^{64,67,90,107,114,221} support the conclusion that the risk for developing prostate cancer is reduced among those men with the greatest serum or plasma total lycopene concentrations (reflecting the greatest routine lycopene intakes). This conclusion is consistent with and provides additional support for the conclusion that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based products containing lycopene.

A prospective case-control study, nested within the randomized placebo-controlled Physicians’ Health Study of aspirin and ß-carotene, compared 578 men who developed prostate cancer during 13 years of the study to 1294 age- and smoking status-matched men who did not develop prostate cancer during 13 years of the study.¹¹⁴ Pre-study median plasma total lycopene concentration was significantly lower in the men who later developed prostate cancer (0.69 x 10-⁶ M) than it was in the men who remained prostate cancer-free (0.72 x 10-⁶ M). Although the risk for developing any type of prostate cancer was not affected by pre-study plasma total lycopene concentrations (OR: 0.75; 95% CI: 0.54, 1.06; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration), the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.56; 95% CI: 0.34, 0.91; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). In the men whose diets were supplemented with placebo but not with aspirin or ß-carotene, the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.40; 95% CI: 0.19, 0.84; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). Similarly, in the men whose diets were supplemented with ß-carotene but not with aspirin or placebo, the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.48; 95% CI: 0.24, 0.94; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). These reductions in the risks for developing aggressive prostate cancer were not affected by age, smoking status, body mass index, exercise level, alcohol consumption, multivitamin dietary supplementation, or plasma total cholesterol concentration and suggest that lycopene may differentially impair the development of more aggressive, invasive and diffuse forms of prostate cancer.

In a case-control study of 65 men with prostate cancer and 132 matched cancer-free men, mean plasma total lycopene concentration was significantly lower among the men with prostate cancer (0.22 x 10-⁶ M) than among the men without cancer (0.31 x 10-⁶ M).64 Among all 197 men, the risk for developing prostate cancer among those men with plasma total lycopene concentrations greater than 0.40 x 10-⁶ M was significantly lower than the risk among those men with plasma total lycopene concentrations lower than 0.18 x 10-⁶ M (OR: 0.17; 95% CI: 0.04, 0.78; adjusted for age, race, years of education, daily total caloric intake, number of pack-years of cigarette smoking, alcohol consumption and family history of prostate cancer). This significant risk reduction was readily apparent among men younger than 60 years (multivariate-adjusted OR: 0.05; 95% CI: 0.01, 0.51) but was not apparent among men 60 years of age or older (multivariate-adjusted OR: 0.10; 95% CI: 0.01, 3.31). However, estimated lycopene intake was not associated with multivariate-adjusted risk for developing prostate cancer in this study, with only 25% of these men consuming more than 3.5 mg of lycopene daily.

In a retrospective case-control study of 12 men with prostate cancer and 12 cancer-free men, mean serum total lycopene concentration was significantly lower among the men with prostate cancer (0.24 x 10-⁶ M) than among the cancer-free men (0.43 x 10-⁶ M).⁹⁰ .In addition, mean prostate tissue total lycopene content also was significantly lower among the men with prostate cancer. Similarly, in a study of 24 men with prostate cancer and 18 men without prostate cancer but undergoing surgical transurethral resection or radical cystoprostatectomy, mean serum total lycopene concentration was significantly lower among the men with prostate cancer than among cancer-free men (data not shown).²²¹ In addition, mean total lycopene contents of benign prostate tissue were significantly lower among the men with prostate cancer.

In a study of 209 men with prostate cancer and 228 cancer-free men, serum total lycopene concentrations greater than 0.46 x 10-⁶ M were associated with significantly reduced risk for the development of aggressive prostate cancer, compared to the risk of men with serum total lycopene concentrations less than 0.20 x 10-⁶ M (OR: 0.37; 95% CI: 0.15, 0.94; adjusted for age, race, study center and month of blood sampling).107 In contrast, serum total lycopene concentration was not associated with multivariate-adjusted risk for developing nonaggressive prostate cancer and the median serum total lycopene concentrations were not different among the men with or without prostate cancer (African Americans without cancer: 0.29 x 10-⁶ M; African Americans with prostate cancer: 0.27 x 10-⁶ M; Caucasian Americans without cancer: 0.35 x 10-⁶ M; Caucasian Americans with prostate cancer: 0.31 x 10-⁶ M).

In another case-control study of 15 men with prostate cancer and 30 cancer-free men, the median plasma total lycopene concentration of men with prostate cancer (0.12 x 10-⁶ M) was significantly lower than that of men without cancer (0.34 x 10-⁶ M).⁶⁷

The findings of an analysis of a series of 112 men without cancer suggest that daily consumption of one serving of cooked tomatoes significantly decreased serum IGF-I concentration by 31.5%.222

A case report supports the conclusion that the risk of developing prostate cancer is reduced by consumption of supplemental lycopene. In this case, a man with androgen-independent pharmacologically-refractive terminal prostate cancer experienced remission within one month of beginning daily dietary supplementation with a combination of 30 mg of lycopene and 900 mg of saw palmetto extract.²²³ At the time of submission of this report, the individual had been in continuing remission (with continued daily dietary supplementation) for 18 months.

Several retrospective epidemiologic case-control observational studies have failed to observe the beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk for developing prostate cancer.^224-232In these studies, lycopene intake or the consumption of tomatoes or tomato-based foods was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing prostate cancer was predictable.

In one such study of 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched cancer-free men, no statistically significant relationships were observed between the daily consumption of lycopene, raw tomatoes or cooked tomatoes and risks for developing prostate cancer (adjusted for social class).²²⁴ However, fewer than 25% of these men consumed at least 0.7 mg of lycopene (amount of lycopene in one-half teaspoon of catsup⁵) daily, fewer than 20% consumed at least 1 serving of raw tomatoes daily and fewer than 20% consumed at least 2 servings of cooked tomato products weekly.

In a study of men 40 to 64 years of age, 628 newly diagnosed with aggressive prostate cancer and 602 who were free of cancer, no statistically significant relationships were observed between the daily consumption of lycopene, raw tomatoes or cooked tomatoes and risks for developing prostate cancer.²²⁵ However, only half of these men routinely consumed over 2 mg of lycopene (less than the amount of lycopene in a level tablespoon of catsup⁵) daily, only 25% consumed at least 10 mg of lycopene daily and fewer than 30% consumed more than an average of one-half of a serving of cooked or raw tomato products daily.

In a retrospective case-control study of 449 African-American men and 483 Caucasian men with prostate cancer and 543 African-American men and 658 Caucasian cancer-free men, the rates of daily consumption of raw tomatoes, cooked tomatoes or tomato sauces, tomato juice, watermelon or these foods combined were not associated with the risks (adjusted for age, study site, daily caloric intake, and race) for developing either early or advanced prostate cancer among African-American men, Caucasian men or both groups of men combined.²²⁶ However, only 25% of these men consumed at least one serving of any of these foods daily.

In a case-control study nested within a 6-year prospective observational study of 58,279 initially cancer-freemen aged 55 to 69 years at the beginning of the study, daily lycopene intake was not associated with the risk for developing any degree of prostate cancer (adjusted for age, family history of prostate cancer, socioeconomic status and alcohol consumption) among 642 men who developed prostate cancer and 1525 men who did not.²²⁷However, among both groups of men, mean daily lycopene intake was estimated to be 1 mg (less than the amount of lycopene in a level teaspoon of catsup⁵) and fewer than 3% of the men who developed prostate cancer consumed more than 3.4 mg of lycopene daily and fewer than 3% of the men who did not develop prostate cancer routinely consumed more than 2.6 mg of lycopene daily.

In a case-control study of 317 men with prostate cancer and 480 matched cancer-free men, daily lycopene intake, raw tomato consumption and consumption of cooked foods containing tomatoes were not associated with the risks for developing prostate cancer (adjusted for age, height, use of nonsteroidal anti-inflammatory medications and socioeconomic status).²²⁸ However, only 25% of these men consumed more than 35 g (equivalent to one-quarter serving5) of raw tomatoes daily, more than 64 g (including water) of cooked foods containing tomatoes or more than 2 mg of lycopene from all sources daily.

In a study of 610 men with prostate cancer and 456 cancer-free men, daily mean tomato and tomato juice intakes did not differ between those with prostate cancer and those without.²²⁹ Tomato and tomato juice consumption were without effect on the risk for prostate cancer (adjusted for age, family history of prostate cancer, socioeconomic status, fruit consumption and vegetable consumption). Among these men, less than 3% consumed more than 60 g of tomatoes and tomato juice combined daily.

In a study of 1619 men with prostate cancer and 1618 cancer-free men, the daily intakes of either all tomato products or of cooked tomato products only were not associated with the risks for developing any prostate cancer or advanced prostate cancer (adjusted for age, education, ethnicity, geographic area of residence and daily total caloric intake).²³⁰ However, only 20% of these men consumed over 108 g of total tomato products (equivalent to three-quarters of one serving⁵) daily. The results were similar when the men were subgrouped by ethnicity (African-Americans, Caucasian-Americans, Chinese-Americans, Japanese-Americans).

In a re-analysis of previously-published data from a retrospective case-control study of 452 prostate cancer cases and 899 cancer-free individuals that was conducted between 1970 and 1983 among the multiethnic population of Hawaii, investigators reported failure to discover a statistically significant relationship between the consumption of tomatoes and the risk for developing prostate cancer.²³¹ The percentage of these men who consumed at least 1 mg of lycopene or 1 tomato daily could not be determined from the data provided. In another case-control study in which daily lycopene intakes cannot be determined, daily lycopene intakes of 215 men with prostate cancer and 593 matched cancer-free men were not associated with risk for developing prostate cancer (adjusted for age, education, family history of prostate cancer and total daily energy intake).²³²

In four retrospective case-control studies, the risk for developing prostate cancer was not observed to be associated with serum or plasma total lycopene concentrations.^{54,75,233,234} In one such study, nested within a 13-year prospective epidemiologic observational study, no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer (OR comparing the highest quartile of serum total lycopene concentration with the lowest quartile of serum total lycopene concentration (0.50) was not different from 1.0; 95% CI: 0.20, 1.29).²³³ However, the 75th percentile of serum total lycopene concentration was only 45 mcg/dL, a concentration only 65% of the mean serum total lycopene concentration achieved with daily dietary supplementation with 30 mg of lycopene in a prospective intervention study (and therefore only 65% of the serum total lycopene concentration achieved by about half of the men that received daily dietary supplementation with 30 mg of lycopene in a prospective intervention study).²¹¹

In a retrospective case-control study of 182 men with prostate cancer and 364 matched cancer-free men (the “CLUE I” study), median serum total lycopene concentrations were not different between men with (0.64 x 10-⁶ M) and without prostate cancer (0.66 x 10-⁶ M) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁵⁴ In a similar study of 142 men with prostate cancer and 284 matched cancer-free men (the “CLUE II” study), median serum total lycopene concentrations were not different between men with (0.72 x 10-⁶ M) and without prostate cancer (0.78 x 10-⁶ M) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁵⁴

In a retrospective case-control study of 142 men with prostate cancer and 142 matched cancer-free men, median serum total lycopene concentrations were not different between men with and without prostate cancer (0.25 x 10-⁶ M in both groups) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁷⁵ In another retrospective case-control study of 103 men with prostate cancer and 103 cancer-free men, serum total lycopene concentration was not observed to be associated with the risk for developing prostate cancer.²³⁴

D. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of the only relevant randomized placebo-controlled clinical trial,²¹⁰ the only relevant uncontrolled clinical trial^44,115,211 and all of the published prospective observational studies^212-216 consistently demonstrate a beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk for developing prostate cancer. This compelling evidence of risk reduction is strengthened by the findings of ten retrospective case-control studies^{64,67,90,107,114,217-221} and by a case series²²² and case report.²²³ Other reviewers have concluded that “Several case-control and prospective cohort studies focusing on dietary assessment suggest that the consumption of tomato and tomato products may be associated with a lower risk of prostate cancer.”235 In addition, “Food processing or cooking of tomatoes does not seem to reduce the benefits and may in fact provide greater advantage by improving the bioavailability of beneficial components.”²³⁵

Although there have been reports of retrospective case-control studies that have failed to observe this protective effect,^{54,75,224-234} these reports likely reflect failure of study subjects to consume lycopene, tomatoes or tomato-based foods, as well as confounding by related factors and heterogeneity of effect (this can occur when a subpopulation of nonresponders dilutes the overall effect of a chemopreventive agent or food and obscures the association in responders), resulting in underestimation of the effects of the nutrient or food of interest on chemoprevention.²³⁶ Furthermore, no report has claimed that an increase in the risk for developing prostate cancer was associated with the consumption of lycopene, tomatoes or tomato-based foods.

The published scientific evidence strongly supports the conclusion that the risk of developing prostate cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based products containing lycopene.
V. Lung Cancer

Lung cancer is the second leading cause of newly-diagnosed cancer in males and females in the US.¹⁵⁹ About 171,900 new cases of lung cancer were forecast for the US for the year 2003, while nearly 89,000 men and 69,000 women in the US were expected to die from this disease that year (accounting for about 28% of all cancer-related deaths).¹⁵⁹ The 1-year relative survival rate for individuals diagnosed with lung cancer is 42% and the 5-year relative survival rate for all lung cancers combined is 15%, although the 5-year relative survival rate is 49% when the disease is localized when detected.¹⁵⁹

A. Pathogenesis of Lung Cancer
Carcinogenesis in the lung occurs in a multistage process involving a series of genetic alterations with progression through a variety of pathways from initial reversible lesions to the development of metastatic disease.²³⁷ The initial triggers of carcinogenic change may be varied as may be the factors that provide the impetus for continued disease progression. For example, reactive oxygen species (such as the hydroxyl radical OH? ) may be implicated in the pathogenesis of lung cancer.²³⁷ Exposure of the lung to ozone produces oxidative damage similar to that of the lesions observed in precancerous change in the lungs.^237,238 Experimental ozone exposure of the human lung to ozone in vivo produces oxidative damage and an increase in the frequency of single-stand DNA damage in lung epithelial cells.^239,240

The insulin-like growth factors (IGF-I and IGF-II) are circulating mitogens that interact with target cells via the cell membrane-bound IGF-receptor to influence the regulation of cell proliferation, differentiation, apoptosis and neoplastic transformation.^195,196 In particular, IGF-I is a potent mitogen that stimulates DNA synthesis and the progression of the cell cycle from the G1 phase to the S phase while also stimulating the expression of proapoptotic Bcl proteins and suppressing the expression of antiapoptotic Bax proteins.¹⁹⁷ There is evidence that the risk of neoplastic transformation within a cell population increases as the proliferation rate of cells within the population increases,^200,201 suggesting that IGF-I availability to IGF-I-responsive tissues contributes to risk of developing tissue-specific cancer.¹⁹⁹ Furthermore, increased IGF-I availability may accelerate the proliferation and clonal expansion of epithelial undergoing the process of neoplastic transformation.¹⁹⁹ The results of a retrospective case-control study support the hypothesis that IGF-I is associated with lung cancer.²⁴¹ In that study, individuals with the highest quartile of plasma IGF-I concentrations were at significantly increased risk of developing lung cancer, compared to the risk among subjects with the lowest quartile of plasma IGF-I concentrations (OR: 2.75; 95% CI: 1.37, 5.53; adjusted for plasma IGF-BP-3 concentration).

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The addition of physiological concentrations of lycopene (1 to 2 x 10-⁶ M) to cultures of NCI-H226 human lung cancer cells significantly inhibited both basal and IGF-I-stimulated rates of DNA synthesis and cell proliferation.²⁴²

C. Animal Studies Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing lung cancer is reduced by consumption of supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of studies in experimental animals. Ferrets exposed to cigarette smoke for 9 weeks developed accelerated epithelial cell proliferation and squamous metaplasia of the lungs which were significantly inhibited by concurrent dietary supplementation with lycopene in amounts equivalent to human intakes of 15mg or 60 mg daily.²⁴³ In addition, both levels of dietary supplementation with lycopene prevented cigarette smoke-induced deactivation of the apoptosis-promoting Bcl-2 proteins. In mice, dietary supplementation with lycopene during the postinitiation stage of lung carcinogenesis significantly reduced the extent of lung neoplasia induced by combined pretreatment with diethylnitrosamine plus N-methyl-N-nitrosourea plus 1,2-dimethyl hydrazine HCl.²⁴⁴

D. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing lung cancer is reduced by consumption of supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of the findings of two prospective observational studies,^68,245,246 a retrospective cohort study²⁴⁷ and five retrospective case-control studies.^248-252

The findings of two prospective observational studies^245,246 have confirmed the beneficial relationship between lycopene consumption (whether as a dietary supplement or consumed as tomatoes or tomato-based foods) and reduced risk for developing lung cancer. When data from the 10-year prospective Health Professionals Follow-Up Study of 46,924 men and the 12-year prospective Nurses’ Health Study of 77,283 women were combined, the men and women with a median daily lycopene intake of 14.7 mg experienced a significantly reduced risk for the development of lung cancer, compared to the risk experienced by men and women with a median daily lycopene intake of 4.4 mg (RR: 0.80; 95% CI: 0.64, 0.99; adjusted for age, smoking status, age when cigarette smoking began, daily dietary total caloric intake and whether the subject joined a study during years 1-4, 5-8 or 9-12).^68,246 Interestingly, the chemopreventive effect of lycopene was not evident among the men and women who either never smoked cigarettes or who had quit smoking prior to or during the study, while men and women who were continuing to smoke at the end of the study with a median daily lycopene intake of 14.7 mg experienced a significantly reduced risk for the development of lung cancer, compared to the risk experienced by men and women who were continuing to smoke at the end of the study with a median daily lycopene intake of 4.4 mg (RR: 0.63; 95% CI: 0.45, 0.88; adjusted for age, age when cigarette smoking began, severity of cigarette smoking at the end of the study, daily dietary total caloric intake and whether the subject joined a study during years 1-4, 5-8 or 9-12).

In a re-analysis of the data obtained during the prospective Alpha-Tocopherol, Beta-Carotene Cohort Study of 27,084 male smokers who completed a 276-food item dietary questionnaire when they each joined the cohort, it was reported that daily intake of lycopene in excess of 1.17 mg significantly reduced the risk for the development of lung cancer, compared to the risk among men who consumed less than 0.23 mg of lycopene daily (RR: 0.72; 95% CI: 0.61, 0.84; adjusted for age, years of cigarette smoking, number of cigarettes smoked daily, whether supplemented with alpha-tocopherol or ß-carotene, whether dietary supplements containing ß-carotene or vitamin A were consumed, and dietary daily intakes of total energy, total fat and cholesterol).²⁴⁵

On the island of Oahu, Hawai’i, among a cohort of 463 men and 212 women with lung cancer, the daily consumption of more than 50 g of tomatoes or tomato-based foods by men with lung cancer significantly reduced the risk of death from lung cancer, compared to the risk among men with lung cancer who consumed less than 6.5 g of tomatoes or tomato-based foods daily (RR: 0.77; significantly different from RR = 1.0, p < 0.05; adjusted for age at diagnosis, stage of lung cancer, histologic appearance of lung cancer and body mass index).²⁴⁷ Among the cohort of women with lung cancer, the daily consumption of more than 42 g of tomatoes or tomato-based foods significantly reduced the risk of death from lung cancer, compared to the risk among women with lung cancer who consumed less than 6.5 g of tomatoes or tomato-based foods daily (RR: 0.50; significantly different from RR = 1.0, p < 0.05; adjusted for age at diagnosis, stage of lung cancer, histologic appearance of lung cancer and body mass index). However, attempts to determine whether this beneficial effect of tomato consumption was specific to specific types of lung cancer (i.e., adenocarcinoma, small cell cancer or squamous cell cancer) were unsuccessful.

The findings of five retrospective case-control studies^248-252 also support the conclusion that the risk for developing lung cancer is reduced by consumption of tomatoes and tomato-based foods and of lycopene. In a study of 230 men and 102 women with lung cancer and 597 men and 268 women who were cancer-free, those subjects with the highest quartile of consumption of tomatoes or tomato-based foods experienced significantly lower risk for developing lung cancer than did those subjects with the lowest quartile of consumption of tomatoes or tomato-based foods (men: OR: 0.43; significantly different from RR = 1.0, p < 0.05; women: OR: 0.27; significantly different from RR = 1.0, p < 0.05; adjusted for age, ethnicity, smoking status, number of pack-years of cigarette smoking and dietary daily cholesterol intake).²⁴⁸ However, among this subject population, despite the chemopreventive effect of tomato consumption, estimated lycopene intake was not associated with reduced risk for developing lung cancer.²⁵³

In another retrospective case-control study of 402 men and 104 women with lung cancer and 741 men and 304 women who were cancer-free, tomato consumption again was protective against the development of lung cancer.²⁴⁹ Men and women who consumed one or more servings of tomatoes daily experienced significantly lower risk for developing adenocarcinoma of the lung than did men and women who consumed only one serving per week (OR: 0.5; 95% CI: 0.4, 0.6; adjusted for age, sex and study center). However, tomato consumption did not appear to affect the risk for developing either small cell carcinoma or squamous cell carcinoma of the lung.

Among another sample of women, 103 with lung cancer and 206 without, although mean tomato intake was not different between those with and those without cancer, the risk of developing lung cancer was significantly altered by tomato intake.²⁵⁰ Women with the highest tertile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did women with the lowest tertile of daily tomato intake (OR: 0.45; 95% CI: 0.22, 0.91; adjusted for smoking status of number of pack-years of cigarette smoking). Although the risk for adenocarcinoma of the lung among all 306 women was not affected by tomato intake, among the 230 women who had never smoked cigarettes, those with the highest tertile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did women with the lowest tertile of daily tomato intake (unadjusted OR: 0.38; 95% CI: 0.17, 0.83).

Similarly, among 183 men with lung cancer and 183 cancer-free men, men with the highest quartile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did men with the lowest quartile of daily tomato intake (OR: 0.42; 95% CI: 0.25, 0.99; adjusted for lifetime exposure to tobacco, age at time of diagnosis of lung cancer, height, number of meals usually eaten at home daily, income, education and occupation).²⁵¹ In addition, the mean daily tomato intake of the men without lung cancer was significantly greater than that of the men with lung cancer.

The influence of plasma lycopene concentration on the risk of developing lung cancer was examined in 93 subjects with non-small cell lung cancer and 102 cancer-free men and women.²⁵² Among these individuals, mean plasma total lycopene concentration was significantly greater among the men and women without lung cancer. In addition, subjects with the highest tertile of plasma total lycopene concentrations had significantly reduced risk for developing any non-small cell form of lung cancer than had subjects with the lowest tertile of plasma total lycopene concentrations (OR: 0.37; significantly different from OR = 1.0, p < 0.05; adjusted for age, sex and race). Among African-Americans with the highest tertile of plasma total lycopene concentrations, the risk for developing any non-small cell form of lung cancer was even lower (OR: 0.12; significantly different from OR = 1.0, p < 0.05; adjusted for age and sex). In addition, among all subjects, those with the highest tertile of plasma total lycopene concentrations had significantly reduced risk for developing squamous cell lung cancer, compared to the risk of subjects with the lowest tertile of plasma total lycopene concentrations (OR: 0.25; significantly different from OR = 1.0, p < 0.05; adjusted for age, sex and race).

The results of several prospective observational studies have failed to demonstrate the beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk of developing lung cancer.^254-258 In most of these studies, lycopene intake or the consumption of tomatoes or tomato-based foods was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing lung cancer was predictable.^254-257

For example, in the 6-year prospective Netherlands Cohort Study on Diet and Cancer, daily lycopene intake appeared to have no effect on the multivariate-risk of developing any lung cancer, small cell carcinoma of the lung, squamous cell carcinoma of the lung or adenocarcinoma of the lung in 58,279 men.²⁵⁴ However, fewer than 5% of these men consumed more than 4 mg of lycopene (equivalent to 1.5 level tablespoons of catsup⁵) daily. Similarly, in a prospective observational study of 4,545 men, daily lycopene intake appeared to have no effect on the age- and smoking status-adjusted risk of developing any lung cancer; less than 30% of these men consumed more than 1 mg of lycopene daily.²⁵⁵ In another, 11.5-year prospective study of 13,785 men and 2,928 women, of whom only 5% consumed at one-half of a serving of tomatoes daily, tomato consumption was not related to risk for developing lung cancer.²⁵⁶ In a much larger prospective 16-year study of 121,700 women in the U.S. (the Nurses’ Health Study), neither tomato consumption nor lycopene intake were significantly related to the incidence of lung cancer; however, the lycopene consumption by these subjects cannot be determined.²⁵⁷ However, the results of a large 6-year prospective study of 34,198 California Seventh-Day Adventists, one-third of whom consumed at least one serving of tomatoes daily, failed to demonstrate a significantly protective effect of tomato consumption on risk of developing lung cancer.²⁵⁸

The investigators of a number of retrospective case-control studies have failed to observe significant risk-reducing relationships between tomato consumption and lung cancer or between lycopene intake and lung cancer.^{45,59,253,259-271}However, in most of these studies, the consumption of tomatoes or lycopene was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing lung cancer was predictable.^{45,59,253,259-268}

In one retrospective case-control study of 230 men and 102 women with lung cancer and 597 men and 268 women who were cancer-free, lycopene intake did not affect the multivariate-risk of developing lung cancer by either the men or the women.²⁵³ However, 75% of the men consumed less than 4.2 mg of lycopene daily and 75% of the women consumed less than 3.6 mg of lycopene (equivalent to 1.5 level tablespoons of catsup⁵) daily. Similarly, although lycopene intake did not affect the risk of developing lung cancer among 103 women with lung cancer and 206 women without lung cancer, fewer than 25% of these women consumed more than 2 mg of lycopene daily.²⁵⁹ In another sample of 541 men with lung cancer and 540 matched cancer-free men, although lycopene intake did not affect the risk of developing lung cancer, fewer than 25% of these men consumed more than 2 mg of lycopene daily.²⁶⁰ In another retrospective case-control study (nested within a much larger prospective study) in which the mean lycopene intake of men with lung cancer was no different from the mean intake of men without lung cancer, less than 3% of the 4,538 subjects consumed more than 2.5 mg of lycopene (the amount of lycopene in one level tablespoon of catsup⁵) daily.²⁶¹

In a retrospective case-control study of 75 men with lung cancer and 97 cancer-free men, tomato consumption did not affect the multivariate-risk of developing lung cancer; 67% of these men consumed less than 29 g (one-quarter serving) of tomatoes daily.²⁶² In another study of 425 men with lung cancer and 1007 cancer-free men, tomato consumption did not affect the multivariate-risk of developing lung cancer; 75% of these men consumed tomatoes less than 0.8 times per month.²⁶³ Among 541 men with lung cancer and 540 matched men without lung cancer, only one-third of whom consumed more than 1.5 servings of tomatoes weekly, such meager tomato consumption had no apparent effect on the prevalence of lung cancer.260 In a case-control study nested within a larger prospective observational study, although the tomato consumption of 138 women with lung cancer and 2,814 randomly selected women without lung cancer had no apparent effect on the prevalence of lung cancer, only one-third of these women consumed at least three servings of tomatoes per week.²⁶⁴ In four additional retrospective case-control studies that failed to observe a protective effect of tomato or lycopene intake on risk of developing lung cancer, the percentages of study subjects with minimal tomato consumption or lycopene intake could not be determined.^265-268

In contrast, tomato consumption or lycopene intake has been substantial in three retrospective case-control studies that have failed to observe a protective effect of tomato or lycopene intake on risk of developing lung cancer.^269-271 For example, in a randomly selected subcohort of a much larger study, the daily lycopene intake of 155 women with lung cancer and 5,361 women without lung cancer had no effect on the risk of developing lung cancer, even though more than 25% of these women had daily intakes of lycopene greater than 14 mg.²⁶⁸ Similarly, the daily lycopene intake of 763 men with lung cancer and 564 men without lung cancer had no effect on the risk of developing lung cancer, even though more than 25% of these men had daily intakes of lycopene greater than 9 mg.²⁷⁰ In another study limited to men, the daily tomato consumption of 281 men with lung cancer and 1,207 men without lung cancer had no effect on the risk of developing lung cancer, even though 39% of these men consumed at least 0.5 servings of tomatoes daily.²⁷¹

In two retrospective case-control studies, the mean serum total lycopene concentration was not different between subjects with lung cancer and those without lung cancer⁵⁹ and serum total lycopene concentration had no effect on the risk of developing lung cancer⁴⁵ or on the risk of dying from lung cancer.⁵⁹

E. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of two prospective observational studies^245,246 and of a retrospective cohort study²⁴⁷ demonstrate a beneficial protective effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing lung cancer. This evidence of risk reduction is strengthened by the findings of five retrospective case-control studies^248-252 and by a case report.²³³

Although there have been reports of retrospective case-control studies that have failed to observe this protective effect,^{45,59,253,258-271} most of those studies^{45,59,253,258-268} have examined subjects with very little routine consumption of tomatoes or lycopene; their failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing lung cancer was predictable and not relevant to the evaluation of the scientific evidence supporting the conclusion that the consumption of lycopene and tomatoes and tomato-based foods confers a beneficial protective effect on the risk for developing lung cancer. Furthermore, no report has claimed that an increase in the risk for developing lung cancer was associated with the consumption of lycopene, tomatoes or tomato-based foods.

The published scientific evidence strongly supports the conclusion that the risk of developing lung cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based products containing lycopene.
VI. Colorectal Cancer

Colorectal cancer is the third most common life-threatening cancer in the US and accounts for about 10% of total cancer incidence and total cancer deaths in the US.159 The incidence of colorectal cancer in the US is about 60 cases per 100,000 adults, with about 148,000 new diagnoses and about 57,000 deaths forecast for the US in 2003.¹⁵⁹ Colorectal cancer occurs with nearly equal frequency in men and women.¹⁵⁹ Five-year survival following diagnosis is between 10% and 90%, depending on the stage of disease at first diagnosis.¹⁵⁹

A. Maintenance of the Normal Colorectal Epithelium
The intestinal epithelium is in a constant state of renewal with a continuous high rate of cell proliferation, differentiation and apoptotic cell death.^272-274 Colonocytes turnover rapidly, with an average lifespan of only 2 to 3 days.^275,276Undifferentiated precursor cells are produced from stem cell populations in the lower 40% to 60% of the crypts of the colonic mucosal villi and quickly begin to migrate toward the villar luminal epithelial surface where they reside briefly, die and are shed directly into the lumen.^273,274 During migration along the crypt axis toward the luminal surface the undifferentiated precursor cells lose their proliferative capability and differentiate into either enteroendocrine or mucus-secreting goblet cells, which tend to remain in the lower portion of the crypt, or absorptive cells, which move to the luminal surface.²⁷⁷ Following 36 to 48 hours of mature differentiated function, senescent absorptive cells extrude into the lumen and die in a regulated manner by apoptosis.²⁷²

Short-lived mammalian cells such as colonocytes are capable of maintaining healthy populations of fully functional cells through a combination of continuous production of new replacement cells and initiation of the death of mature cells (programmed cell death) in response to signal transduction through specific receptors.²⁷⁸ Condensation of the nuclear chromatin and mitochondria, blebbing of the cell membrane, characteristic swelling of the endoplasmic reticulum and fragmentation of the cells into membrane-bound apoptotic bodies are signs of total cell destruction.^279,280 The most important characteristic of this self-destruction is that apoptotic cells themselves actively provide the molecules necessary for the apoptotic mechanism to proceed.²⁸¹

The first step in apoptotic change is the opening of the permeability transition pores in the inner mitochondrial membrane.²⁸² The onset of the mitochondrial permeability transition (MPT; depolarization of the mitochondrial membrane) is the key event in apoptotic cell death.^283,284 Opening of the pores results in electrolyte movement and depolarization of the inner mitochondrial membrane, entry of water into the mitochondrial matrix, swelling of the matrix, and deformation of cristae.283,285 Contortional change in cristae damages the outer mitochondrial membrane, resulting in the release of pro-apoptotic intermembrane proteins (including cytochrome c, procaspases and apoptosis-inducing factor (AIF)) into the cytosol.^52,54 AIF activates a nuclease which hydrolyzes nuclear DNA while cytochrome c activates caspase 9 which activates caspase 3 which performs pro-apoptotic proteolysis of intracellular proteins.^283,285

B. Conversion of the Normal Colorectal Epithelium into a Neoplastic Epithelium
In a general model, cancer progresses through 4 stages: initiation (conversion of a normal cell to a cancer cell), promotion (the induction of cellular replication and shortening of the latency period, reducing the length of the cell cycle and accelerating proliferation), clonal expansion (unrestrained proliferation resulting in tumor formation) and progression (the accumulation of defects in growth control and differentiation that produce metastasis).^286,287 Colorectal carcinogenesis is an even more complex, multistep process involving initiation, promotion, expansion and progression stages that are not necessarily discrete or well-defined events.^172,288

Mutations in the adenomatous polyposis coli (APC) gene (such as occur in individuals with familial adenomatous polyposis) increase the risk for colon cancer.^289-293 Mutations in this gene may be the initiating events in the development of most or all colorectal neoplasia.^294-296 It is estimated that 85% of colorectal cancers are associated with mutations in the APC gene that promote unrestrained hyperproliferation of the colorectal epithelium in response to a proliferation-inducing stimulus.^295,296 In the normal colorectal mucosa, exposure to carcinogenic compounds is irritating and produces damage to the epithelium. In response, a temporary hyperproliferative phase, with increase in volume (“expansion”) of the proliferative compartment of the colorectal mucosal crypt, restores damaged luminal epithelium in a compensatory healing process.^297-302 When cells carrying a mutation in the APC gene are stimulated to respond to a proliferation-inducing stimulus, unrestrained hyperproliferation produces preneoplastic structures of dysplastic tissue (aberrant crypt foci).³⁰³Aberrant crypt foci (ACF) are preneoplastic lesions predictive of increased risk for colon cancer.^304-316

The normal reparative hyperproliferative response increases colorectal tissue sensitivity to chemically-induced carcinogenesis. For example, injecting 1,2-dimethylhydrazine dihydrochloride (DMH) into rats and mice produces (compared to vehicle) significant increases in the rate of colorectal crypt cell proliferation,^317-323 colonocyte content of damaged DNA,³²⁰ the formation of aberrant crypt foci,^{317,320,321,323} the formation of adenomatous polyps,^{317,322,324,325}the growth of adenomatous polyps326 and the progression of adenomas to carcinomas.^317,324 DMH-induced rat colon carcinogenesis closely resembles human colon neoplasia in all of these characteristics.^327,328

In rats, hepatic conversion of ingested azoxymethane (AOM) to activated methyl-azoxymethane also produces significant increases in the rate of colorectal crypt cell proliferation,^329-331 the formation of aberrant crypt foci,^330-334 the formation of adenomatous polyps,^336-339 the growth of adenomatous polyps,³³⁹ and the progression of adenomas to carcinomas.³³⁹

The ingestion of N-methyl-N-nitrosourea (MNU) results in the induction of invasive carcinomas of the colon and rectum in laboratory rodents.^340-342

Although the adenoma-to-carcinoma sequence results primarily from a series of mutations affecting cell growth, differentiation and programmed cell death,^343-347 colorectal neoplasms also can arise from another distinct genetic pathway in which the frequent loss of expression of one of the DNA mismatch repair enzymes, usually hMLH1 or hMSH2, results in microsatellite instability^348,349 and produces predisposition to colorectal adenoma and carcinoma.350,351 For example, hereditary nonpolyposis colorectal cancer is characterized by defective DNA mismatch repair enzymes.^{349,350,352-356}

C. The Rate of Colorectal Mucosal Crypt Cell Proliferation and Colorectal Cancer in Animal Models
A number of experimental manipulations produce increased cellular proliferation in the colonic crypts of laboratory animals, including injection with 1,2-dimethylhydrazine dihydrochloride (DMH),^317-323 and ingestion of N-methyl-N-nitrosourea (MNU),^340,341 N-methyl-N´-nitro-N-nitrosoguanidine³⁵⁷ or azoxymethane (AOM).^329-331 In such animals, increased cellular proliferation in the colonic crypts is associated with colonic hyperplasia and a statistically significantly increased incidence of tumorigenesis along the length of the large intestine.^{317-323,340,341} These data from animal studies demonstrate that increased proliferative activity in the colonic mucosa (“hyperproliferation”) is correlated with an increased risk of developing colon cancer.^317-321,323

D. The Rate of Colorectal Mucosal Crypt Cell Proliferation and Colorectal Cancer in Humans
Increased proliferation in the mucosa is an early step in the genesis of colorectal neoplasia; accelerated proliferation increases the rate of random mutations^358,359 and is procarcinogenic.^358-361 On the other hand, a decrease in the rate of colorectal epithelial cell proliferation significantly decreases the risk for colorectal cancer in humans.³⁶² Compared with cancer-free individuals and those at low risk for colon cancer, patients with current or previous colon cancer^{358-360,363-368}and patients at high risk for colon cancer (patients with sporadic adenoma,^361,366-377 familial adenomatous polyposis,^359,378,379 ulcerative colitis,^366,379-382 or a family history of colon cancer^{358,367,373,384} or following intestinal bypass surgery³⁸⁵ and most elderly individuals^386,387), on average, exhibit in their grossly normal-appearing colorectal mucosa both an increased epithelial cell proliferation rate and an extension (“expansion”) of the colon crypt proliferative zone from the lower (basal) 60% of the crypt to include the upper (luminal) 40% of the crypt, including the most superficial portions of the crypts.^{388,373,376,381,388,389} Expansion of the proliferative compartment of the colorectal mucosa into the areas of colonic crypts that normally are occupied by differentiated and nondividing cells, forming foci of aberrant crypt morphology (“aberrant crypt foci”), presages increased risk for colorectal cancer in humans.304,307-313,368,387-394 In patients with previous colon cancer or sporadic adenomas, these changes also predict adenoma recurrence.^365,371 All available evidence indicates that these two proliferation abnormalities (hyperproliferation and upward shift – “expansion” – of the proliferative zone) are reversible biomarkers or precursors for colon neoplasia.^395-399

E. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Colorectal Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
Two lines of human colon carcinoma cells have been developed that either spontaneously lack DNA mismatch repair enzymes (HCT116 cells) or have received the addition of normal human chromosome 3, restoring mismatch repair capability (HCT116/ch3 cells).⁴⁰⁰ In the absence of lycopene, the rate of spontaneous mutagenesis in HCT116 cells is more than 20-fold greater than the rate in HCT116/ch3 cells. In the presence of a physiologically-relevant concentration of lycopene (5 x 10-⁶ M), the rate of spontaneous mutation was significantly reduced in HCT116 cells and was no longer greater than the rate in HCT116/ch3 cells. These results indicate that in human colon carcinoma cells unable to repair DNA mismatch mutations, lycopene prevented the initiation of such defects.

F. Animal Studies Provide Scientific Support for the Conclusion that Risk of Developing Colorectal Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The colonic mucosal epithelium responds to subcutaneous injections of DMH with a hyperproliferative response reflected in the rate of incorporation of 5-bromo-2’-deoxyuridine (BrdU) into newly synthesized DNA.⁴⁰¹ Supplementation of the diets of DMH-injected mice with lycopene significantly reduced the rate of DMH-stimulated synthesis of new DNA.

Similarly, dietary supplementation with lycopene significantly inhibited AOM-induced aberrant crypt foci formation in the colons of rats.¹³⁹ Interestingly, the oral consumption of tomato paste also significantly inhibited AOM-induced hyperproliferation and suppression of apoptosis, resulting in significantly decreased development of aberrant crypt foci, in the colons of rats.⁴⁰²

Intrarectal administration of MNU results in the induction of precarcinogenic colonic aberrant crypt foci and invasive carcinomas of the colon and rectum in laboratory rodents.^{340-342,403,404} Dietary supplementation with lycopene, tomato juice or lycopene-enriched tomato juice following MNU administration all significantly inhibited subsequent development of MNU-induced precarcinogenic colonic aberrant crypt foci and invasive carcinomas of the colon.^403,404

G. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Colorectal Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing colorectal cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of the findings of seven retrospective case-control studies.^{67,73,82,405-409} In a study that compared 56 men and 55 women with colon cancer to 56 matched men and 55 matched women without colon cancer, the consumption of more than 15 kg of tomatoes annually (about 40 g daily) significantly reduced the risk of developing colon cancer, compared to the risk associated with the consumption of less than 15 kg annually (OR calculated using estimates of tomato consumption in 1966: 0.26; 95% CI: 0.12, 0.56; OR calculated using estimates of tomato consumption in 1985: 0.40; 95% CI: 0.17, 0.94).⁴⁰⁵ Similarly, although tomato consumption had no apparent effect on the risk for developing rectal cancer by 109 women with rectal cancer and 109 matched cancer-free women, the consumption of more than 20 kg of tomatoes annually (about 55 g daily) by 116 men with rectal cancer and 116 matched men without rectal cancer significantly reduced their risk of developing rectal cancer, compared to the risk associated with the consumption of less than 20 kg annually (OR calculated using estimates of tomato consumption in 1985: 0.40; 95% CI: 0.17, 0.94).⁴⁰⁵

In a retrospective case-control study, 955 men and women with colon cancer and 620 men and women with rectal cancer were compared to 2,879 cancer-free men and women.⁴⁰⁶ Tomato consumption reduced the risk of developing cancer at both sites. The consumption of tomatoes at least once daily reduced the risk of developing colon cancer by 61%, compared to the risk associated with consuming tomatoes less than three times per week (OR: 0.39; 95% CI: 0.31, 0.49; adjusted for age, sex, education, dietary daily total caloric intake, alcohol consumption, smoking status and study center). Similarly, the consumption of tomatoes at least once daily reduced the risk of developing rectal cancer by 58%, compared to the risk associated with consuming tomatoes less than three times per week (OR: 0.42; 95% CI: 0.32, 0.55; adjusted for age, sex, education, dietary daily total caloric intake, alcohol consumption, smoking status and study center).

In a retrospective case-control study, 1225 men and women with colon cancer and 728 men and women with rectal cancer were compared to 4,154 cancer-free men and women.⁴⁰⁷ Tomato consumption reduced the risk of developing cancer at both sites. The consumption of at least 3.5 servings of tomatoes per week reduced the risk of developing any colorectal cancer by 24%, compared to the risk associated with consuming less than 3.5 servings of tomatoes per week (OR: 0.76; 95% CI: 0.6, 0.9; adjusted for age, sex, body mass index, dietary daily total caloric intake and physical exercise). The consumption of at least 3.5 servings of tomatoes per week reduced the risk of developing colon cancer by 21%, compared to the risk associated with consuming less than 3.5 servings of tomatoes per week (OR: 0.79; 95% CI: 0.6, 0.9; adjusted for age, sex, body mass index, dietary daily total caloric intake and physical exercise). Similarly, the consumption of at least 3.5 servings of tomatoes per week reduced the risk of developing rectal cancer by 29%, compared to the risk associated with consuming less than 3.5 servings of tomatoes per week (OR: 0.71; 95% CI: 0.5, 0.9; adjusted for age, sex, body mass index, dietary daily total caloric intake and physical exercise).

In a retrospective case-control study of 154 subjects with gastric cancer, 252 subjects with colorectal cancer and 812 subjects without any cancer, compared to the risk of developing gastrointestinal cancer among those subjects who never consumed tomatoes or tomato-based foods, the daily consumption of tomatoes or tomato-based foods significantly reduced the risk of developing gastrointestinal cancer anywhere along the gastrointestinal tract (OR: 0.82; significantly different from OR = 1.0; p < 0.05).⁴⁰⁸

In a small retrospective case-control study of 11 subjects with colorectal cancer and 30 cancer-free individuals, mean plasma total lycopene concentration was significantly lower in the subjects with colorectal cancer (0.02 x 10-⁶ M) than in the subjects who were without cancer (0.34 x 10-⁶ M).⁶⁷

In a small study, the lycopene content of mucosal tissues harvested from 10 patients with adenomatous polyps was significantly lower (by about 90%) than that of colonic mucosal tissue donated by patients without adenomatous polyps.⁷³Nonadematous human colonic epithelium receives lycopene from the systemic circulation.⁴⁰⁹ If present in sufficient concentration, lycopene enters actively proliferating deep crypt cells. If lycopene is not present in the circulation in sufficient concentration, actively proliferating deep crypt cells will be lycopene-deficient and at increased risk for carcinogenesis. In another small study, the lycopene content of mucosal tissues harvested from 7 patients with adenomatous polyps and 7 patients with colon cancer was significantly lower than that of both colonic and rectal mucosal tissue donated by patients without adenomatous polyps.⁸²

InConsistent with these reports describing the chemopreventive effects of lycopene intake and tomato consumption on risk reduction for colorectal cancer, the investigators of a prospective observational study⁴¹⁰ and seven retrospective case-control studies have failed to observe the beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk of developing colorectal cancer.^234,411-417 In several of these studies, the consumption of tomatoes or lycopene was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing colorectal cancer was predictable.^410-412

For example, in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of male cigarette smokers, lycopene intakes of less than 1.5 mg daily did not reduce the risk of developing colorectal cancer (90% of the men in this study had daily lycopene intakes of less than 1.5 mg, slightly more than the amount of lycopene in a level teaspoon of catsup⁵).⁴¹⁰ In a simplistic retrospective case-control study of 453 subjects with colon cancer, 365 subjects with rectal cancer and 2,851 cancer-free subjects, when compared to no consumption of tomatoes or tomato-based foods, any such consumption failed to significantly affect the risk of developing either colon or rectal cancer.⁴¹¹ In a study that compared 27 men and 15 women with colon cancer and 25 men and 26 women with rectal cancer to 111 men and 75 women without cancer, tomato consumption (only once or more weekly) had no effect on the risk of developing either colon or rectal cancer.⁴¹²

In a study of 488 subjects with colorectal adenomas and 488 matched subjects without adenomas, 90% consumed less than 7.2 mg of lycopene daily, with no effect of lycopene intake on the risk for developing colorectal adenomas.⁴¹³ In a study comparing 437 men and 291 women with rectal cancer and 688 men and 537 women with colon cancer to 2,073 cancer-free men and 2,081 cancer-free women, lycopene intake had no effect on the risks for developing any colorectal cancer, colon cancer or rectal cancer; however, 80% of these subjects consumed less than 11.7 mg of lycopene daily.⁴¹⁴ In a study comparing 1,993 subjects with colon cancer to 2,410 cancer-free men and women, mean lycopene intakes did not differ between subjects with and without colon cancer and lycopene intake had no effect on the risks for developing either proximal or distal colon cancer; however, 83% of these subjects consumed less than 13 mg of lycopene daily and 97% consumed less than 20 mg of lycopene daily.⁴¹⁵ In a study comparing 295 women with colorectal cancer to 5,334 cancer-free women, lycopene intake had no effect on the risk for developing colorectal cancer; however; 80% of these women consumed less than 17 mg of lycopene daily.⁴¹⁶ In a retrospective case-control study, estimated lycopene intakes did not affect the multivariate-adjusted risk of developing colorectal cancer among 142 men and 81 women with colorectal cancer and 211 men and 280 women without cancer.⁴¹⁷ However, lycopene intakes were not given.

In a retrospective case-control observational study, serum total lycopene concentration was not associated with the risk for developing rectal cancer.234 However, lycopene intakes were not given.

H. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Colorectal Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of seven retrospective case-control studies^{67,73,82,405-409} demonstrate a beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing colorectal cancer. The results of a prospective observational study⁴¹⁰ and of retrospective case-control studies^234,411-417 have confirmed that the consumption of lycopene, tomatoes or tomato-based foods is required in order for this benefit to be realized.

The published scientific evidence strongly supports the conclusion that the risk of developing colorectal cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
VII. Gastric Cancer

Although gastric cancer is the second most common cancer in the world, its prevalence in the US has been declining.¹⁵⁹The American Cancer Society forecast about 22,400 new diagnoses of gastric cancer, and about 12,100 deaths related to gastric cancer, for the US in 2003.¹⁵⁹ Gastric cancer occurs with nearly equal frequency in men and women.¹⁶⁰ Overall 5-year relative survival is 20% or less, but increases to about 60% in the small percentages of cases where the tumor is localized to the stomach.¹⁵⁹

A. Pathogenesis of Gastric Cancer
Gastric cancer may be differentiated into the intestinal type, with well-differentiated tissue, and the diffuse type consisting largely of undifferentiated cells.⁴¹⁸ The pathogenesis of gastric cancer depends on its initiating mutations; diffuse-type gastric cancer follows mutations in the E-cadherin gene while intestinal-type gastric cancer appears to follow a multistage model, progressing from the interactions of normal mucosa with Helicobacter pylori organisms that produce chronic superficial gastritis to chronic atrophic gastritis, intestinal metaplasia, dysplasia and carcinoma.^419,420 Intragastric formation of carcinogenic N-nitroso compounds is carcinogenic in animals.⁴²¹ In humans it may be potentiated by the gastric alkalinization that accompanies atrophy and facilitates gastric microbial conversion of ingested nitrates to nitrites and then to N-nitrosamines.⁴¹⁹ N-nitrosamines may initiate or accelerate the carcinogenic sequence in humans.^419,421,422

B. Animal Studies Provide Scientific Support for the Conclusion that Risk of Developing Gastric Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
Rats fed tomato paste containing lycopene (236 ppm) exhibited significant inhibition of the hepatic damage (centrolobular necrosis, exangia and appearance of pyknotic nuclei) typical after treatment with the combination of aminopyrin and sodium nitrite, precursors of intragastric N-nitrosamine formation.⁴²³ Similarly, oral gavage with lycopene (2.5 mg per kg body weight) significantly inhibited the development of gastric carcinogenesis typically induced by intragastric intubation with the combination of N-methyl-N’´-nitro-N-nitrosoguanidine and saturated sodium chloride.^424,425

C. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Gastric Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing gastric cancer is reduced by consumption of supplemental lycopene or tomatoes and tomato-based foods containing lycopene is supported by the results of seven retrospective case-control studies.^{405,406,426-430} In a study that compared 520 men and 221 women with gastric cancer to 520 matched men and 221 matched women without gastric cancer, the consumption of the highest tertile of tomato intake significantly reduced the risk of developing gastric cancer, compared to the risk associated with the consumption of the lowest tertile of tomato intake (OR: 0.77; significantly different from OR = 1.0; p < 0.05).⁴²⁶ In another study that compared 220 men and women with gastric cancer to 440 men and women without cancer, the consumption of four or more servings of tomatoes per month significantly reduced the risk of developing gastric cancer, compared to the risk of men and women consuming less than 4 servings per month (sex-adjusted OR: 0.51; significantly different from OR = 1.0; p < 0.05).⁴²⁷

In another study that compared 723 men and women with gastric cancer to 2,024 men and women without cancer, the consumption of seven or more servings of tomatoes per week significantly reduced the risk of developing gastric cancer, compared to the risk of men and women consuming less than 2 servings per week (OR: 0.43; 95% CI: 0.34, 0.59; adjusted for age, sex, education, study center, alcohol consumption, smoking status and dietary daily total caloric intake).⁴⁰⁵ In another study that compared 65 African-American men and women with gastric cancer to 82 African-American men and women without cancer, tomato consumption greater than the sample median (not given) significantly reduced the risk of developing gastric cancer, compared to the risk of men and women consuming less than the sample median of tomatoes (OR: 0.56; 95% CI: 0.34, 0.90; adjusted for age, sex, education, income, alcohol consumption and tobacco use).⁴²⁸

In a retrospective case-control study of 154 subjects with gastric cancer, 252 subjects with colorectal cancer and 812 subjects without any cancer, compared to the risk of developing gastrointestinal cancer among those subjects who never consumed tomatoes or tomato-based foods, the daily consumption of tomatoes or tomato-based foods significantly reduced the risk of developing gastrointestinal cancer anywhere along the gastrointestinal tract (OR: 0.82; significantly different from OR = 1.0; p < 0.05).⁴⁰⁶

A study compared the lifetime dietary habits of 218 men and 120 women with gastric cancer to those habits of 444 men and 235 women without cancer.⁴²⁹ The consumption of more than three servings of tomatoes per month during adolescence significantly reduced the risk of developing gastric cancer in adulthood, compared to the risk after tomatoes and tomato-based foods were completely avoided during adolescence (OR: 0.36; 95% CI: 0.23, 0.58; adjusted for age, sex and socioeconomic status). However, the risk of developing gastric cancer during adulthood was not affected by tomato consumption during adulthood.

In another study that matched 85 men and 35 women with gastric cancer to 255 men and 105 women without cancer, the consumption of more than 3.5 mg of lycopene daily significantly reduced the risk of developing gastric cancer, compared to the risk of men and women consuming less than 2 mg of lycopene daily (OR: 0.37; 95% CI: 0.19, 0.73; adjusted for age, sex, area of residence, education, family history of gastric cancer, body mass index and dietary daily intakes of total calories, vitamin C and fructose).⁴³⁰

The results of a prospective observational study do not supports the conclusion that the consumption of lycopene and tomatoes and tomato-based foods reduces the risk for developing gastric cancer.⁴³¹ In this study (the 6-year Netherlands Cohort Study of 120,852 men and women), although dietary lycopene intake had no effect on the risk of developing gastric cancer, fewer than 3% of these subjects consumed at least 3 mg of lycopene (slightly more than the amount of lycopene in a level tablespoon of catsup⁵) daily. The absence or virtual absence of lycopene from the diets of almost all study subjects rendered the failure of these investigators to observe the beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing gastric cancer both predictable and irrelevant.

The results of several retrospective case-control studies do not support the conclusion that the consumption of lycopene and tomatoes and tomato-based foods reduces the risk for developing gastric cancer.^{104,105,412.427,432-437} In these studies, the absence or virtual absence of lycopene from the diets of almost all study subjects rendered the failure of these investigators to observe the beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing gastric cancer both predictable and irrelevant. For example, in a retrospective case-control study of 282 men and women with gastric carcinoma and 3,123 cancer-free men and women, dietary lycopene intake was reported to have to influence on the risk of developing disease.432 However, less than 3% of this population consumed more than 3 mg of lycopene (slightly more than the amount of lycopene in a level tablespoon of catsup⁵) daily.

80 Caucasian men and women with gastric cancer and 91 Caucasian men and women without gastric cancer, the consumption of tomatoes in amounts greater than the sample median did not reduce the risk of gastric cancer experienced by men and women consuming less than the median amount of tomatoes.⁴²⁷ In a study that compared 59 men and 34 women with gastric cancer to 111 men and 75 women without cancer, tomato consumption (once or more weekly) had no effect on the risk of developing gastric cancer.⁴¹² In another retrospective case-control study of 235 men and 119 women with gastric cancer and 235 men and 119 women without gastric cancer, lycopene intake had no effect on the risk of developing gastric cancer.⁴³³ However, fewer than 25% of these subjects consumed at least 2 mg of lycopene (less than the amount of lycopene in a level tablespoon of catsup5) daily. The results of three retrospective case-control studies are consistent with the conclusion that avoidance or minimization of tomato consumption or lycopene intake does not reduce the risk of developing gastric cancer; however, actual intakes were not given.^434-436

The results of one retrospective case-control study suggest that the risk of dying from gastric cancer is independent of regional mean plasma total lycopene concentration.^103,104

D. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Gastric Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of seven retrospective case-control studies^{405,406,426-430} demonstrate a beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing gastric cancer. Although the results of a prospective observational study⁴³¹ and retrospective case-control studies^{103,104,412.427,432-436} have not confirmed this conclusion, the absence or virtual absence of lycopene from the diets of almost all subjects in these studies rendered the failure of these investigators to observe the beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing gastric cancer both predictable and irrelevant to an evaluation of the scientific support for the conclusion that the consumption of lycopene and tomatoes and tomato-based foods reduces the risk for developing gastric cancer.

The published scientific evidence supports the conclusion that the risk of developing gastric cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.

VIII. Breast Cancer

The American Cancer Society forecast 211,300 new cases of invasive breast cancer for the US in 2003.¹⁵⁹ Over 99% of these cases occurred in women and about 20% will lead to premature death; over 40,000 breast cancer-related deaths were predicted for the US in 2003.¹⁵⁹ About 20% of these cases were diagnosed as ductal carcinoma in situ (DCIS), characterized by the proliferation of malignant mammary ductal epithelial cells within the confines of the basement membrane without evidence of invasion;⁴³⁷ however, 5% to 10% of cases of DCIS are characterized by microinvasion of the ductal basement membrane.⁴³⁸ Breast cancer ranks second (to lung cancer) among cancer deaths in women and is the most frequently diagnosed non-skin cancer in women.¹⁵⁹ The 5-year relative survival rate for localized breast cancer is 97%, for regionally invasive breast cancer, 78%, and for metastatic breast cancer, 23%.^159,438 Lifetime risk for breast cancer in women is 12.5% and increases with age, estrogen use, the appearance of atypical hyperplasia, increased breast density, earlier age of menarche, later age of menopause, obesity after menopause, alcohol use, radiation exposure, never having had children and a positive family history of breast disorders.^159,439-441 Risk may be decreased by physical activity and maintenance of appropriate body weight.¹⁵⁹

A. Pathogenesis of Breast Cancer
The pathogenesis of breast cancer is multifactorial and only incompletely understood.⁴⁴² However, similarities suggest that breast cancer follows a multistage pathogenesis not unlike that of other epithelial cancers such as lung, prostate and colorectal cancer.⁴⁴²

Insulin-like growth factor-I (IGF-I) is a potent circulating mitogen that interacts with target cells via the cell membrane-bound IGF-receptor to stimulate DNA synthesis and the progression of the cell cycle from the G1 phase to the S phase while inhibiting apoptosis.^197-199 Breast tumor tissue overexpresses IGF-I receptors⁴⁴³ and therefore is hypersensitive to this mitogen.

There is evidence that the risk of neoplastic transformation within a cell population increases as the proliferation rate of cells within the population increases,^202,203 suggesting that IGF-I availability to IGF-I-responsive tissues (such as in the breast) contributes to risk of developing tissue-specific cancer.²⁰¹ Furthermore, increased IGF-I availability may accelerate the proliferation and clonal expansion of epithelial undergoing the process of neoplastic transformation.²⁰¹ Elevated plasma IGF-I concentration was found to increase the risk of developing breast cancer among premenopausal women under the age of 50 years participating in the Nurses’ Health Study.⁴⁴⁴

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Breast Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The addition of physiological concentrations of lycopene (0.75 to 3.0 x 10-⁶ M) to cultures of MCF7, MDA-MB-231 and T-47D human mammary cancer cells significantly inhibited both basal and IGF-I-stimulated rates of DNA synthesis and cell proliferation and suppressed IGF-I-stimulated cell cycle progression.^242,445-448 In these systems, lycopene was without effect on the rates of cellular apoptosis.

C. Animal Studies Provide Scientific Support for the Conclusion that Risk of Developing Breast Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
Dietary supplementation with lycopene significantly decreased the incidence of spontaneous mammary gland tumors in SHN virgin mice.⁴⁴⁹ Similarly, lycopene-enriched tomato oleoresin significantly inhibited 7,12-dimethyl-benz[a]anthracene-induced mammary tumors in rats,⁴⁵⁰ although this dietary supplement had no effect on the induction of mammary tumorigenesis in rats treated with N-methylnitrosourea.⁴⁵¹

D. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Breast Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing breast cancer is reduced by consumption of supplemental lycopene or tomatoes and tomato-based foods containing lycopene is supported by the results of six retrospective case-control studies.^{56,67,94,452-454} For example, in a study that compared 289 women with breast cancer to 442 matched women without breast cancer, lycopene intakes greater than 5 mg daily was associated with significantly reduced risk of developing breast cancer, compared to the risk associated with lycopene intakes of less than 2 mg daily (OR: 0.43; 95% CI: 0.28, 0.66; adjusted for age, education, parity, menopausal status, body mass index, alcohol consumption and dietary daily total caloric intake).⁴⁵² The chemopreventive effect of lycopene was not apparent among premenopausal subjects in this study but among postmenopausal women, lycopene intakes greater than 5 mg daily was associated with significantly reduced risk of developing breast cancer, compared to the risk associated with lycopene intakes of less than 2 mg daily (OR: 0.42; 95% CI: 0.26, 0.66; adjusted for age, education, parity, body mass index, alcohol consumption and dietary daily total caloric intake). Lycopene intakes greater than 5 mg daily were associated with significantly reduced risk of developing breast cancer, compared to the risk associated with lycopene intakes of less than 2 mg daily, among women with body mass index of 25 or more (OR: 0.37; 95% CI: 0.21, 0.66; adjusted for age, education, parity, menopausal status, alcohol consumption and dietary daily total caloric intake) as well as among women with body mass index less than 25 (OR: 0.51; 95% CI: 0.33, 0.80; adjusted for age, education, parity, menopausal status, alcohol consumption and dietary daily total caloric intake). Lycopene intakes greater than 5 mg daily were associated with significantly reduced risk of developing breast cancer, compared to the risk associated with lycopene intakes of less than 2 mg daily, among women who consumed alcohol (OR: 0.45; 95% CI: 0.27, 0.75; adjusted for age, education, parity, body mass index, menopausal status and dietary daily total caloric intake) as well as among women who abstained from alcohol consumption (OR: 0.57; 95% CI: 0.34, 0.97; adjusted for age, education, parity, body mass index, menopausal status and dietary daily total caloric intake).

Among another sample of 400 women with breast cancer and 405 cancer-free women, women who consumed more than 4.3 mg of lycopene daily experienced significantly reduced risk of developing breast cancer, compared with the risk among women who consumed less than 2.3 mg of lycopene daily (OR: 0.30; 95% CI: 0.19, 0.47; adjusted for age, area of residence, urban or rural status, family history of breast cancer in a first-degree relative, body mass index, age at menarche, parity, menopausal status and dietary daily total caloric intake), suggesting that simply doubling the daily consumption of lycopene may well significantly reduce an individual woman’s risk of developing breast cancer.⁴⁵³ The chemopreventive effect of lycopene remained statistically significant even after further adjustment of the data for dietary daily intakes of all vegetables, dietary fiber, ß-carotene, alpha-carotene, lutein, zeaxanthin, ß-cryptoxanthin, vitamin C, vitamin E, folate, phytosterols, and glutathione (OR: 0.35; 95% CI: 0.21, 0.59). In addition, women who consumed more than three servings of foods enriched with tomato sauce weekly significantly reduced their risk of developing breast cancer, compared to women who consumed fewer than 1.5 servings of foods enriched with tomato sauce weekly (OR: 0.30; 95% CI: 0.17, 0.52; adjusted for age, residence, urban/rural status, family history of breast cancer in a first-degree relative, body mass index, age at menarche, parity, menopausal status and dietary daily total energy intake), indicating that simply doubling the consumption of such foods may well significantly reduce an individual woman’s risk of developing breast cancer. Furthermore, women who consumed more than 5.5 servings of all tomato-containing foods weekly significantly reduced their risk of developing breast cancer, compared to women who consumed fewer than 2 servings of all tomato-containing foods weekly (OR: 0.30; 95% CI: 0.17, 0.52; adjusted for age, residence, urban/rural status, family history of breast cancer in a first-degree relative, body mass index, age at menarche, parity, menopausal status and dietary daily total energy intake).

Consistent with the findings of these consumption studies,^452,453 a retrospective case-control study of 295 women with breast and 295 matched women without breast cancer observed that the median serum total lycopene concentration of the women with breast cancer was significantly lower than was the median serum total lycopene concentration of the women without breast cancer.⁹⁴ However, in this study, serum total lycopene concentration did not appear to influence the risk of developing breast cancer (adjusted for menopausal status, family history of breast cancer, maternal age at first child’s birth, age at menarche, alcohol consumption, smoking status, body mass index, duration of periods of lactation, education, serum total cholesterol concentration, length of time between most recent meal and blood sampling and use of hormonal replacement therapy). In contrast, another study of 206 women with breast cancer and 211 women without breast cancer concluded that the mean serum total lycopene concentration of women with breast cancer was significantly lower than the mean serum total lycopene concentration of women without breast cancer.⁵⁶ This conclusion was unchanged after separating the women into subgroups according to menopausal status. A similar smaller study of 15 women with breast cancer and 30 women without breast cancer also concluded that the mean plasma total lycopene concentration of women with breast cancer was significantly lower than the mean plasma total lycopene concentration of women without breast cancer.⁶⁷

In a retrospective case-control study of breast adipose tissues donated by 46 women with breast cancer and 63 women without breast cancer, women with breast adipose tissue lycopene contents above the combined median were at significantly reduced risk of developing breast cancer, compared to the risk among women with breast adipose tissue lycopene contents below the combined median (OR: 0.32; 95% CI: 0.11, 0.94; adjusted for age, smoking status and menopausal status).⁴⁵⁴

Contrary to these reports describing the chemopreventive effects of lycopene intake and tomato consumption on risk reduction for breast cancer, the results of one prospective observational study¹⁵³ and an analysis of pooled prospective (largely unpublished) epidemiologic data⁴⁵⁵ do not support the conclusion that the consumption of lycopene and tomatoes reduces the risk of developing breast cancer.⁴⁵⁵

In the prospective study, at the end of 14 years of observation of 83,234 nurses (the Nurses’ Health Study), it was reported that lycopene intake was not associated with the risk of developing breast cancer (adjusted for age, length of time observed in the study, parity, age at first child’s birth, age at menarche, history of breast cancer in mother or a sister, history of benign breast disease in subject, alcohol consumption, body mass index at age 18 years, weight change from age 18 years until the end of the study, height and dietary daily total caloric intake).¹⁵³ However, the highest quintile of daily lycopene intake among these women averaged only 12.7 mg of lycopene intake daily. A pooled analysis of the raw data collected during eight prospective epidemiologic studies reported that the consumption of tomatoes was not related to the risk of developing breast cancer.⁴⁵⁵ However, the basis of effect was the consumption of increments of 100 g of tomatoes daily; very few of the over 350,000 subjects in these studies consumed even one increment of tomatoes daily.

Several retrospective case-control studies have failed to observe the beneficial effect of tomato consumption or lycopene intake on the multivariate-adjusted risk of developing breast cancer.^{55,97,101,112,117-119,234,456-461} However, in these studies, lycopene intake or consumption of tomatoes or tomato-based foods was minimal in a large percentage of study participants or was not reported and therefore their relevance cannot be ascertained.

Two retrospective case-control studies reported that no effect of tomato consumption on the prevalence of breast cancer was observed; however, tomato consumption was not reported.^456,457 Similarly, it was reported that lycopene intake had no effect on the prevalence of breast cancer, although lycopene intakes were not reported.⁴⁵⁸ In another retrospective case-control study of 297 women with breast cancer and 311 women without breast cancer, lycopene intake was reported to have no influence on the risk of developing breast cancer, although 75% of these women consumed less than 7 mg of lycopene daily.⁴⁵⁹ In a similar study that compared 2,569 women with breast cancer to 2,588 women without breast cancer, lycopene intake was reported to have no influence on the risk of developing breast cancer, although 80% of these women consumed less than 8.5 mg of lycopene daily.⁴⁶⁰ In another retrospective case-control study of 1,452 women with breast cancer and 5,239 women without breast cancer, lycopene intake was reported to have had no effect on the risk of developing breast cancer (adjusted for age, screening center, allocation, smoking status, body mass index, hours of vigorous physical activity daily, education, family history of breast cancer, subject history of benign breast disease, age at menarche, parity, menopausal status, oral contraceptive use, use of estrogen replacement therapy, practice of breast self-examination, multivitamin supplement use, alcohol consumption and dietary daily intakes of total calories, dietary fiber, folate and calcium).⁴⁶¹ However, 70% of these subjects consumed less than 13 mg of lycopene daily.

The results of several retrospective case-control studies have not demonstrated that the risk of developing breast cancer was influenced by serum or plasma total lycopene concentration. ^{55,97,101,112,117-119,234} However, the results of one such study suggest that serum total lycopene concentrations in excess of 0.5 x 10-⁶ M (commonly attained with dietary supplementation with lycopene or with increased consumption of tomato-based foods) may reduce the risk of developing breast cancer.¹¹⁹

In a retrospective study of breast adipose tissues donated by 46 women with benign breast disease and 44 women with breast cancer, breast adipose tissue lycopene content was not significantly different in cancerous or benign diseased tissues.¹¹²

E. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Breast Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of six retrospective case-control studies^{56,67,94,452-454} demonstrate a beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing breast cancer. Although the results of /sup> have not confirmed this conclusion, the absence or virtual absence of lycopene from the diets of almost all subjects in these studies rendered the failure of these investigators to observe the beneficial effect of the consumption of lycopene and tomatoes and tomato-based foods on the risk for developing gastric cancer both predictable and irrelevant to an evaluation of the scientific support for the conclusion that the consumption of lycopene and tomatoes and tomato-based foods reduces the risk for developing breast cancer.

The published scientific evidence supports the conclusion that the risk of developing breast cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.

IX. Cervical Cancer

The American Cancer Society forecast 12,200 new cases of cervical cancer and 4,100 deaths from cervical cancer in the US during 2003. Survival for women with preinvasive lesions (CIN) is nearly 100%.¹⁵⁹ The 5-year relative survival for women with invasive cervical cancer detected early is 92%.¹⁵⁹

A. Pathogenesis of Cervical Cancer
Cervical cancer begins as preneoplastic lesions (cervical dysplasia; cervical intraepithelial neoplasia; CIN). In early disease development (CIN grade I), intracellular lesions often undergo spontaneous remission.⁴⁶² CIN grade I may progress to CIN grade II and then to CIN grade III (carcinoma in situ), a recognized immediate precursor of invasive cervical cancer.⁴⁶² Multiple genetic events and human papillomavirus-induced disruptions in cell cycle regulation appear to be involved in the progression of cervical dysplasia to invasive cervical cancer.^462-465

B. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Cervical Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing cervical cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of five retrospective case-control studies.^{72,81,83,106,466} In a study that compared 257 women with cervical dysplasia, a well-recognized precursor to cervical cancer, to 705 women without cervical dysplasia, the consumption of tomatoes more than twice a week significantly reduced the risk of developing cervical dysplasia, compared to the risk associated with never consuming tomatoes (unadjusted OR: 0.63; 95% CI: 0.42, 0.94)⁴⁶⁶ Similarly, in another study that compared 102 women with premalignant cervical intraepithelial neoplasia (CIN) to 102 matched women without CIN, the highest quartile of dietary lycopene intakes significantly reduced the risk of developing CIN, compared to the risk in women consuming the lowest quartile of dietary lycopene intakes (OR: 0.19; 95% CI: 0.04, 0.77; adjusted for dietary daily total caloric intake, smoking status at the time of the study, monthly personal income bracket, number of sexual partners, dietary daily vitamin C intake, frequency of Pap smear testing, use of spermicidal contraceptive agents, history of genital warts and body mass index).¹⁰⁶ In the same groups of women, the highest quartile of serum total lycopene concentrations also was associated with significantly reduced risk of developing CIN, compared to the risk associated with the lowest quartile of serum total lycopene concentrations (OR: 0.26; 95% CI: 0.08, 0.91; adjusted for smoking status at the time of the study, monthly personal income bracket, number of sexual partners, dietary daily vitamin C intake, frequency of Pap smear testing, use of spermicidal contraceptive agents, history of genital warts and body mass index).

In a study of 27 women with cervical cancer, 33 women with CIN and 27 women without cervical lesions, the mean plasma total lycopene concentration was significantly lower in the women with cervical cancer than in the women with either CIN or no lesions.⁸³ However, there was no difference in the mean plasma total lycopene concentrations of women with CIN and women without cervical lesions. In another study of 15 women with cervical cancer, 56 women with grade I CIN, 40 women with grade II CIN, 29 women with grade III CIN and 95 women without cervical lesions, plasma total lycopene concentrations were significantly inversely correlated with the severity of cervical disease.⁸¹ In a study of 156 women with cervical dysplasia and 156 matched dysplasia-free women, the mean serum total lycopene concentration of women with cervical dysplasia was significantly lower than the serum total lycopene concentration of women without cervical dysplasia.⁷² However, among these women, the multivariate-adjusted risk of developing cervical dysplasia was not associated with serum total lycopene concentration.

In contrast, the reported findings of eight retrospective case-control epidemiologic studies have not demonstrated significant relationships between tomatoes or lycopene and cervical disease.^{50,61,87,88,95,96,120,467} For example, among a subset of 201 women participating in the prospective Young Women’s Health Study, lycopene intake was not associated with the prevalence of human papillomavirus infection (a predominant cause of invasive cervical cancer^462-465).96 Similarly, when 32 women with CIN were compared to 113 women free of cervical disease, estimated lycopene intake was not significantly associated with multivariate-adjusted disease risk, although the unadjusted risk was significantly lower for women who consumed more than 1 mg of lycopene (less than the amount of lycopene in a level teaspoon of catsup⁵) daily.⁶¹ In a case-control study of 513 women with cervical cancer and 490 women without cervical disease, the mean daily consumption of tomatoes was not different between the two groups of women.⁴⁶⁷

Seven retrospective studies have not observed any relationship between circulating concentrations of lycopene and cervical disease.^{50,61,87,88,95,96,120} For example, among a subset of 201 women participating in the prospective Young Women’s Health Study, neither plasma trans-lycopene or cis-lycopene concentrations were associated with the prevalence of human papillomavirus infection.⁹⁶ Among 32 women with CIN and 113 women free of cervical disease, serum total lycopene concentration did not affect either unadjusted or multivariate-adjusted risk of developing CIN, even though the median serum total lycopene concentration among women with CIN was only 65% that of women without CIN.⁶¹ Similarly, among 81 women with CIN and 160 without, serum total lycopene concentration did not affect the multivariate-adjusted risk of developing CIN.⁹⁵ In four other studies, the mean serum total lycopene concentrations of women with or without cervical cancer were not different^87,88,120 and did not affect the prevalence of cervical cancer.^50,87,120

C. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Cervical Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Food Products
The results of five retrospective case-control studies^{72,81,83,106,466} demonstrate a beneficial effect of the consumption of lycopene and tomatoes and tomato-based food products on the risk for developing cervical cancer. In contrast, the findings of eight retrospective case-control epidemiologic studies have not demonstrated significant relationships between tomatoes or lycopene and cervical disease; ^{50,61,87,88,95,96,120,467} these reports likely reflect confounding by related factors, very low lycopene intakes by study participants or heterogeneity of effect (this can occur when a subpopulation of nonresponders dilutes the overall effect of a chemopreventive agent or food and obscures the association in responders), resulting in underestimation of the effects of the nutrient or food of interest on chemoprevention.²³⁶

The published scientific evidence supports the conclusion that the risk of developing cervical cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
X. Endometrial Cancer

The American Cancer Society forecast 40,100 new cases of endometrial cancer and 6,800 deaths associated with endometrial cancer in the US during 2003.¹⁶⁰ The survivability of endometrial cancer is inversely proportional to its severity when first diagnosed, with the 5-year relative survival rate ranging from 96% for localized cancer to 26% for metastatic disease.¹⁶⁰

A. Pathogenesis of Endometrial Cancer
Endometrial cancer results from the progression of hyperestrogenic endometrial hyperproliferation, perhaps secondary to defective DNA mismatch repair systems.⁴⁶⁸ The loss of expression of one of the DNA mismatch repair enzymes, usually hMLH1 or hMSH2, can result in microsatellite instability and produce predisposition to endometrial cancer.⁴⁶⁹

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Endometrial Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The addition of physiological concentrations of lycopene (1 to 2 x 10-⁶ M ) to cultures of Ishikawa and ECC-1 human endometrial cancer cells significantly inhibited both basal and IGF-I-stimulated rates of DNA synthesis and cell proliferation.^242,446

C. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Endometrial Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing endometrial cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of two retrospective studies of cohorts of women with and without endometrial cancer.^470,471 Among 221 women with endometrial cancer and 3,697 women with healthy endometrial tissues, the daily consumption of at least 14 mg of lycopene significantly reduced the risk of developing endometrial cancer, compared to the risk in women consuming less than 4.5 mg of lycopene daily (RR: 0.63; 95% CI: 0.43, 0.94; adjusted for age, body mass index, smoking status, oral contraceptive use, hormone replacement therapy use, education, parity, age at menarche and dietary daily total caloric intake). The findings of a retrospective case-control study of 232 women with endometrial cancer and 639 women without endometrial cancer suggest that the routine daily intake of more than 7.3 mg of lycopene significantly reduced the risk of developing endometrial cancer, compared to the risk in women with routine daily lycopene intakes less than 3.5 mg (trend for increasing lycopene intake to reduce risk of endometrial cancer: significantly different from no trend, p = 0.01; OR, daily intake of lycopene greater than 7.3 mg vs. daily intake of lycopene less than 4.5 mg: 0.6; 95% CI: 0.4, 1.0; adjusted for age, education, body mass index, diabetes, hypertension, number of pack-years of cigarette smoking, age at menarche, parity, oral contraceptive use, menopausal status, postmenopausal estrogenuse and dietary daily total caloric intake).⁴⁷¹

The published scientific evidence supports the conclusion that the risk of developing endometrial cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
XI. Ovarian Cancer

The American Cancer Society forecast 25,400 new cases of ovarian cancer and 14,300 deaths associated with ovarian cancer in the US during 2003.¹⁵⁹ The survivability of ovarian cancer is inversely proportional to its severity when first diagnosed, with the 5-year relative survival rate ranging from 95% for localized cancer to 31% for metastatic disease.¹⁵⁹

A. Pathogenesis of Ovarian Cancer
Ovarian cancer usually begins in a single layer of the epithelial that line the surface of the ovary that may have lost the regulation of its normal post-ovulatatory proliferative phase.⁴⁷² Loss of cell cycle regulation in the ovarian epithelium results from multiple genetic alterations in proto-oncogenes as well as mutation of the p53 tumor suppressor gene.⁴⁷²

B. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Ovarian Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing ovarian cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of a retrospective case-control study.⁴⁷³Among 549 women with ovarian cancer and 516 women with healthy ovaries, the daily consumption of at least 15 mg of lycopene significantly reduced the risk of developing ovarian cancer, compared to the risk in women consuming less than 5 mg of lycopene daily (OR: 0.53; 95% CI: 0.35, 0.82; adjusted for age, body mass index, oral contraceptive use, family history of breast, ovarian or prostate cancer in a first-degree relative, tubal ligation, education, parity, marital status and dietary daily total caloric intake). Although this relationship was not statistically significant among only the postmenopausal members of this study, it was even stronger among the study’s premenopausal participants (OR: 0.37; 95% CI: 0.20, 0.66; adjusted for age, body mass index, oral contraceptive use, family history of breast, ovarian or prostate cancer in a first-degree relative, tubal ligation, education, parity, marital status and dietary daily total caloric intake). In addition, the consumption of tomato sauce more than once a week significantly reduced the risk of developing ovarian cancer, compared to the risk in women consuming tomato sauce less than once a month (OR: 0.60; 95% CI: 0.37, 0.99; adjusted for age, body mass index, oral contraceptive use, family history of breast, ovarian or prostate cancer in a first-degree relative, tubal ligation, education, parity, marital status and dietary daily total caloric intake). Interestingly, the risk of developing ovarian cancer did not appear to be affected by the rate of consumption of either raw tomatoes or tomato juice, suggesting that heating or cooking the organic matrix of plant sources of lycopene substantially increases the bioavailability and chemopreventive effectiveness of naturally-occurring lycopene in the ovary. Circulating lycopene concentrations were not reported in this study; in a much smaller case-control study, serum total lycopene concentrations were reportedly not predictive of risk for ovarian cancer in 35 women with ovarian cancer and 67 women without ovarian cancer.⁵²

Although not abundant, the published scientific evidence supports the conclusion that the risk of developing ovarian cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
XII. Pancreatic Cancer

It was expected that 30,700 new cases of pancreatic cancer would be diagnosed in the US in 2003 and that 30,000 deaths related to pancreatic cancer would occur.159 For all stages of pancreatic cancer combined, the 1-year relative survival rate is 21% and the 5-year relative survival rate is 4%.¹⁵⁹ When the initial diagnosis is localized disease, the 5-year relative survival rate rises to 17%.¹⁵⁹ Mutations in cellular proto-oncogenes and tumor suppressor genes are implicated in the pathogenesis of pancreatic cancer.⁴⁷⁴

A. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Pancreatic Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing pancreatic cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based products containing lycopene is supported by the results of three retrospective studies.^{116,233,475,476} Among 164 men and women with pancreatic cancer and 480 men and women without evidence of pancreatic disease, the daily consumption of the highest quintile of raw tomatoes significantly reduced the risk of developing pancreatic cancer, compared to the risk in subjects consuming the lowest quintile of raw tomatoes (OR: 0.23; significantly different from OR = 1.0, p < 0.05; adjusted for age, sex, smoking status and dietary daily total caloric intake).⁴⁷⁵In another study of 52 men and 52 women with pancreatic cancer and 142 cancer-free men and 111 cancer-free women, mean tomato consumption by subjects with pancreatic cancer was significantly less than that by cancer-free subjects.⁴⁷⁶

Consistent with the chemopreventive effectiveness of tomato consumption, mean serum total lycopene concentration was significantly higher among 18 men and 26 women without cancer than among 9 men and 13 women with pancreatic cancer.^116,233 In addition, subjects with the serum total lycopene concentrations greater than 1.01 x 10-⁶ M experienced significantly less risk of developing pancreatic cancer than did subjects with serum total lycopene concentrations less than 0.66 x 10-⁶ M (unadjusted OR: 0.19; significantly different from OR = 1.0, p < 0.05). Furthermore, subjects with the serum total lycopene concentrations greater than 0.66 x 10-⁶ M experienced significantly less risk of developing pancreatic cancer than did subjects with serum total lycopene concentrations less than 0.66 x 10-⁶ M (unadjusted OR: 0.16; 95% CI: 0.04, 0.57).

In contrast to these reports, the results of a 6-year prospective study of 34,556 Seventh-Day Adventists suggested that tomato consumption had no effect on the age and sex-adjusted incidence of pancreatic cancer.⁴⁷⁷

Although the results of the only published prospective study of the relationship between tomato intake and pancreatic cancer did not observe a relationship,⁴⁷⁷ all of the published retrospective epidemiologic data consistently indicate the presence of a chemoprotective relationship.^{116,233,475,476}

The published scientific evidence supports the conclusion that the risk of developing pancreatic cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.
XIII. Amounts of Supplemental Dietary Lycopene and Tomatoes and Tomato-Based Foods that Are Effective in Reducing the Risks of Developing Cancers of the Prostate, Lung, Stomach, Colon, Rectum, Breast, Cervix, Endometrium, Ovaries and Pancreas

The reliable and credible scientific literature indicates that daily dietary supplementation with lycopene or the daily consumption of tomatoes and tomato-based foods to ensure a daily intake of at least 15 mg of lycopene will be effective in reducing the risks of prostate, lung, gastric, colorectal, breast, cervical, endometrial, ovarian and pancreatic cancer.
XIV. Safety of Dietary Supplementation with Lycopene in Amounts that Are Effective in Reducing the Risks of Developing Cancers of the Prostate, Lung, Stomach, Colon, Rectum, Breast, Cervix, Endometrium, Ovaries and Pancreas

There have been no reports of adverse reactions to supplemental lycopene reported in the literature.

No signs of toxicity have been observed in rats fed supplemental lycopene in amounts up to 500 mg of lycopene per kg of body weight daily for 14 weeks or up to 1000 mg of lycopene per kg of body weight daily for 4 weeks.⁴⁷⁸ No teratogenic effects occurred in rats in a 2-generation study of animals fed 1000 ppm of lycopene or 1000 mg of lycopene per kg of body weight.⁴⁷⁸ The oral LD50 in the mouse is at least 3,000 mg per kg body weight; the oral LD50 in the rat is at least 4,000 mg per kg body weight.⁴⁷⁹ Supplemental lycopene is not hepatotoxic, genotoxic or mutagenic.^478,479

The concurrent ingestion of 60 mg of ß-carotene and 60 mg of lycopene had no effect on the bioavailability of ß-carotene but significantly increased the apparent absorption of lycopene.¹²⁷ Dietary supplementation with 15 mg of synthetic lycopene (LycoVit 10%, BASF, Ludwigshafen, Germany) had no effect on serum concentrations of a-carotene, ß-carotene, ß-cryptoxanthin, lutein or zeaxanthin.³⁴

Synthetic lycopene (LycoVit 10%, BASF, Ludwigshafen, Germany) has been found to be stable at room temperature (less than 5% loss in 12 months) and at 60o C (less than 5% loss in 40 days).³³ Such excellent stability may result from the significantly greater resistance of synthetic lycopene to oxidative degradation.³³

Adults treated with either cholestyramine or probucol have exhibited significant 30% decreases in serum total lycopene concentrations, suggesting that individuals receiving those medications require restorative dietary supplementation with lycopene.⁴⁸⁰

The concurrent consumption of plant stanol esters has significantly decreased plasma total lycopene concentrations¹³² or has had no effect on plasma total lycopene concentrations.¹⁴⁸ The consumption of food products containing olestra significantly reduced serum total lycopene concentrations.¹²⁸
XV. Safety of the Consumption of Tomatoes and Tomato-Based Foods in Amounts that Are Effective in Reducing the Risks of Developing Cancers of the Prostate, Lung, Stomach, Colon, Rectum, Breast, Cervix, Endometrium, Ovaries and Pancreas

There have been no cases of tomato overdose reported in the literature.

Conclusions

• The prevention of cancer is a national priority.

• Every means of preventing cancer deserves widespread dissemination.

• Lycopene absorbed from tomatoes, tomato-based foods and dietary supplements containing lycopene can significantly increase circulating total lycopene concentrations.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing certain kinds of cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing prostate cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing lung cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing gastric cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing colorectal cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing breast cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing cervical cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing endometrial cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing ovarian cancer.

• Individuals with the greatest circulating concentrations of total lycopene are at the lowest risk of developing pancreatic cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing prostate cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing lung cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing gastric cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing colorectal cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing breast cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing cervical cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing endometrial cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing ovarian cancer.

• Individuals with the greatest daily intakes of lycopene are at the lowest risk of developing pancreatic cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing prostate cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing lung cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing gastric cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing colorectal cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing breast cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing cervical cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing endometrial cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing ovarian cancer.

• Individuals consuming the greatest amounts of tomatoes and tomato-based foods on a daily basis are at the lowest risk of developing pancreatic cancer.

• Supplemental lycopene is safe.

• Tomatoes are safe.

• Tomato-based foods containing lycopene are safe.

• Routine ingestion of sufficient amounts of tomatoes, tomato-based foods and supplemental lycopene to reduce the risks of developing cancer is safe.
Summary Conclusions

In conclusion, I find that there is significant scientific agreement in support of the following health claims:

• Lycopene may reduce the risk of cancer.
• Lycopene may reduce the risk of prostate cancer.
• Lycopene may reduce the risk of lung cancer.
• Lycopene may reduce the risk of gastric cancer.
• Lycopene may reduce the risk of colorectal cancer.
• Lycopene may reduce the risk of breast cancer.
• Lycopene may reduce the risk of cervical cancer.
• Lycopene may reduce the risk of endometrial cancer.
• Lycopene may reduce the risk of ovarian cancer.
• Lycopene may reduce the risk of pancreatic cancer.
• Tomatoes may reduce the risk of cancer.
• Tomatoes may reduce the risk of prostate cancer.
• Tomatoes may reduce the risk of lung cancer.
• Tomatoes may reduce the risk of gastric cancer.
• Tomatoes may reduce the risk of colorectal cancer.
• Tomatoes may reduce the risk of breast cancer.
• Tomatoes may reduce the risk of cervical cancer.
• Tomatoes may reduce the risk of endometrial cancer.
• Tomatoes may reduce the risk of ovarian cancer.
• Tomatoes may reduce the risk of pancreatic cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cancer.
• Lycopene-containing tomato-based foods may reduce the risk of prostate cancer.
• Lycopene-containing tomato-based foods may reduce the risk of lung cancer.
• Lycopene-containing tomato-based foods may reduce the risk of gastric cancer.
• Lycopene-containing tomato-based foods may reduce the risk of colorectal cancer.
• Lycopene-containing tomato-based foods may reduce the risk of breast cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cervical cancer.
• Lycopene-containing tomato-based foods may reduce the risk of endometrial cancer.
• Lycopene-containing tomato-based foods may reduce the risk of ovarian cancer.
• Lycopene-containing tomato-based foods may reduce the risk of pancreatic cancer.

References Cited

 

[original signed and dated]
Michael J. Glade, Ph.D., F.A.C.N., C.N.S.