Cancer Education Interventions in Adolescents: A Systematic Review of Scope and Content.

Given the long induction time of many cancers and the fact that modifiable risk factors (e.g., cigarette smoking) including preventive factors (e.g., human papillomavirus [HPV] vaccination, healthy dietary and physical activity patterns) are influenced in adolescence, educating adolescents about cancer causation and risk reduction may have a large impact on reducing the cancer burden. We conducted a systematic review of literature evaluating the impact of cancer education interventions on adolescent knowledge of cancer risk reduction. We searched for articles published from 2000 to 2019 and identified 33 studies meeting our criteria. Given the methodological heterogeneity across studies, we briefly assessed effectiveness but focused on examining the design of the intervention and study. The majority of studies took place outside of the United States (67%). Most studies solely addressed skin or cervical cancer (67%) with only 18% (n = 6) discussing multiple cancers. The majority of interventions were a single-session (55%), did not involve a control or comparison group (67%), and were evaluated using a pre-test and a single post-test (61%); some studies administered multiple post-tests. Few studies (12%) investigated adolescents' knowledge of lifestyle and environmental risk factors at both the individual and community level. Most studies (94%) reported improvement in knowledge following an intervention. Our review revealed wide methodological variation and a deficit in research evaluating interventions that address multiple cancer types and risk factors. Future research should robustly test whether comprehensive cancer education for adolescents can reduce the cancer burden, particularly in communities with major cancer health disparities.

Discordant attitudes and beliefs about cancer clinical trial participation between physicians, research staff, and cancer patients.

BACKGROUND/AIMS: Essential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but approximately 8% of American cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment. METHODS: Physicians (MD, DO, fellows, residents) and research staff (physician assistants, nurse practitioners, staff and research nurses, clinical assistants, and program coordinators) involved in clinical research at a comprehensive cancer center completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. To inform the construct of our physician/staff and patient surveys and to assess barriers to clinical trial enrollment, we first conducted in-depth interviews among 14 key informants representing medical, hematologic, gynecologic, neurologic, radiation oncology, as well as members of the clinical research team (one clinical research coordinator, one research nurse practitioner). Perceived structural, provider- and patient-level barriers to clinical trial enrollment were assessed. Differences in perceptions, attitudes, and beliefs toward clinical trial enrollment between (1) physicians and staff, (2) patients by ethnicity, and (3) physicians/staff and patients were examined. RESULTS: In total, 120 physicians/staff involved in clinical research (39.2% physicians, 60.8% staff; 48.0% overall response rate) and 150 cancer patients completed surveys. Nearly three-quarters of physician/staff respondents reported difficulty in keeping track of the eligibility criteria for open studies but was more often cited by physicians than staff (84.4% vs 64.3%, p = 0.02). Physicians more often reported lack of time to present clinical trial information than did staff(p < 0.001); 44.0% of staff versus 18.2% of physicians reported patient family interaction as a clinical trial enrollment barrier (p = 0.007). Hispanic patients more often stated they would join a trial, even if standard therapy was an option compared to non-Hispanic patients (47.7% vs 20.8%, p = 0.002). Comparing the beliefs and perceptions of physicians/staff to those of patients, patients more often reported negative beliefs about clinical trial enrollment (e.g. being in a trial does not help patients personally, 32.9% vs 1.8%, p < 0.001) but less often felt they had no other options when agreeing to join (38.1% vs 85.6%, p < 0.001), and less often refused clinical trial enrollment due to lack of understanding (9.1% vs 63.3%, p = 0.001) than reported by physicians/staff. CONCLUSION: Our findings indicate a wide gap between physician/staff and patient attitudes and beliefs about clinical trial enrollment and highlight the importance of focusing future initiatives to raise awareness of this incongruency. Reconciling these differences will require tailored education to reduce implicit biases and dispel misperceptions. Strategies to improve the quality of patient-provider communication and address infrastructure and resource issues are also needed to improve patient enrollment onto cancer clinical trials.

Randomized Double-Blind Placebo-Controlled Biomarker Modulation Study of Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812).

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.

Latent class analysis suggests four distinct classes of complementary medicine users among women with breast cancer.

BACKGROUND: Breast cancer patients commonly report using >1 form of complementary and alternative medicine (CAM). However, few studies have attempted to analyze predictors and outcomes of multiple CAM modalities. We sought to group breast cancer patients by clusters of type and intensity of complementary and alternative medicine (CAM) use following diagnosis. METHODS: Detailed CAM use following breast cancer diagnosis was assessed in 2002-2003 among 764 female residents of Long Island, New York diagnosed with breast cancer in 1996-1997. Latent class analysis (LCA) was applied to CAM modalities while taking into account frequency and intensities. RESULTS: Four distinct latent classes of CAM use emerged: 1) "Low-dose supplement users" (40%), who used only common nutritional supplements; 2) "Vitamin/mineral supplement users" (39%), using an abundance of supplements in addition to other practices; 3) "Mind-body medicine users" (12%), with near-universal use of supplements, mind-body medicine techniques, and massage; and 4) "Multi-modality high-dose users" (9%), who were highly likely to use nearly all types of CAM. Predictors of membership in classes with substantial CAM use included younger age, more education, higher income, Jewish religion, ideal body mass index, higher fruit and vegetable intake, higher levels of physical activity, receipt of adjuvant chemotherapy, and prior use of oral contraceptives. CONCLUSIONS: LCA identified important subgroups of breast cancer patients characterized by varying degrees of complementary therapy use. Further research should explore the reproducibility of these classes and investigate the association between latent class membership and breast cancer outcomes.

Polyunsaturated fatty acid interactions and breast cancer incidence: a population-based case-control study on Long Island, New York.

PURPOSE: Experimental studies demonstrate that ω-3 polyunsaturated fatty acids (PUFAs) inhibit inflammatory eicosanoids generated by ω-6 PUFAs. Epidemiologic studies on dietary ω-3 PUFA intake show consistent inverse associations with breast cancer incidence among Asian populations, where ω-3, relative to ω-6, intake is high. In contrast, associations are inconsistent among Western populations, where intake of ω-3, relative to ω-6, is low. We hypothesized that examining interactions between ω-3 and ω-6 would help elucidate the PUFA-breast cancer association in the United States. METHODS: In a Long Island, New York, population-based study of 1463 breast cancer cases and 1500 controls, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression to examine interactions between ω-3 and ω-6 intake. RESULTS: We observed a super-additive interaction (relative excess risk due to interaction = 0.41; 95% confidence interval = 0.06-0.76) between ω-3 and ω-6 intake in association with breast cancer incidence, although the CIs for the joint exposure of low ω-3/high ω-6 compared to high ω-3/low ω-6 intake were wide (odds ratio = 1.20; 95% confidence interval = 0.85-1.69). CONCLUSIONS: Breast cancer risk reduction may be possible for U.S. women with dietary consumption of higher ω-3, which has anti-inflammatory properties, in concert with lower ω-6, which induces inflammation. Replication from future U.S.-based investigations is needed.

Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York.

BACKGROUND: In laboratory experiments, ω-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from ω-6 PUFA metabolism via competitive inhibition, and the ω-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary ω-3 PUFA intake benefits survival after breast cancer are limited and inconsistent. METHODS: The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression. RESULTS: All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain ω-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97). CONCLUSIONS: All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long-chain ω-3 PUFAs. Long-chain ω-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer.

Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk.

PURPOSE: Studies of vitamin D-pathway genetic variants in relation to cancer risk have been inconsistent. We examined the associations between vitamin D-related genetic polymorphisms, plasma 25-hydroxyvitamin D [25(OH)D], and breast cancer risk. METHODS: In a population-based case-control study of 967 incident breast cancer cases and 993 controls, we genotyped 25 polymorphisms encoding the vitamin D receptor (VDR) gene, 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D-binding protein (GC) and measured plasma 25(OH)D. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS: Among CYP24A1 polymorphisms, rs6068816 was associated with a 72 % reduction in breast cancer risk (TT vs. CC, OR 0.28, 95 % CI 0.10-0.76; p trend = 0.01), but for rs13038432, the 46 % decrease included the null value (GG vs. AA, OR 0.54, 95 % CI 0.17-1.67; p trend = 0.03). Increased risk that included the null value was noted for CYP24A1 rs3787557 (CC vs. TT, OR 1.34, 95 % CI 0.92-1.89). The VDR polymorphism, TaqI (rs731236), was associated with a 26 % risk reduction (TT vs. CC, OR 0.74, 95 % CI 0.56-0.98; p trend = 0.01). For other polymorphisms, ORs were weak and included the null value. The inverse association for plasma 25(OH)D with breast cancer was more pronounced (OR 0.43, 95 % CI 0.27-0.68) among women with the common allele for CYP24A1, rs927650 (p for interaction on a multiplicative scale = 0.01). CONCLUSION: Breast cancer risk may be associated with specific vitamin D-related polymorphisms, particularly CYP24A1. Genetic variation in the vitamin D pathway should be considered when designing potential intervention strategies with vitamin D supplementation.

Use of Self-Care and Practitioner-Based Forms of Complementary and Alternative Medicine before and after a Diagnosis of Breast Cancer.

Purpose. We examine factors associated with self-care, use of practitioner-based complementary and alternative medicine (CAM), and their timing in a cohort of women with breast cancer. Methods. Study participants were women with breast cancer who participated in the Long Island Breast Cancer Study Project. Self-care is defined as the use of multivitamins, single vitamins, botanicals, other dietary supplements, mind-body practices, special diets, support groups, and prayer. Within each modality, study participants were categorized as continuous users (before and after diagnosis), starters (only after diagnosis), quitters (only before diagnosis), or never users. Multivariable logistic regression was used for the main analyses. Results. Of 764 women who provided complete data, 513 (67.2%) initiated a new form of self-care following breast cancer diagnosis. The most popular modalities were those that are ingestible, and they were commonly used in combination. The strongest predictor of continuous use of one type of self-care was continuous use of other types of self-care. Healthy behaviors, including high fruit/vegetable intake and exercise, were more strongly associated with continuously using self-care than starting self-care after diagnosis. Conclusions. Breast cancer diagnosis was associated with subsequent behavioral changes, and the majority of women undertook new forms of self-care after diagnosis. Few women discontinued use of modalities they used prior to diagnosis.

Serum antioxidant nutrients, vitamin A, and mortality in U.S. Adults.

BACKGROUND: Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks. However, most randomized trials have failed to show survival benefits. Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings. METHODS: We evaluated all-cause, cancer, and cardiovascular mortality risks associated with quintiles (Q1-Q5) of serum antioxidant (vitamins C and E, ß-carotene, and selenium) and vitamin A levels, in 16,008 adult participants of The Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994). RESULTS: Over a median follow-up period of 14.2 years, there were 4,225 deaths, including 891 from cancer and 1,891 from cardiovascular disease. We observed a dose-response decrease in cancer and overall mortality risks with higher vitamin C levels. In contrast, for vitamin A, risk of cancer death decreased from Q1-Q2, with no further decline in risk at higher levels. For vitamin E, having levels in Q4 was associated with the lowest cancer mortality risk. Both vitamin A and E had U-shaped associations with all-cause mortality. Cancer mortality risks decreased from Q1-Q2 for ß-carotene and from Q1-Q4 for selenium. However, for ß-carotene and selenium, overall mortality risks decreased from Q1-Q2 but then did not change significantly with higher levels. CONCLUSIONS: Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks. IMPACT: These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels, and possibly, markers of oxidative stress and systemic inflammatory response.

Prevalence and predictors of antioxidant supplement use during breast cancer treatment: the Long Island Breast Cancer Study Project.

BACKGROUND: Although many patients take antioxidant dietary supplements during breast cancer treatment, the benefits of such supplementation are unproven. The authors of this report analyzed the prevalence of and factors associated with antioxidant supplement use during breast cancer (BC) treatment among women who participated in the Long Island Breast Cancer Study Project. METHODS: From 2002 through 2004, women with BC who had participated a case-control study from 1996 to 1997 were invited to participate in a follow-up interview. Antioxidant supplement use was defined as any self-reported intake of supplemental vitamin C, vitamin E, beta-carotene, or selenium in individual supplements or multivitamins. RESULTS: Follow-up interview participants were younger, more predominantly white, and of higher socioeconomic status than women who did not respond. Among 764 participants who completed the follow-up interview, 663 (86.8%) reported receiving adjuvant treatment for their BC. Of those 663 women, 401 (60.5%) reported using antioxidants during adjuvant treatment: One hundred twenty of 310 women (38.7%) used antioxidants during chemotherapy, 196 of 464 women (42.2%) used them during radiation, and 286 of 462 women (61.9%) used them during tamoxifen therapy. Of 401 antioxidant users, 278 women (69.3%) used high doses (doses higher than those contained in a Centrum multivitamin). The factors that were associated with high antioxidant supplement use during treatment were higher fruit and vegetable intake at diagnosis (relative risk [RR], 1.71; 95% confidence interval [CI], 1.13-2.59), tamoxifen use (RR, 3.66; 95% CI, 2.32-5.78), ever using herbal products (RR, 3.49; 95% CI, 2.26-5.38), and ever engaging in mind-body practices (RR, 1.72; 95% CI, 1.13-2.64). CONCLUSIONS: Given the common use of antioxidant supplements during BC treatment, often at high doses and in conjunction with other complementary therapies, future research should address the effects of antioxidant supplementation on BC outcomes.

Association between plasma 25-hydroxyvitamin D and breast cancer risk.

Vitamin D has been associated with decreased risk of several cancers. In experimental studies, vitamin D has been shown to inhibit cell proliferation and induce differentiation and apoptosis in normal and malignant breast cells. Using a population-based case-control study on Long Island, New York, we examined the association of breast cancer with plasma 25-hydroxyvitamin D (25-OHD) levels, a measure of vitamin D body stores. In-person interviews and blood specimens were obtained from 1,026 incident breast cancer cases diagnosed in 1996 to 1997 and 1,075 population-based controls. Plasma 25-OHD was measured in batched, archived specimens by Diasorin RIA. The mean (SD) plasma 25-OHD concentration was 27.1 (13.0) and 29.7 (15.1) ng/mL in the cases and controls, respectively (P < 0.0001). Plasma 25-OHD was inversely associated with breast cancer risk in a concentration-dependent fashion (P(trend) = 0.002). Compared with women with vitamin D deficiency (25-OHD, <20 ng/mL), levels above 40 ng/mL were associated with decreased breast cancer risk (odds ratio, 0.56; 95% confidence interval, 0.41-0.78). The reduction in risk was greater among postmenopausal women (odds ratio, 0.46; 95% confidence interval, 0.09-0.83), and the effect did not vary according to tumor hormone receptor status. In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of >32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is >or=40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.

Telomere length, oxidative damage, antioxidants and breast cancer risk.

Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell DNA telomere length on breast cancer risk, and examined whether urinary 15-F(2)-isoprostanes (15-F(2t)-IsoP) and 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) or dietary antioxidant intake modified the relationship between telomere length and breast cancer risk. A population-based case-control study-the Long Island Breast Cancer Study Project-was conducted among 1,067 cases and 1,110 controls. Telomere length was assessed by quantitative PCR. Overall, the mean levels of telomere length (T/S ratio), 15-F(2t)-IsoP and 8-oxodG were not significantly different between cases and controls. Among premenopausal women only, carrying shorter telomeres (Q3 and Q4), as compared with the longest (Q1), was associated with significantly increased breast cancer risk. Age-adjusted OR and 95% CI were 1.71 (1.10-2.67) and 1.61 (1.05-2.45). The 5-F(2t)-IsoP and 8-oxodG biomarkers did not modify the telomere-breast cancer association. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of beta-carotene, vitamin C or E intake [OR (95% CI) = 1.48 (1.08-2.03), 1.39 (1.01-1.92) and 1.57 (1.14-2.18), respectively], although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (p(trend) = 0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among premenopausal women or women with low dietary intake of antioxidants or antioxidant supplements.

Associations between breast cancer risk and the catalase genotype, fruit and vegetable consumption, and supplement use.

Observed weak or null associations between fruit and vegetable intake and breast cancer risk could be due to heterogeneity in endogenous antioxidant capabilities. The authors evaluated potential relations between a functional polymorphism in catalase, an antioxidant enzyme, and breast cancer risk, particularly in relation to fruit and vegetable intake and supplement use. Women (1,008 cases and 1,056 controls) in the Long Island Breast Cancer Study Project (1996-1997) were interviewed, completed a food frequency questionnaire, and provided blood for genotyping. The high-activity catalase CC genotype was associated with an overall 17% reduction in risk of breast cancer compared with having at least one variant T allele (odds ratio = 0.83, 95% confidence interval: 0.69, 1.00). Vegetable and, particularly, fruit consumption contributed to the decreased risk associated with the catalase CC genotype. Associations were more pronounced among women who did not use vitamin supplements, with a significant multiplicative interaction (p(interaction) = 0.02) for the CC genotype and high fruit intake (odds ratio = 0.59, 95% confidence interval: 0.38, 0.89), and there was no association among supplement users. These results indicate the importance of diet, rather than supplement use, in concert with endogenous antioxidant capabilities, in the reduction of breast cancer risk. CC genotypes were prevalent in approximately 64% of controls; thus, the preventive potential for fruit consumption has widespread implications.

MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk.

O(6)-methylguanine DNA methyl-transferase (MGMT) is the only known critical gene involved in cellular defense against alkylating agents in the DNA direct reversal repair (DRR) pathway. Three single nucleotide polymorphism (SNP) coding for non-conservative amino acid substitutions have been identified [C250T (Leu84Phe), A427G (Ile143Val) and A533G (Lys178Arg)]. To examine the importance of the DRR pathway in risk for breast cancer and the potential interaction with cigarette smoking and dietary antioxidants, we genotyped for these variants using biospecimens from the Long Island Breast Cancer Study Project. Genotyping was performed by a high throughput assay with fluorescence polarization and included 1067 cases and 1110 controls. Overall, there was no main effect between any variant genotype, haplotype or diplotype and breast cancer risk. Heavy smoking (>31 pack-year) significantly increased breast cancer risk for women with the codon 84 variant T-allele [odds ratio, OR = 3.0, 95% confidence interval (95% CI) = 1.4-6.2]. An inverse association between fruits and vegetables consumption and breast cancer risk was observed among women with the wild-type genotype for codon 84 (OR = 0.8, 95% CI = 0.6-0.9 for > or =35 servings of fruits and vegetables per week and CC genotype versus those with <35 servings per week and CC genotype). The association between fruits and vegetables consumption and reduced breast cancer risk was apparent among women with at least one variant allele for codon 143 (OR = 0.6, 95% CI = 0.5-0.9 for > or =35 servings of fruits and vegetables per week and AG or GG genotype versus those with <35 servings per week and AA genotype). Similar patterns were observed for dietary alpha-carotene and supplemental beta-carotene, but not for supplemental vitamins C and E. These data suggest that polymorphisms in MGMT may modulate the inverse association previously observed between fruits and vegetables consumption, dietary antioxidants and breast cancer risk, and support the importance of fruits and vegetables on breast cancer risk reduction.

Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk.

The variability in DNA repair capacity of the general population may depend in part upon common variants in DNA repair genes. X-ray repair cross complementing group 1 (XRCC1) is an important DNA base excision repair gene and exhibits polymorphic variation. Using the Long Island Breast Cancer Study Project, a population-based case-control study, we evaluated the hypothesis that two common single nucleotide polymorphisms of XRCC1 (codon 194 Arg-->Trp and 399 Arg-->Gln) influence breast cancer susceptibility and interact with polycyclic aromatic hydrocarbon (PAH)-DNA adducts, cigarette smoking, and intake of fruits and vegetables and antioxidants. The available sample for genotyping included 1,067 cases and 1,110 controls. Genotyping was done by a high-throughput single-nucleotide extension assay with fluorescence polarization detection of the incorporated nucleotide. We observed no significant increases in risk among all subjects who were carriers of XRCC1 194Trp or 399Gln alleles. Among never smokers, we observed an increased risk of breast cancer in 399Gln carriers [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7). Further analysis indicated a suggestive weak additive interaction between the 399Gln allele and detectable PAH-DNA adducts (OR for exposure with mutant genotype, 1.9; 95% CI, 1.2-3.1). The estimated age-adjusted interaction contrast ratio (ICR) and 95% CI (ICR, 0.38; 95% CI, -0.32 to 1.10) indicated that the departure from additivity was not statistically significant, but that there was some suggestion of a relative excess risk due to the interaction. In subjects with at least one copy of XRCC1 194Trp allele, there was a moderate interaction with high intake of fruits and vegetables (>/=35 half-cup servings per week of any fruits, fruit juices, and vegetables, OR, 0.58; 95% CI, 0.38-0.89; ICR, -0.49; 95% CI, -0.03 to -0.95), and dietary plus supplement antioxidant intake with 33% to 42% decreases in breast cancer risk compared with those with the Arg194Arg genotype and low-intake individuals. These results do not show that the two genetic polymorphisms of XRCC1 independently influence breast cancer risk. However, there is evidence for interactions between the two XRCC1 single nucleotide polymorphisms and PAH-DNA adducts or fruit and vegetable and antioxidant intake on breast cancer risk. Further understanding of the biological function of XRCC1 variants and their interactions with PAH-DNA adducts, antioxidants, and other genes in the pathway are needed.

One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer.

Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene [i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C] on breast cancer risk. The study uses the resources of a population-based case-control study, which includes 1,481 cases and 1,518 controls. Significant inverse associations between B vitamin intake and breast cancer risk were observed among non-supplement users. The greatest reduction in breast cancer risk was observed among non-supplement users in the highest quintile of dietary folate intake [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.41-0.93] as compared with non-supplement users in the lowest quintile of dietary folate intake (high-risk individuals). The MTHFR 677T variant allele was associated with increased risk of breast cancer (P, trend = 0.03) with a multivariate-adjusted OR of 1.37 (95% CI, 1.06-1.78) for the 677TT genotype. The 1298C variant allele was inversely associated with breast cancer risk (P, trend = 0.03), and was likely due to the linkage of this allele to the low-risk allele of 677C. The MTHFR-breast cancer associations were more prominent among women who did not use multivitamin supplements. Compared with 677CC individuals with high folate intake, elevation of breast cancer risk was most pronounced among 677TT women who consumed the lowest levels of dietary folate (OR, 1.83; 95% CI, 1.13-2.96) or total folate intake (OR, 1.71; 95% CI, 1.08-2.71). From a public heath perspective, it is important to identify risk factors, such as low B vitamin consumption, that may guide an effective prevention strategy against the disease.

Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status.

Whether fruit, vegetable, and antioxidant micronutrient consumption is associated with a reduction in breast cancer incidence remains unresolved. To address this issue, we analyzed data from a large population-based case-control study, with consideration given to whether the associations varied with menopausal status or with clinical characteristics of the cases' disease. Study participants completed a modified Block food frequency questionnaire, which included assessment of the frequency and portion sizes of 13 fruits and fruit juices and 16 vegetables and the use of multiple and single vitamin supplements. Statistical analyses were done on 1,463 cases and 1,500 controls. Among postmenopausal women, reduced odds ratios [OR; 95% confidence intervals (95% CI)] were noted for the highest fifth, as compared with the lowest fifth, of intake of any vegetables [0.63 (0.46-0.86); P for trend < 0.01] and leafy vegetables [0.66 (0.50-0.86); P for trend = 0.03] after controlling for age and energy intake. Adjusted ORs (95% CIs) were also decreased for postmenopausal breast cancer in relation to high intake of carotenoids, alpha-carotene, beta-carotene, lutein, and particularly lycopene [0.66 (0.48-0.90); P for trend = 0.03]. Inverse associations for fruits and vegetables were stronger for postmenopausal women with estrogen receptor (ER)+ tumors (OR, 0.65; 95% CI, 0.51-0.82) than ER- tumors (OR, 0.92; 95% CI, 0.64-1.32), but results were less consistent for micronutrients. No similarly reduced associations were observed among premenopausal women. ORs did not appreciably differ by in situ or invasive breast cancer or by whether cases had begun chemotherapy. Our results support an inverse association for fruit and vegetable intake among postmenopausal but not premenopausal breast cancer, which may be more pronounced among women with ER+ tumors.