Antioxidant Use After Breast Cancer Diagnosis

Greenlee H, Kwan M, Kushi L, et al. Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort. Cancer. 2011 Sep 27. [Epub ahead of print]

 

Data for this study came from the Life After Cancer Epidemiology (LACE) Study, a prospective cohort study of women with early-stage breast cancer with an average follow-up of 8.3 years ± 2.4 years. Data on personal and medical history and supplement use was collected via self-administered mailed questionnaire. Clinical data was obtained from electronic databases or medical chart review. Breast cancer recurrence and death outcomes were assessed via semiannual or annual mailed questionnaires, with nonresponders contacted by telephone.

 

The LACE cohort was 2,264 women, average age of 58.3 years, diagnosed with early-stage [stage I or IIA (80%)–stage IIIA] breast cancer between 1997 and 2000. The women were identified from the cancer registries of northern California and Utah. All participants enrolled between 1 and 3 years after diagnosis, with the average woman enrolling after completion of treatment at 1.9 years after diagnosis. Participants had completed breast cancer treatment (including surgery and/or chemotherapy, radiation therapy, and hormonal therapy); showed no evidence of recurrent disease; and had no history of other cancers within the previous 5 years.

 

The questionnaire detailed information about the length and frequency of combination supplements and individual nutrient supplements. The primary goal of the study was to correlate the use of antioxidant supplements after breast cancer diagnosis with subsequent recurrence and death.

 

The majority (81%) of women in this study utilized antioxidants and, of these, the majority (70%) took a multivitamin supplement. Some of the women also used individual antioxidants: vitamin E (48%), vitamin C (40%), zinc (10%), selenium (7%), combination carotenoids (7%), beta carotene alone (6%), and lycopene alone (1%). Supplement users differed from non-supplement users in key ways: Supplement users tended to be more physically active, ate more fruits and vegetables, had lower body mass index (BMI), had more education, tended to be non-Hispanic white, and were older.

 

 

 

Significant correlations with breast cancer recurrence and death were found with vitamin C intake, vitamin E intake, and carotenoid intake. Specifically, compared with nonusers, frequent users (6 to 7 days per week) of vitamin C evidenced a lower risk of all-cause mortality (HR=0.78; 95% CI: 0.61–1.00) and reduced risk of breast cancer recurrence (HR=0.71; 95% CI: 0.54–0.92). Frequent users of vitamin E had significantly lower all-cause mortality (HR=0.75; 95% CI: 0.59–0.96) and reduced risk of breast cancer recurrence (HR=0.70; 95% CI: 0.54–0.90). On the other hand, combination carotenoid intake was associated with significantly increased (almost 2-fold) risk of all-cause mortality versus no use (HR=1.63; 95% CI: 1.06–2.50). There was no significant association between intake of multivitamins, selenium, and zinc and any of the breast cancer outcomes. Of note, concurrent use of combination carotenoids with chemotherapy increased risk of death from breast cancer (HR=0.75; 95% CI: 0.59–0.96). This was also seen in the concurrent use of mixed carotenoids with radiation therapy (HR=2.54; 95% CI: 1.28–5.05) and with hormone therapy (HR=2.14; 95% CI: 1.16–3.97). On the other hand, vitamin C and E use during radiation therapy and during hormonal therapy had a decreased risk of recurrence:

This study is another nail in the carotene coffin. Earlier trials, notably the Alpha-Tocopherol, Beta-Carotene Prevention (ATBC) Study¹ and the Beta-Carotene and Retinol Efficacy Trial (CARET) study² demonstrated an increase in all-cause mortality correlated with beta-carotene intake in people at risk for lung cancer. This trial by Greenlee et al is the first prospective cohort trial of women diagnosed with breast cancer that indicates the correlation between carotenoids and risk of death by cancer or all causes. The slowly accumulating evidence of the danger of supplemental carotenoids, notably beta-carotene, cannot be ignored. This should give serious pause to the use of multivitamins with beta-carotene and certainly beta-carotene supplementation in people with a recent cancer diagnosis.

 

Carotenoids are highly conjugated, easily oxidized molecules.³ They quench singlet oxygen species but are oxidized in the process and require other antioxidants to regain their negative redox potential. This means that the fate of carotenoids is dependent upon the oxidative state of the host tissue. It is also true that the more than 500 individual carotenoids have unique oxidative tendencies. For instance in a test using model membranes enriched with polyunsaturated fatty acids, nonpolar carotenoids (ie, beta-carotene, lycopene) have pronounced prooxidant effects, while astaxanthin, another carotenoid, has the opposite effect and acts as an antioxidant under identical conditions.⁴ Additionally, a change in one double bond from a trans to a cis configuration markedly changes the shape of the carotene molecule and hence its absorption and metabolic fate. Supplements with purified and/or synthesized carotenoids contain a combination of all-trans and cis isomers; however, the majority is absorbed as all-trans-carotene. Synthetic beta-carotene is in the all-trans isomer form, and the majority of beta-carotene in plants is found in the all-trans-form. While trans-beta carotene is better absorbed than cis-containing beta carotene, it is important to realize that in whole foods there are other carotenoids besides beta carotene. The additional carotenoids may help to maintain the reduced state of beta-carotene, minimizing its prooxidative potential.

 

Overall, it is confusing at best to generate specific practice guidelines from an observational study regarding the supplementation of carotenes. Because this was an observational trial based upon the participants’ recall, the study lacked information on specific doses, formulations, and duration of use. Nonetheless, this study’s correlation of supplemental carotene with increased risk of death warrants caution. This caution does not, however, extend to eating a diet of foods rich in carotenoids (red, green orange, and yellow vegetables and fruits). A diet rich in carotenoid-containing foods has not been associated with increased risk of death or cancer recurrence as measured in a number of epidemiological and observational studies.

 

The data collected was from a questionnaire that asked the participants to document their supplement use for, on average, 1.9 years’ prior to completing the questionnaire. This could have led to recall bias. Additionally, the dose, formulations, timing, and duration of supplements used were unknown. This is a significant limitation given the different physiological actions of synthetic vitamins and natural vitamins. Additionally, as the authors point out, the beneficial correlation of vitamins C and E with decreased risk of recurrence and death may simply be an indicator of other causal lifestyle factors that women taking these supplements were more likely to be engaged in. This being the case, the observed hazard of death associated with carotenoids becomes even more significant.

 

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