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Article

Plasma Carotenoids Are Biomarkers of Long-Term High Vegetable Intake in Women with Breast Cancer^{1 ,2}

Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA 92093-0901

³To whom correspondence and reprint requests should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We investigated predictors of change in plasma carotenoids from baseline to 3 y and examined plasma carotenoid concentrations at 1 and 3 y in response to a high vegetable diet. Participants were 56 women diagnosed with breast cancer and enrolled in a randomized feasibility study for a trial examining the effect of a diet high in vegetables and fruits on the risk of breast cancer recurrence. Independent t test analysis revealed that the intervention group had significantly higher vegetable and fruit servings and fiber at 12 mo and significantly higher vegetable servings at 36 mo compared with the control group (P < 0.05). Energy intake from fat was significantly lower in the intervention group at 12 and 36 mo. The intervention group had significantly higher consumption of ß-carotene, -carotene, lutein and ß-cryptoxanthin at 12 mo (P < 0.05). ß-Carotene, -carotene and lutein intakes also were significantly higher at 36 mo (P < 0.05). At 36 mo, the intervention group had significantly higher plasma concentrations of -carotene and ß-carotene compared with the control group. Repeated-measures ANOVA revealed that the intervention group had significantly increased (P < 0.05 with Bonferroni correction) plasma ß-carotene, -carotene, lutein and lycopene concentrations at 12 and 36 mo compared with baseline. Baseline carotenoid concentrations were significantly inversely predictive (P < 0.05) of plasma carotenoid change. In addition, change in body mass index (BMI) and plasma cholesterol concentrations were predictive of plasma carotenoid change from baseline to 3 y. Results of this study demonstrate that change in plasma carotenoid concentrations is associated with change in BMI, change in plasma cholesterol and baseline carotenoid concentrations. Plasma carotenoid response can be an indicator of long-term high vegetable intake for women at risk of breast cancer recurrence.

KEY WORDS: • carotenoids • biomarkers • humans • breast cancer

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Ecological comparisons among countries demonstrate an association between several dietary variables and the risk of breast cancer (Armstrong and Doll 1975 ). Results from laboratory studies suggest that phytochemicals and micronutrients such as carotenoids may exhibit anticarcinogenic activities that may reduce the risk of cancer (Adlercreutz et al. 1992 , Steinmetz and Potter 1996 ). Dietary and plasma carotenoids also reflect consumption of total fruits and vegetables and thus are reasonable biomarkers of dietary intakes of these foods (Campbell et al. 1994 , Le Marchand et al. 1994 , Micozzi et al. 1992 ). In feeding studies, an increase in consumption of fruits and vegetables has been correlated with an increase in circulating plasma carotenoid concentrations (Martini et al. 1995 , Yeum et al. 1995 ); however, a wide range of interindividual variability in responsiveness has been observed.

Factors influencing bioavailability of carotenoids may affect plasma carotenoid response. Dietary components such as fat and the matrix of the food consumed may affect the absorption of carotenoids (Olson 1994 , Parker 1997 , Rock 1997 ) and plasma response. Fiber, another component of vegetables and fruits, may interfere with micelle formation and thereby reduce absorption of carotenoids, potentially influencing plasma carotenoid response (Rock and Swendseid 1992 ). The transport of circulating carotenoids in plasma by cholesterol-rich lipoproteins suggests that plasma lipids also may affect carotenoid concentrations (Clevidence and Bieri 1993 ).

Rock et al. (1992) demonstrated that a reduction in dietary consumption of vegetables and fruits is followed by a rapid decrease in plasma carotenoid concentrations. Monitoring plasma carotenoid concentrations may be useful in dietary intervention trials examining the influence of vegetable and fruit consumption on disease outcomes. Plasma carotenoids can function as biomarkers of vegetable and fruit intake. The first aim of this study was to investigate plasma carotenoid concentrations, dietary carotenoid consumption, and vegetable and fruit intakes at baseline, 12 and 36 mo postrandomization in postsurgically resected breast cancer patients participating in a randomized feasibility study for a trial examining the effect of a high vegetable and fruit diet on the recurrence of breast cancer. An additional aim was to examine predictors of change in plasma carotenoid concentrations from baseline to 36 mo postrandomization.

	MATERIALS AND METHODS

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Subjects.

This study examined the feasibility of a randomized diet intervention trial to reduce the risk of breast cancer recurrence in women who had been diagnosed with primary breast cancer within the previous 4 y. Between May 1993 and October 1994, 93 subjects were recruited from cancer registry lists and from community-based efforts. Inclusion criteria were as follows: 1) 18–70 y of age at time of diagnosis; 2) a history of primary operable invasive breast carcinoma categorized as Stage I, Stage II or Stage IIIA within the previous 4 y; 3) treatment with total mastectomy and axillary dissection, or breast-sparing surgical removal of cancer with clear macroscopic margins and axillary dissection, followed by adjuvant breast radiation; 4) completion of any prescribed adjuvant chemotherapy; 5) no evidence of recurrent disease or new breast cancer since completion of initial local treatment; 6) in good general health; 7) accessible geographically and by telephone for participation and follow-up; and 8) able to communicate dietary data via 24-h food recall. Exclusion criteria were the following: 1) current enrollment in another dietary clinical trial; 2) diagnosed with a comorbidity requiring a specific diet or taking a medication that contraindicates a high fiber diet; 3) receiving estrogen replacement therapy; 4) other primary or recurrent invasive cancer within the last 10 y; and 5) unable to commit to the intervention schedule.

Within the 1st y of the feasibility study, a total of 10 women dropped out (4 from the intervention group; 6 from the control group). Seven women experienced a recurrence of breast cancer before the 12-mo data collection point. An additional five did not complete their 12-mo assessments, although they remained in the study. Initially, the pilot study was scheduled to end within 1 y of randomization; however, consent for continued participation was requested from the women after the 1st y so that they could participate in the remaining 7 y of the clinical trial. Seventy women elected to continue at the end of the 1st y. Of these 70 women, three experienced breast cancer recurrence before 36 mo; nine did not complete dietary recalls at 36 mo, but were still in the study; one did not have dietary data at all three time points; and one died before 36 mo. For the clinic visits necessary for blood collection, eight did not participate (but were still in the study), and five did not have data available at all three time points. In this study, we include all women for whom blood samples (n = 53) and dietary data (n = 56) were available at baseline and at the 12- and 36-mo follow-up periods.

Dietary supplements were not a component of this trial, and participants were particularly discouraged from using high dose micronutrient formulations that could interfere with the interpretation of the diet intervention results. However, ~20 women used ß-carotene supplementation at 1 y and 27 at 3 y postrandomization. Quantification of ß-carotene intake includes that obtained from ß-carotene supplements for those participants who used supplements containing the micronutrient.

The study intervention involved an intensive telephone counseling regimen aimed at assisting participants to reach the following daily dietary goals: five vegetable servings, 16 oz of fresh vegetable juice, three fruit servings, 15% energy from fat, and 30 g of fiber. The vegetable juice was included as a way to increase micronutrient intake from food sources without the side effects of consuming too much fiber. A serving of fruit or vegetable was defined as 0.5 cup of sliced or chopped raw or cooked vegetables or fruit, 0.25 cup of dried fruit, one medium piece of fresh fruit, 1 cup of raw green leafy vegetables, or equivalent amounts provided in multi-ingredient foods. Three ounces of vegetable juice were considered equivalent to one serving of vegetables on the basis of an evaluation of the micronutrient content (described below), thus vegetable juice could replace vegetable servings. Therefore, quantified vegetable servings reported below are a total of vegetable and vegetable juice consumption. The control group was provided the National Cancer Institute (NCI) guidelines to consume five fruits and vegetable servings a day and general public health dietary guidelines (USDA 1990 ). An analysis of dietary change from baseline to 12 mo has been published previously (Pierce et al. 1997 ).

Participants provided fasting blood samples and other relevant information at scheduled clinic visits. Weight and height were measured at enrollment, 12 and 36 mo, and body mass index [BMI; weight (kg)/height (m²)]) was calculated. Follow-up clinic visits and dietary assessments were scheduled year-round and coincided with the participant’s randomization date. Procedures for this study were approved by the Human Subjects Committee of the University of California, San Diego, School of Medicine.

Dietary assessment.

Dietary intake was assessed by trained telephone interviewers, who collected four 24-h dietary recalls on randomly selected days stratified for weekend vs. weekdays over a 2-wk period. Dietary data were collected and analyzed with the Nutrition Data System software (University of Minnesota, Minneapolis, MN); nutrient analysis was conducted with the University of Minnesota Database (Version 2.91, 1996, University of Minnesota,Minneapolis, MN). Dietary intakes of carotenoids were computed using the USDA-NCI carotenoid food composition database, which contains values for - and ß-carotene, ß-cryptoxanthin, lycopene and lutein plus zeaxanthin in >2240 fruits and vegetables and multi-ingredient foods containing fruits and vegetables (Chug-Ahuja et al. 1993 ).

Plasma measurements.

Fasting blood samples were collected by venipuncture at baseline, 12 and 36 mo postrandomization. Samples were protected from light throughout processing and handling. Samples collected to derive plasma were obtained using EDTA-treated tubes, and separation of plasma was accomplished with centrifugation at 2300 x g at 4°C for 10 min. Samples were stored at -70°C until lipid extraction and HPLC analysis. We were required to change laboratories at the end of the 1st and 2nd y of the feasibility study. Therefore, plasma carotenoids were separated and quantified using the HPLC methods of Nierenberg and Nann (1992) , Peng et al. (1994) and Gamboa-Pinto et al. (1998) . Accuracy was assessed by periodic analysis of the National Institute of Standards and Technology (NIST) Reference Material SRM 986: Fat-Soluble Vitamins; the laboratories that provided the HPLC analyses for this study participated in the NIST Micronutrients Measurement Quality Assurance Program. Total plasma cholesterol was determined with the Kodak Ektachem Analyzer system (Johnson & Johnson, Rochester, NY) (Shirey 1985 ).

Statistical analysis.

Log transformation of plasma carotenoid concentrations and carotenoid intake data was conducted to convert the data from a highly skewed distribution to an approximated Gaussian distribution. Plasma carotenoid concentrations were also adjusted for plasma cholesterol concentrations before analysis of these data. To account for variations in energy intake that could influence micronutrient consumption, dietary carotenoid consumption, before analysis, was energy adjusted by dividing the micronutrient consumption by the participant’s energy intake (the nutrient density method). Baseline BMI, carotenoid consumption, age, stage and ethnicity of these subjects (with data at all three time points) were compared with subjects not included in the analysis using an independent t test.

An independent samples t test was conducted to compare differences for dietary carotenoid consumption, plasma carotenoid concentrations, daily dietary intakes of vegetable and fruit servings, fiber, and percentage of energy from fat between the intervention and control groups at baseline, 12 and 36 mo. To reduce the variance due to the small sample size, repeated-measures ANOVA was also used to examine the differences within the intervention and control groups in plasma carotenoid concentrations at baseline, 12 and 36 mo. After observing an overall significant F-ratio for time in the repeated-measures ANOVA, we evaluated contrasts among the baseline, 12- and 36-mo values. Because three comparisons were made (baseline vs. 12 mo, baseline vs. 36 mo, and 12 mo vs. 36 mo), the Bonferroni method was used to adjust the nominal level of significance for these multiple comparisons (0.05/3 = 0.017). Pearson correlation coefficient analysis was conducted to examine associations between fruit and vegetable intakes and plasma carotenoid concentrations.

We used stepwise regression analysis to examine predictors of change in plasma -carotene, ß-carotene, lutein, lycopene and ß-cryptoxanthin concentrations from baseline to 36 mo for the entire group. This increased power and permitted observation of any associations. The independent variables used in the models for predicting change were as follows: change in dietary carotenoid intake, change in BMI, age, change in plasma cholesterol concentration, baseline plasma carotenoid concentrations and change in percentage of energy from fat. Associations between the independent variables and the outcome variable (change in plasma carotenoid concentration) produced from the stepwise regression analysis are reported. All statistical analysis was performed using the Statistical Analysis System (Version 6.12, 1998, SAS Institute,Cary,NC).

	RESULTS

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Of the women for whom dietary data were available at all three time points (n = 56), 52 (93%) were white, 3 (5%) were Hispanic, and 1 (2%) was Asian-American. The mean age was 57.6 ± 1.3 y (mean ± SEM) and mean BMI was 26.5 ± 0.6 kg/m². Breast carcinoma stage at diagnosis [based on the American Joint Commission on Cancer System (Beahrs et al. 1988 )] was 26 (46%) stage I, 27 (48%) stage II and 3 (5%) stage IIIA. Age, BMI, stage at diagnosis and ethnicity were not significantly different between the intervention and control groups. There were no significant differences among participants with data at all three time points and participants not included in this analysis with regard to baseline BMI, age, stage, ethnicity and carotenoid consumption, with the exception of lutein (the nonparticipants had significantly higher consumption of lutein compared with participants in this analysis).

Table 1 summarizes data on vegetable (including vegetable juice), fruit, fat and fiber intakes at baseline, 12 and 36 mo.

Independent t test analysis revealed that vegetable, fruit and fiber intakes were significantly higher at 12 mo for the intervention compared with the control group (P < 0.05). Also, vegetable intake was significantly higher at 36 mo for the intervention group. In addition, the percentage of energy from fat was significantly lower at 12 and 36 mo for the intervention group (P < 0.05).

Predictors of change from baseline to 36 mo for plasma ß-carotene, -carotene, lutein, lycopene and ß-cryptoxanthin concentrations for the entire study sample were examined. The significance level used for variables to enter the stepwise regression models was P < 0.15. The stepwise regression model for change in plasma ß-carotene revealed a significant inverse correlation with baseline carotenoid concentrations (P < 0.05) and a positive association with age. Similarly, change in plasma -carotene was significantly inversely related to baseline -carotene concentrations (P < 0.05). Change in plasma lutein concentration was also significantly inversely related to baseline concentration (P < 0.05), marginally inversely related to change in BMI (P < 0.09) and positively correlated with change in plasma cholesterol concentration (P < 0.09). Change in circulating lycopene concentration was independently inversely associated with baseline lycopene concentration (P < 0.05) and inversely marginally significantly associated with change in BMI (P < 0.09). Finally, change in plasma ß-cryptoxanthin concentration had an inverse significant association with baseline ß-cryptoxanthin concentration (P < 0.05), a marginally positive association with change in plasma cholesterol concentration (P < 0.09), a marginal inverse association with change in BMI (P < 0.09) and a negative relationship with age. Change in dietary micronutrient intake and change in the percentage of energy from fat did not enter the models at P < 0.15 and were not significantly associated with changes in the plasma carotenoid concentrations from baseline to 36 mo.

	DISCUSSION

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We found that at 1 and 3 y postrandomization, the intervention group had a significantly higher intake of vegetable and lower intake of fat compared with the control group. Fruit and fiber intakes were also significantly higher at 1 y. The intervention group had significantly higher intakes of ß-carotene, -carotene and lutein at 3 y postrandomization and significantly higher consumption of all carotenoids, except lycopene, at 1 y postrandomization, compared with the control group. When comparing circulating carotenoids between groups, at 36 mo, plasma - and ß-carotene concentrations remained significantly higher for the intervention group. Also, all plasma carotenoid concentrations, except for ß-cryptoxanthin, remained significantly higher compared with baseline in the intervention group, whereas the control group showed no significant changes from baseline. This suggests that, even if some plasma concentrations were not significantly different between groups, plasma carotenoid concentrations in the intervention group had significantly increased at the time of the 3-y follow-up, whereas the control group remained close to baseline levels. Analysis of plasma carotenoid change revealed that change in BMI, change in plasma cholesterol concentration and baseline plasma carotenoid concentrations are independent predictors of change in plasma carotenoid concentrations from baseline to 3 y. Overall, these results indicate that making long-term dietary changes via increasing vegetable and fruit intake can correspond with long-term changes in plasma carotenoid concentrations.

Our findings of predictors of change in plasma carotenoids are consistent with several previous studies. After adjusting for other variables in the model, Ascherio et al. (1992) found an inverse association between BMI and plasma concentrations of ß-carotene, -carotene, lycopene, lutein and zeaxanthin in a cross-sectional study; other studies have observed this inverse relationship with ß-carotene (Nierenberg et al. 1989 , Rock and Swendseid 1993 , Rock et al. 1997 , Stryker et al. 1988 ), -carotene and ß-cryptoxanthin (Rock et al. 1997 ). In addition, we found that change in plasma cholesterol concentration was positively associated with changes in plasma carotenoids (particularly ß-cryptoxanthin and lutein plasma concentrations), an association that has been observed in cross-sectional examinations (Ascherio et al. 1992 , Brady et al. 1996 , Clevidence and Bieri 1993 ). The relationship between change in plasma carotenoids with plasma cholesterol concentrations may be explained by the transport of carotenoids by cholesterol-rich lipoproteins in the plasma. The inverse association between age and ß-carotene change observed in this study has also been noted in some cross-sectional analyses (Brady et al. 1996 , Nierenberg et al. 1989 ), but not in others (Ascherio et al. 1992 , Rock et al. 1997 ).

A earlier study conducted by Nierenberg et al. (1991) reported factors that influenced change in plasma ß-carotene concentrations from baseline to 1 y after ß-carotene supplementation. In that study, change in plasma ß-carotene concentration was significantly related to baseline ß-carotene concentration, but in the opposite direction. Results from other studies, similar to the present findings, indicated an inverse relationship between change in plasma ß-carotene concentration and baseline concentrations in men (Wahlqvist et al. 1994 ) and in women (Rock et al. 1997 ). In the study of Nierenberg et al. (1991) change in plasma ß-carotene concentration was inversely related to change in BMI (in females), which parallels results of this study; however, this relationship was observed only for changes in plasma lutein, lycopene and ß-cryptoxanthin concentrations, and not for changes in plasma ß-carotene concentration. The models predicting change in our study explained 21–54% of the variation, revealing that further investigations must be conducted to find other factors that may further contribute to change in plasma carotenoid concentrations.

In the study conducted by Rock et al. (1997) , data were obtained from a cohort similar to that of the present investigation, but at different time points. We found some comparable results when analyzing predictors of change from baseline to 3 y. The present results, in agreement with the findings of Rock et al. (1997) , revealed an inverse association with baseline plasma concentrations and change from baseline to 36 mo for plasma ß-carotene, lutein, lycopene and ß-cryptoxanthin. We also found this association for change in plasma -carotene concentration. In this study, age was not related to plasma carotenoid change (except for ß-carotene), but was inversely associated with change in plasma ß-carotene, -carotene, lutein and lycopene in the earlier report. Although these results coincide to some extent, differences in sample size, the addition of 36-mo data and differences in predictors used in the models may account for some discrepant findings when examining change in plasma carotenoid concentrations.

Changes in intakes of specific carotenoids were not correlated with changes in plasma carotenoids in this study. Individual differences in food content of carotenoids, including seasonal variation, and differences in bioavailability from various food sources may constrain the ability to find correlations between change in carotenoid intakes and serum carotenoid concentrations (Chug-Ahuja et al. 1993 , Mangels et al. 1993 ).

We demonstrated that a twofold increase in vegetable servings corresponded to nearly a twofold increase in plasma ß-carotene concentration and an almost fourfold increase in plasma -carotene concentration at 3 y postrandomization in the intervention group. We also found significant correlation between total fruit and vegetable servings and both of these plasma carotenoids. Several cross-sectional studies have reported associations between plasma carotenoid concentrations and vegetable and fruit servings (Campbell et al. 1994 , Polsinelli et al. 1998 ); however, only one randomized trial has previously reported an association between plasma carotenoid response to a high vegetable and fruit diet at 3 mo (Le Marchand et al. 1994 ).

From baseline to the end of y 1, ~25% of the women were no longer participating in the study; from y 1 to 3, another 20% were not included in the analysis (either due to recurrence or lack of participation). Therefore, the decrease in sample size may diminish power and ability to detect differences between the two groups. However, the rates of nonparticipation are nondifferential in both the intervention and control groups, thus eliminating bias due to differential loss to follow-up that could have altered the findings of this study.

In summary, these results suggest that carotenoids can be used as biomarkers of a high vegetable diet in women at risk of breast cancer recurrence participating in a randomized clinical trial. In addition, the results indicate that factors associated with plasma carotenoid response in cross-sectional examinations also predict plasma carotenoid change.

	FOOTNOTES

 
¹ Presented in part at Experimental Biology 99, April 1999, Washington, DC [McEligot, A. J., Rock, C. L., Newman, V., Sanborn, K. A. & Pierce, J. P. (1999) Plasma carotenoids and intakes at 3-y follow-up in a feasibility study of high vegetable diet to prevent breast cancer. FASEB J. 13: A554 (abs.)].

² Supported in part by an award from the Walton Family Foundation.

Manuscript received June 10, 1999. Initial review completed July 28, 1999. Revision accepted September 7, 1999.

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