Secondhand smoke exposure in early life and the risk of breast cancer among never smokers (United States)

Evidence is increasing that some early life exposures affect breast cancer risk. Exposure to secondhand smoke (SHS) during childhood may be one such exposure. As part of the WEB Study (Western New York Exposures and Breast Cancer Study), we conducted a population-based, case-control study with 1166 women aged 35 to 79 diagnosed with histologically confirmed, primary, incident breast cancer. Controls (n = 2105) were randomly selected from the Department of Motor Vehicles driver’s license list (≤age 65) and the Center for Medicare & Medicaid Services rolls (>age 65). Participants were queried regarding household and workplace SHS exposure. Person-years of lifetime cumulative SHS exposure were computed as well as cumulative exposure up to 21 years of age. Unconditional logistic regression adjusting for potential confounders was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Lifetime cumulative exposure to household SHS was not associated with an increase in breast cancer risk for premenopausal (OR = 1.17, 95% CI = 0.54–2.56) or postmenopausal (OR = 1.29; 95% CI = 0.82–2.01) women. Neither was risk increased among women exposed to SHS before the age of 21 or at the time of birth, menarche, or a women’s first birth. In this study, exposure to SHS either in adult or early life does not appear to be associated with the risk of breast cancer.     

Exposure to traffic emissions throughout life and risk of breast cancer: the Western New York Exposures and Breast Cancer (WEB) study

Objective We previously reported that total suspended particulates exposure (a measure of air pollution) at the time of birth was related to increased postmenopausal breast cancer risk. In this study, we examined breast cancer risk in relation to exposure to air pollution from traffic emissions throughout life. Methods We conducted a case–control study of breast cancer. Participants were women, aged 35–79, residents of Erie and Niagara Counties. Cases had incident, primary, histologically confirmed breast cancer. Controls were randomly selected from the population, frequency-matched on age and race. Using lifetime residential histories, exposure to traffic emissions was modeled for each woman using her residence as a proxy. Estimates were calculated for residence at menarche, her first birth, and 20 and 10 years before interview. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results Higher exposure to traffic emissions at the time of menarche was associated with increased risk of premenopausal breast cancer (OR 2.05, 95% CI 0.92–4.54, p for trend 0.03); and at the time of a woman’s first birth for postmenopausal breast cancer (OR 2.57, 95% CI 1.16–5.69, p for trend 0.19). Statistically significant associations were limited to lifetime non-smokers; there was a significant interaction between exposure at time of menarche and smoking for premenopausal women. Conclusion Our findings add to accumulating evidence that early life exposures impact breast cancer risk and provide indication of potential importance of traffic emissions in risk of breast cancer.     

Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal women

OBJECTIVE: We examined breast cancer risk related to lifetime exposure to oral contraceptives (OCs) and hormone replacement therapy (HRT) in postmenopausal women. METHODS: The Women's Contraceptive and Reproductive Experiences (CARE) Study was a population-based case-control study that included 1847 postmenopausal women with incident invasive breast cancer, and 1932 control subjects, identified using random digit dialing. RESULTS: 45% of cases and 49% of controls used both OCs and HRT. OC users were not at increased risk regardless of subsequent HRT exposure. HRT users who had used OCs previously did not have a higher risk of breast cancer than women with no exposure to OCs. We observed a negative interaction (p-value: 0.032) of combined hormone replacement therapy (CHRT) and past OC use. The increase in risk with CHRT was stronger in women who had never used OCs in the past (odds ratio: 1.05; 95% confidence interval: 1.01-1.10 per year of exclusive CHRT use) than in women who had used OCs (odds ratio: 1.00; 95% confidence interval: 0.97-1.03). CONCLUSIONS: We found no indication that adverse effects of exposure to OCs or HRT appeared only in the presence of the other hormone or were exacerbated by exposure to the other hormone.     

Comparison of breast cancer recurrence risk and cardiovascular disease incidence risk among postmenopausal women with breast cancer

The majority of breast cancers are diagnosed in postmenopausal women. Competing comorbidities, particularly cardiovascular disease (CVD), should be considered when individualizing adjuvant therapies for these women. We compared the 10-year predicted breast cancer recurrence risk with CVD risk among postmenopausal women with hormone receptor-positive (HR+), non-metastatic breast cancer. CVD risk factor data were prospectively collected from postmenopausal women with stage I-III, HR+?breast cancer initiating adjuvant aromatase inhibitor therapy. We compared predicted 10-year CVD risk, including the composite index heart age, computed from modified Framingham risk score, with predicted 10-year risk of breast cancer recurrence using Adjuvant! Online. We created multivariable logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (CI) for greater CVD risk than breast cancer recurrence risk. Among 415 women, mean age and heart age were 60 and 67?years, respectively. Overall, 43% of women had a predicted 10-year CVD risk equivalent to breast cancer recurrence risk and 37% had CVD risk higher than breast cancer recurrence risk. Predicted CVD risk was higher than breast cancer recurrence risk for stage I disease (OR: 6.1, 95% CI: 3.4-11.2) or heart age >65 (OR: 12.4, 95% CI: 7.0-22.6). The majority of postmenopausal women with HR+ early breast cancer had a predicted 10-year CVD risk that was equivalent to or higher than breast cancer recurrence risk. Physicians should weigh competing risks and offer early screening and cardiac prevention strategies for women at a greater risk for CVD.     

Estrogen-biosynthesis gene CYP17 and its interactions with reproductive, hormonal and lifestyle factors in breast cancer risk: results from the Long Island Breast Cancer Study Project

The genes that are involved in estrogen biosynthesis, cellular binding and metabolism may contribute to breast cancer susceptibility. We examined the effect of the CYP17 promoter T --> C polymorphism and its interactions with the reproductive history, exogenous hormone use and selected lifestyle risk factors on breast cancer risk among 1037 population-based incident cases and 1096 population-based controls in the Long Island Breast Cancer Study Project. Overall, there were no associations between the CYP17 genotype and breast cancer risk. Among postmenopausal women, the joint exposure to higher body mass index (BMI) and the variant C allele was associated with an increased risk of breast cancer [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.15-2.22]. The joint exposure to the variant C allele and long-term use of hormone replacement therapy (HRT) (>51 months) was related to an increased risk of breast cancer (OR, 1.51; 95% CI, 0.99-2.31) especially estrogen receptor-positive, progesterone receptor-positive breast cancer (OR, 1.87; 95% CI, 1.08-3.25). Among the control population, the CYP17 variant C allele was inversely associated with long-term use of postmenopausal HRT and a higher BMI in postmenopausal women. In conclusion, the findings suggest that the CYP17 variant C allele may increase breast cancer risk in conjunction with long-term HRT use and high BMI in postmenopausal women.     

Exposure to breast milk in infancy and risk of breast cancer

Early life exposures, such as being breastfed in infancy, may influence the risk of breast cancer in adulthood. We evaluated the risk of breast cancer in relation to ever having been breastfed in infancy among 9,442 women who participated in a population-based, case–control study. Cases were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); controls were identified through statewide drivers’ license lists or medicare lists. Data on known and suspected risk factors were obtained through telephone interview. We used unconditional logistic regression to assess the relation of breast cancer with ever having been breastfed and with breastfeeding duration (available for only 19% of breastfed women) in premenopausal women (1,986 cases and 1,760 controls) and postmenopausal women (2,600 cases and 2,493 controls). We found no evidence that ever having been breastfed in infancy was associated with breast cancer risk in either premenopausal women (odds ratio [OR] = 0.96; 95% confidence interval [CI] = 0.83–1.10) or postmenopausal women (OR = 0.98; 95% CI = 0.87–1.10). The association did not differ according to breast cancer stage, mother’s history of breast cancer, or any other reproductive factor assessed. Likewise, we found no association between breastfeeding duration and risk of breast cancer. Our results did not support the hypothesis that exposure to breast milk in infancy influences the risk of adult breast cancer.     

Serum concentrations of estrogens, sex hormone binding globulin, and androgens and risk of breast hyperplasia in postmenopausal women.

OBJECTIVE: We sought to determine whether serum concentrations of estrogens, androgens, and sex hormone binding globulin in postmenopausal women were related to the presence of mammary hyperplasia, an established breast cancer risk factor. METHODS: Study participants provided serum before breast biopsy or mastectomy in three hospitals in Grand Rapids, Michigan, between 1977 and 1987. A total of 179 subjects with breast hyperplasia were compared with 152 subjects with nonproliferative breast changes that are not associated with increased breast cancer risk. RESULTS: The odds ratios (OR) associated with the three upper quartiles of estradiol in comparison with the lowest quartile were 2.2 [95% confidence interval (95% CI) 1.1-4.6], 2.5 (95% CI, 1.1-5.3), and 4.1 (95% CI, 2.0-8.5; Ptrend = 0.007). The corresponding ORs for bioavailable estradiol, estrone, and estrone sulfate were of generally similar magnitude (Ptrend = 0.003 for bioavailable estradiol, 0.0004 for estrone, and 0.0009 for estrone sulfate). Relative to women concurrently in the lowest tertile for serum estradiol, estrone, and estrone sulfate, women concurrently in the highest tertile for all three hormones had an OR of 5.8 (95% CI, 2.2-15.2). Serum concentrations of sex hormone binding globulin, testosterone, dehydroepiandrosterone, androstenedione, and androstenediol were not associated with risk of hyperplasia. CONCLUSIONS: Serum concentrations of estrogens, but not of androgens or sex hormone binding globulin, were strongly and significantly associated with risk of breast hyperplasia in postmenopausal women, suggesting that estrogens are important early in the pathologic process towards breast cancer.     

Plasma isoflavones and fibrocystic breast conditions and breast cancer among women in Shanghai, China.

BACKGROUND: Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions. MATERIALS AND METHODS: We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173). RESULTS: Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (P(trend) < 0.01 for all comparisons with controls). Women in the highest quartile of plasma genistein (>76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (<9.42 ng/mL). Observed risks for breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone. CONCLUSION: Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis.     

Weight at birth and adolescence and premenopausal breast cancer risk in a low-risk population

We assessed breast cancer risk in relation to weight at birth and adolescence. In-person interviews were completed with the biological mothers of women aged 45 years and younger who participated in the Shanghai Breast Cancer Study in 1996-98 (288 cases, 350 controls). After adjustment for confounding, women who were 4000 g or more at birth were not at increased risk of breast cancer (odds ratio=0.7; 95% confidence interval 0.4-1.4) relative to women whose birth weight was 2500-2999 g. Compared with women of average perceived weight at age 15 years, no relation was apparent for heavier than average weight based on maternal report (odds ratio=0.7; 95% confidence interval 0.5-1.2) or self-report (odds ratio=1.0; 95% confidence interval 0.7-1.6). Perceived adolescent weight and height did not modify the association of birth weight with breast cancer risk. These results suggest that weight early in life is not related to premenopausal breast cancer risk in this low-risk population.     

Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies.

We evaluated whether our previous reports of increased postmenopausal breast cancer risk with higher body mass index (BMI) or of reduced premenopausal and postmenopausal breast cancer risk with higher physical activity levels varied according to the tumor's estrogen receptor (ER) and progesterone receptor (PR) status. Participants enrolled in either of two population-based case-control studies in Los Angeles County, California: one of premenopausal women (ages < or = 40 years), and one of postmenopausal women (ages 55-64 years). Case participants were diagnosed for the first time with in situ or invasive breast cancer from 7/1/83 through 12/31/88 (premenopausal women) or from 3/1/87 through 12/31/89 (postmenopausal women). Joint ER/PR status was collected for 424 premenopausal and 760 postmenopausal case participants. The analysis included 714 premenopausal and 1091 postmenopausal age-matched, race-matched (white or Hispanic), parity-matched (premenopausal women only), and residential neighborhood-matched control participants. Among the postmenopausal women, obesity was associated with an increased odds of ER+/PR+ breast cancer (odds ratio, 2.45 for women in the highest versus the lowest body mass index quartile; 95% confidence interval, 1.73-3.47). Body mass index was associated with neither ER-/PR- tumors among the postmenopausal women nor with any ER/PR subgroup among the premenopausal women. For both premenopausal and postmenopausal women, higher recreational physical activity levels (> or = 17.6 MET-hours/week versus no activity) were associated with a 30-60% reduction in risk of nearly all ER/PR subtypes, although the associations were generally of borderline statistical significance. Examining these potentially modifiable breast cancer risk factors by tumor ER and PR status may provide us with greater insight into breast cancer etiology and the mechanisms underlying the risk factor associations.     

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.     

Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women

We assessed the relationship between serum concentrations of estrogens, androgens, and sex hormone-binding globulin and risk of breast cancer among postmenopausal women. Study participants provided serum prior to breast biopsy or mastectomy in 3 hospitals in Grand Rapids, Michigan between 1977 and 1987. A total of 179 subjects with localized breast cancer were compared to 152 subjects with nonproliferative breast changes that have not been associated with elevated breast cancer risk. Increasing serum concentrations of estrone and estrone sulfate were associated with increases in breast cancer risk; the odds ratios (ORs) in the fourth quartiles compared to the first were 2.3 (95% confidence interval (CI) 1.1-4.6) for both (p-trend = 0.02 and 0.03, respectively). Estradiol and bioavailable estradiol concentrations were associated with nonstatistically significant increases in risk. Androstenediol levels were associated with risk (p-trend = 0.01); the OR in the fourth compared to the first quartile was 2.2 (95% CI 1.0-4.6). Testosterone, dehydroepiandrosterone and androstenedione levels were not associated with increased risk. Sex hormone-binding globulin was associated with a nonsignificant decrease in risk. Associations with estrone and estrone sulfate persisted after adjustment for androstenediol (ORs for fourth compared to first quartiles were 2.0 (95% CI 0.9-4.5) and 2.2 (95% CI 1.0-4.6), respectively (p-trend = 0.16 for both). The association with androstenediol was attenuated after adjustment for estrone (OR for fourth compared to first quartile was 1.6 (95% CI 0.7-3.6); p-trend = 0.13). Higher serum concentrations of estrogens were associated with increased breast cancer risk in postmenopausal women. Androgen levels were not independently associated with substantially increased risk.     

A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer.

To investigate the incidence of breast cancer and prediagnostic serum levels of folate, B12, and pyridoxal 5'-phosphate (B6), we conducted a nested case-control study using resources from the Washington County (Maryland) serum bank. In 1974, 12,450 serum specimens were donated, and in 1989, 14,625 plasma specimens were donated by female residents of Washington County. One hundred ninety-five incident breast cancer cases and 195 controls were matched by age, race, menopausal status at donation, and cohort participation as well as by date of blood donation. In both cohorts and all menopausal subgroups, median B12 concentrations were lower among cases than controls. Differences reached statistical significance only among women who were postmenopausal at donation (1974 cohort, 413 versus 482 pg/ml, P = 0.03; 1989 cohort, 406 versus 452 pg/ml, P = 0.02). Among women postmenopausal at blood donation, observed associations of B12 suggested a threshold effect with increased risk of breast cancer in the lowest one-fifth compared to the higher four-fifths of the control distribution [lowest versus highest fifth: 1974 cohort, matched odds ratio = 4.00 (95% confidence interval = 1.05-15.20); 1989 cohort, matched odds ratio = 2.25 (95% confidence interval = 0.86-5.91)]. We found no evidence for an association between folate, B6, and homocysteine and breast cancer. Findings suggested a threshold effect for serum B12 with an increased risk of breast cancer among postmenopausal women in the lowest one-fifth compared to the higher four-fifths of the control distribution. These results should stimulate further investigations of potentially modifiable risk factors, such as these B-vitamins, for prevention of breast cancer.     

Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese women.

BACKGROUND: Recent laboratory studies have suggested that cadmium is an estrogenic compound and may be a potential risk factor for breast cancer. METHODS: We investigated the relationship between urinary cadmium concentrations and serum concentrations of estrone, testosterone, and dehydroepiandrosterone sulfate in 164 postmenopausal Japanese women. RESULTS: There was a significant positive association between the urinary cadmium and serum testosterone levels after controlling for age and body mass index. The mean testosterone level was 28% higher in women with high urinary cadmium (> or = 3.00 microg/g creatinine) than in those with low urinary cadmium (< 2.00 microg/g creatinine). Urinary cadmium was not significantly associated with serum estrone and dehydroepiandrosterone sulfate levels. Additional adjustment for smoking, alcohol and reproductive factors including known risk factors for breast cancer did not substantially alter the results. CONCLUSION: Data suggested that cadmium exposure is associated with increased testosterone levels. As high testosterone levels have been associated with the risk of breast cancer, the involvement of cadmium exposure in breast cancer risk should be evaluated in future studies.     

Lifetime recreational and occupational physical activity and risk of in situ and invasive breast cancer.

Numerous studies have observed reduced breast cancer risk with increasing levels of physical activity, yet these findings have been inconsistent about optimal times of activity and effect modification by other factors. We investigated the association between recreational and occupational physical activity and breast cancer risk in a population-based case-control study in Massachusetts, New Hampshire, and Wisconsin. During structured telephone interviews, 7,630 controls, 1,689 in situ, and 6,391 invasive breast cancer cases, ages 20 to 69 years, reported lifetime history of recreational physical activity and occupation. Neither lifetime recreational nor strenuous occupational physical activity appeared to be associated with risk of breast carcinoma in situ. In contrast, recreational physical activity was associated with a reduced risk of invasive breast cancer. After adjustment for potentially confounding factors, women averaging >6 h per week of strenuous recreational activity over their lifetime had a 23% reduction in the odds ratio of invasive breast cancer when compared with women reporting no recreational activity (95% confidence interval, 0.65-0.92; P(trend) = 0.05). However, this reduction in risk was limited to women without a first-degree family history of breast cancer (P(interaction) = 0.02). Inverse associations were observed for physical activity early in life, in the postmenopausal years, and in the recent past, but these findings were confined to women without a family history of breast cancer. Lifetime strenuous occupational activity was not associated with invasive breast cancer risk. These results provide further evidence that, for most women, physical activity may reduce the risk of invasive breast cancer.     

Insulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women

We explored the relationship between insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk. Also, we examined whether obesity, sex hormone-binding globulin (SHBG), and estradiol influenced IGF-1 concentrations. A pilot study of 60 postmenopausal African-American women (30 cases and 30 controls) was used. Plasma concentrations of IGF-1 were higher among the cases, as compared to the controls. A negative trend was seen for plasma concentrations of IGF-1 and TNM (tumor-node-metastasis) stage and IGF-1 and body mass index. IGF-1 was found to be associated negatively with SHBG. After adjustment, plasma concentrations of IGF-1 remained significantly and positively associated with breast cancer risk (odds ratio, 1.183; 95% confidence interval, 1.167-1.201). No significant associations for breast cancer risk were observed for estradiol, SHBG, and body mass index. Further research with a larger sample is needed to clarify the relationships between obesity and IGF-1 concentrations to breast cancer risk in this population.     

Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer

Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan? allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.     

Selenium in breast cancer

AIM: Controversy surrounds the hypothetical relationship between low serum levels of selenium and reduced activity of selenium-dependent enzymes, such as glutathione peroxidase, and an increased risk of cancer in humans. This study investigated serum concentrations of selenium in women with and without breast cancer. METHODS: In this case-control study, we compared serum concentrations of selenium in women with breast cancer (n = 200), healthy women (n = 100), and women with chronic diseases (n = 100). Patients with breast cancer were divided into premenopausal (n = 99) and postmenopausal subjects (n = 101). RESULTS: Mean serum concentrations of selenium were 81.1 microg/l in women with breast cancer and 98.5 microg/l in women with non-tumoral disease (p < 0.001). CONCLUSION: Alterations in serum concentrations of selenium in women with breast cancer appear to be a consequence, rather than a cause of cancer. In accordance with the hypothesis, the findings suggest that very low selenium status could be due to the nature of cancer.     

Long-term oral contraceptive use increases breast cancer risk in women over 55 years of age: the DOM cohort

The role of past oral contraceptive use in the development of breast cancer is unclear, particularly in postmenopausal women. The authors investigated this relationship among pre- and postmenopausal middle-aged women in a nested case-control study within the population-based DOM cohort, Utrecht, the Netherlands. Among a total population of 12,184 women followed up for an average of 7.5 years, 309 breast cancer cases aged 42 to 63 years, diagnosed from November 1982 through May 1996, and 610 controls were examined. Overall, duration of oral contraceptive use was not clearly related to breast cancer. In women older than 55 years, however, oral contraceptive use for more than 10 years was associated with a 2-fold increased risk of breast cancer (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.0). We conclude that long duration of oral contraceptive use increases the risk of breast cancer in women over 55 years of age but not in younger women.     

N-Acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women.

Heterocyclic amines found in well-done meat require host-mediated metabolic activation before initiating DNA mutations and tumors in target organs. Polymorphic N-acetyltransferase-2 (NAT2) catalyzes the activation of heterocyclic amines via O-acetylation, suggesting that NAT2 genotypes with high O-acetyltransferase activity (rapid/intermediate acetylator phenotype) increase the risk of breast cancer in women who consume well-done meat. To test this hypothesis, DNA samples and information on diet and other breast cancer risk factors were obtained from a nested case-control study of postmenopausal women. Twenty-seven NAT2 genotypes were determined and assigned to rapid, intermediate, or slow acetylator groups based on published characterizations of recombinant NAT2 allozymes. NAT2 genotype alone was not associated with breast cancer risk. A significant dose-response relationship was observed between breast cancer risk and consumption of well-done meat among women with the rapid/intermediate NAT2 genotype (trend test, P = 0.003) that was not evident among women with the slow acetylator genotype (trend test, P = 0.22). These results suggest an interaction between NAT2 genotype and meat doneness, although a test for multiplicative interaction was not statistically significant (P = 0.06). Among women with the rapid/intermediate NAT2 genotype, consumption of well-done meat was associated with a nearly 8-fold (odds ratio, 7.6; 95% confidence interval, 1.1-50.4) elevated breast cancer risk compared with those consuming rare or medium-done meats. These results are consistent with a role for O-acetylation in the activation of heterocyclic amine carcinogens and support the hypothesis that the NAT2 acetylation polymorphism is a breast cancer risk factor among postmenopausal women with high levels of heterocyclic amine exposure.