Plasma organochlorine levels and the risk of breast cancer: an extended follow-up in the Nurses' Health Study

The environmental organochlorines 2,2-bis(p-chlorophenyl)1,1,1,trichloroethane (DDT) and polychlorinated biphenyls (PCBs) have been implicated as potential causes of female breast cancer. We continued follow-up of our 1997 case-control study nested in the Nurses' Health Study cohort, adding 143 postmenopausal cases and controls to the original 238 pairs, and examining specific PCB congeners for the first time. We measured plasma levels of 2,2-bis(p-chlorophenyl)ethylene (DDE), the major metabolite of DDT, and PCBs prospectively, comparing women who were diagnosed with breast cancer between 1 month and 4 years after blood collection with control women in whom breast cancer did not develop. Median concentrations of lipid-adjusted DDE, total PCBs, and PCB numbers 118, 138, 153 and 180, assessed individually, were similar among the cases and controls. The multivariate relative risk of breast cancer for women in the highest quintile of exposure as compared with women in the lowest quintile was 0.82 for DDE (95% confidence interval [CI]: 0.49-1.37) and 0.84 for total PCBs (95% CI: 0.47-1.52), 0.69 for PCB 118 (95% CI: 0.39-1.22), 0.87 for PCB 138 (95% CI: 0.50-1.50), 0.83 for PCB 153 (95% CI: 0.47-1.48), and 0.98 for PCB 180 (95% CI: 0.55-1.75). Sub-group analyses were also performed. Overall, our results do not support the hypothesis that exposure to DDT and PCBs increases the risk of breast cancer.     

Polychlorinated biphenyls and their association with survival following breast cancer

BackgroundPolychlorinated biphenyls (PCBs) are hypothesised to influence breast carcinogenesis due to their persistence and potential to induce oestrogenic and anti-oestrogenic effects. Whether PCBs influence survival following breast cancer is unknown.MethodsA population-based cohort of women diagnosed with first primary invasive or in situ breast cancer in 1996–1997 and with blood-measured PCBs (n=627) collected shortly after diagnosis was followed for vital status through 2011. After 5 and 15 years, we identified 54 and 187 deaths, respectively, of which 36 and 74 were breast cancer related. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality for baseline PCB concentrations, individually and as oestrogenic (ΣGroup 1B: PCB101, PCB174, PCB177, PCB187, and PCB199), anti-oestrogenic (ΣGroup 2A: PCB66, PCB74, PCB105, and PCB118; ΣGroup 2B: PCB138 and PCB170), and cytochrome P450 enzyme-inducing (ΣGroup 3: PCB99, PCB153, PCB180, PCB183, and PCB203) groups.ResultsThe highest PCB174 tertile was associated with an increase in all-cause (HR=2.22, 95% CI: 1.14–4.30) and breast cancer-specific (HR=3.15, 95% CI: 1.23–8.09) mortalities within 5 years of diagnosis and remained associated with breast cancer-specific mortality (HR=1.88, 95% CI: 1.05–3.36) at 15 years. At 5 years, the highest tertile of PCB177 was positively associated with all-cause mortality (HR=2.12, 95% CI: 1.05–4.30). At 15 years, the highest tertiles of ΣGroup 2A congeners and PCB118 were inversely associated with all-cause mortality (HR=0.60, 95% CI: 0.39–0.83; HR=0.63, 95% CI: 0.43–0.92, respectively).ConclusionsIn this first US study of PCBs and breast cancer survival, PCBs were associated with mortality in biologically plausible directions. The investigation of other, structurally similar, chemicals may be warranted.     

Adipose organochlorine concentrations and risk of breast cancer among postmenopausal Danish women.

OBJECTIVE: Exposure to environmental organochlorines has been examined as a potential risk factor for human breast cancer with mixed results. Our purpose was to examine associations between organochlorines and the development of breast cancer in a large prospective study using stored adipose tissue. METHODS: We conducted a nested case-control study of 409 postmenopausal women who developed breast cancer and 409 controls selected from the 29,875 women enrolled in the Danish Diet, Cancer, and Health cohort between 1993 and 1997. We measured concentrations of 14 pesticides and 18 polychlorinated biphenyls in adipose tissue, collected upon enrollment, and estimated relative risk (RR) of breast cancer using conditional logistic regression. RESULTS: The results showed no higher risk of breast cancer among women with higher levels of any pesticides or polychlorinated biphenyls; the RR associated with the upper quartile of 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene concentration was 0.7 [95% confidence interval (95% CI), 0.5-1.2] contrasting the lower quartile, and for the sum of polychlorinated biphenyls the similar risk was 1.1 (95% CI, 0.7-1.7). We observed a pattern of substantially lower risk of estrogen receptor-negative breast cancer in association with higher levels of most of the pesticides and polychlorinated biphenyls; the RR for the higher quartile of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene was 0.1 (95% CI, 0.0-0.5) and for the sum of polychlorinated biphenyls it was 0.3 (95% CI, 0.1-0.9). CONCLUSION: The results do not support that higher organochlorine body levels increase the risk of breast cancer in postmenopausal women. The interpretation of the inverse association for estrogen receptor-negative breast cancer is currently unclear.     

Hormone replacement therapy and breast cancer in former users of oral contraceptives--The Norwegian Women and Cancer study

Combined estrogen-progestin menopausal therapy (HRT) and combined estrogen-progestin contraceptives (OC) both increase breast cancer risk during current use and a few years after. We investigated risk of breast cancer in women who were users of HRT dependant on former history of OC use in a large, national population-based cohort study, the Norwegian Women and Cancer study (NOWAC). Exposure information was collected through postal questionnaires. Based on follow-up of 30,118 postmenopausal women by linkage to national registers of cancer, deaths, and emigration we revealed 540 incident breast cancer cases between 1996 and 2004. Compared to never users of either drugs current use of HRT gave a significant (p = 0.002) higher risk of breast cancer in former OC users, RR = 2.45 (95% CI 1.92-3.12), than among never users of OCs, RR = 1.67 (1.32-2.12). Relative risk of current use of HRT was similar for estrogen only and combinations with progestin added in ever users of OCs. The increased risk of breast cancer in current HRT users with a history of former OC use could have potential great impact on postmenopausal breast cancer risk as the proportion of postmenopausal women with former OC use will continue to increase.     

Early oral contraceptive use and breast cancer among premenopausal women: final report from a study in southern Sweden

In southern Sweden during the 1960s, women began to use oral contraceptives (OCs) extensively at a young age. This case-control study investigates the relationship between the use of OCs and breast cancer development in women in southern Sweden diagnosed in the early 1980s. The risk for breast cancer after OC use among premenopausal women was modeled, after adjustment was made for age, age at menarche, and age at first full-term pregnancy or parity. Both the duration of OC use before 25 years of age and commencement of OC use at a young age were associated with a significant increase in the risk of breast cancer as well as a significant trend. The duration of OC use before the first full-term pregnancy was associated with an increased risk of breast cancer, but it did not show a significant trend. The total duration of OC use was weakly, but not significantly, associated with breast cancer development. The odds ratio for women starting OC use before 20 years of age was 5.8 [95% confidence interval (CI), 2.6-12.8]; for women using OCs for greater than 5 years before age 25, it was 5.3 (95% CI, 2.1-13.2); and for women using OCs for greater than or equal to 8 years before first full-term pregnancy, it was 2.0 (95% CI, 0.8-4.7). In multivariate analyses including the different measurements of OC use, only starting age of OC use was significantly associated with breast cancer. The exposure-response relationship between duration of OC use and risk of breast cancer depended on the age at first use of OCs. Given a fixed duration of OC use, the risk increased with younger starting age of OC use. The findings point to the importance of the early reproductive years as risk determinants for breast cancer after OC use.     

Breast Cancer Risk and the Combined Effect of Environmental Estrogens

OBJECTIVE: The present study aimed to determine whether the combined effects of environmental estrogens measured as the total effective xenoestrogen burden (TEXB-alpha) are a risk factor for breast cancer over and above the risk potentially linked to specific pesticides. METHODS: We measured the levels of 16 organochlorine pesticides as well as TEXB in adipose tissue of 198 women at the time of breast cancer diagnosis. These were compared with findings in 260 age and hospital matched control women without breast cancer. RESULTS: The median levels of p,p'-DDE (1,1-dichloro-2,2-bis( p -chlorophenyl)ethylene), aldrin, endosulfan ether and lindane (the pesticides detected in > 40% of the study population) were higher in cases than controls, although the differences did not reach statistical significance. After adjusting for potential confounders, the odds ratio (OR) for breast cancer in women with detectable levels of aldrin was 1.55 (95% confidence interval (CI) 1.00-2.40). Among the postmenopausal women, the OR for aldrin and lindane was 1.84 (95% CI 1.06-3.18) and 1.76 (95% CI 1.04-2.98), respectively. Among cases with body mass index (BMI) below the median (28.6 kg/m2), the OR was 3.42 (95% CI 1.22-9.58) for women in the highest quartile of TEXB-alpha versus those in the lowest. The subgroup of leaner postmenopausal women showed an increased risk (OR: 5.67; 95% CI 1.59-20.21) for those in the highest tertile versus those in the lowest. CONCLUSIONS: We found an increased risk for breast cancer in the leaner women, especially in the leaner postmenopausal subgroup, related to the TEXB-alpha. The pesticides aldrin and lindane are also individually associated with risk.     

A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States)

Results of previous epidemiologic studies have provided reassurance that there is little, if any, increase in risk of breast cancer with oral contraceptive (OC) use in general. However, in several studies, an increased risk of breast cancer has been observed in two subgroups, young women who used OCs for extended durations and in women who used OCs prior to a first-term pregnancy. We evaluated these relationships using data from the ongoing Nurses' Health Study cohort (United States). We documented 3,383 cases of breast cancer from 1976 to 1992 among 1.6 million person-years of follow-up. We observed no overall relationship between duration of OC use and breast cancer risk, even among women who reported using OCs for 10 or more years (multivariate relative risk [RR]=1.11, 95 percent confidence interval [CI]=0.94-1.32). Among women less than 45 years of age, the multivariate RR for using OCs for 10 or more years was 1.07 (CI=0.70-1.65) compared with never-users. The risk associated with five or more years of OC use prior to a first full-term pregnancy compared with never-use was 0.96 (CI=0.65-1.43). Among women less than 45 years of age, we observed no evidence of an increased risk with OC use before a first full-term pregnancy (use for five or more years: RR=0.57, CI=0.24-1.31). Because of the age distribution of our cohort, we were unable to evaluate these relationships among women less than 40 years of age. Our study provides considerable evidence that long-term past OC use, either overall or prior to a first full-term pregnancy, does not result in any appreciable increase in breast cancer risk in women over 40 years of age.     

Use of oral contraceptives and breast cancer risk: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study.

Current use of oral contraceptives (OCs) has been reported to increase breast cancer risk slightly. In 1991/1992, a prospective cohort study specifically designed to examine the role of hormonal contraceptives in relation to breast cancer was conducted in Norway and Sweden. This study was entitled Women's Lifestyle and Health. Of 196,000 invited women aged 30-49 years, 106,844 women answered a 4-page questionnaire. Altogether, 103,027 women providing information on contraceptive use were included in the analysis presented here, and 1,008 primary invasive breast cancers were diagnosed throughout 1999 (end of follow-up). Proportional hazard regression was used to calculate relative risks (RRs) with adjustment for age and other possible confounders. An increased breast cancer risk was observed among women who were current/recent users of OCs of any type at the start of follow-up [RR, 1.6; 96% confidence interval (CI), 1.2-2.1]. Current/recent use (i.e., use in the year preceding cohort enrolment) of combined OCs (RR, 1.5; 95% CI, 1.0-2.0) and progestin-only pills (RR, 1.6; 95% CI, 1.0-2.4) entailed similar levels of increased risk. An increased risk of borderline significance was found among short-term (i.e., less than 13 months) users before age 20 years (RR, 1.3; 95% CI, 1.0-1.7) and before first full-term pregnancy (RR, 1.4; 95% CI, 1.0-1.8). Long-term users of OCs were at a higher risk of breast cancer than never users (test for trend, P = 0.005). Current/recent use of OCs is associated with an increased breast cancer risk. Use of combined OCs and progestin-only pills seem to increase the risk at the same level.     

Oral contraceptive use and risk of breast cancer in older women (New Zealand)

the effect of oral contraceptive (OC) use at older ages on the risk of breast cancer was examined in a national population-based case-control study conducted in New Zealand. A total of 891 women aged 25 to 54 years with a first diagnosis of breast cancer, and 1,864 control subjects, randomly selected from the electoral rolls, were interviewed. The relative risk (RR) of breast cancer for women aged 45 to 54 years at diagnosis who had ever used OCs was 1.0 (95 percent confidence interval [CI]=0.77–1.3). There was no significant increase in risk of breast cancer among recent users of OCs of any age. Analyses according to age at first and last use among women aged 40 years and older at diagnosis showed no group with an elevated risk of breast cancer. Women who had used OCs for 10 years or longer after age 40 had an apparent increase in risk (RR=2.7, CI=0.97–7.5), but the trend in risk with duration of use was not significant. These findings suggest that OC use in older women does not affect their risk of breast cancer appreciably, but it is not possible to rule out a modest increase in risk with such use.This research was supported by grants from the Medical Research Council of New Zealand and from the Special Programme of Research, Development, and Research Training in Human Reproduction, World Health Organization.     

Dichlorodiphenyldichloroethene, polychlorinated biphenyls, and breast cancer among African-American and white women in North Carolina.

We examined plasma dichlorodiphenyldichloroethene (DDE) and total polychlorinated biphenyl (PCB) levels in relation to breast cancer in a population-based, case-control study of African-American women (292 cases and 270 controls) and white women (456 cases and 389 controls) in North Carolina. Adjusted odds ratios (ORs) for breast cancer comparing the highest to lowest third of DDE were 1.41 [95% confidence interval (CI), 0.87-2.29] in African-American women and 0.98 (95% CI, 0.67-1.43) in white women. ORs comparing the highest to lowest third of total PCBs were 1.74 (95% CI, 1.00-3.01) in African-American women and 1.03 (95% CI, 0.68-1.56) in white women. Among African-Americans, the OR for total PCBs was highest for obese women (body mass index 234.2; OR, 4.92; 95% CI, 1.63-14.83). In contrast, the OR for DDE was highest for the leanest African-American women (body mass index, <25; OR, 3.84; 95% CI, 0.98-15.08). ORs for DDE were not elevated among women who lived or worked on farms or elevated among farming women who reported exposure to pesticides. Our results suggest absence of a strong effect for DDE or total PCBs in breast cancer but lend support for associations among subgroups of women. In our study, factors such as income, parity, breastfeeding, race/ethnicity, and body mass index influenced the relationship of organochlorines and breast cancer. Differing distributions of such factors may explain some of the inconsistencies across previous studies.     

Dietary cadmium exposure and risk of postmenopausal breast cancer: a population-based prospective cohort study

The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER)-defined (ER(+) or ER(-)) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow-up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER(+) and 290 ER(-)). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P(trend) = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07-1.50) and for ER(+) tumors (RR, 1.25; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER(-) tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each tertile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P(interaction) = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development.     

Oral contraceptives and breast cancer in northern Italy. Final report from a case-control study.

To assess the relation between oral contraceptive (OC) use and breast cancer, we analysed data from a case-control study conducted in Northern Italy between 1983 and 1991 on 2,309 cases below age 60 and 1,928 controls admitted to hospital for acute diseases unrelated to OC use and to any of the known or potential risk factors for breast cancer. OC use was reported by 16% of cases and 14% of controls. The multivariate relative risk (RR) for ever vs never use of combination OC was 1.2 (95% confidence interval (CI) 1.0-1.4). However, there was no trend in risk with duration. The RR was elevated for very short use, but declined to 0.8 (95% CI = 0.5-1.0) for five or more years'' use. No noteworthy relationship was found for other major measures of OC use, although RR estimates were above unity for women who had stopped use less than 5 years before (RR = 1.5, 95% CI = 1.1-2.0), started use less than 10 years before (RR = 1.3, 95% CI = 1.0-1.9), started when 25 or more years old (RR = 1.4, 95% CI = 1.1-1.7), or after first birth (RR = 1.2, 95% CI = 1.0-1.5). No interaction was observed between OC use and family history of breast cancer, parity and age at first birth. A separate analysis of 373 cases and 456 control below age 40 showed no association with ever use (RR = 0.9, 95% CI = 0.6-1.2).     

Breast cancer risk in relation to adipose concentrations of organochlorine pesticides and polychlorinated biphenyls in Long Island, New York.

To assess a possible etiological role of organochlorine compounds in breast cancer development on Long Island, a high-risk region of New York State, concentrations of organochlorine pesticides and polychlorinated biphenyls (PCBs) were measured in the adipose tissue of 232 women with breast cancer and 323 hospital controls admitted to surgery for benign breast disease or non-breast-related conditions. Seven pesticide residues and 14 PCB congeners were assayed via a supercritical fluid extraction method followed by gas chromatography with electron capture detection. After adjustment for age and body mass index, which were strongly correlated with organochlorine levels, adipose concentrations of 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, and total polychlorinated biphenyls (PCBs) did not differ significantly between cases and controls. The relative abundance of individual pesticide species and PCB congeners was similar in cases and controls. Odds ratios adjusted for age, BMI, hospital, and race gave no evidence of a dose-response for 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, or total PCBs, whether stratified by estrogen receptor status or not. Breast cancer risk among Long Island residents was not elevated compared with residents of the adjacent New York City borough of Queens. We did not confirm a previously reported association between breast cancer risk and levels of PCB congener 118 (2,3',4,4',5-pentachlorobiphenyl), nor did we observe an association with the most abundant congener 153 (2,2',4,4',5,5'-hexachlorobiphenyl), a strong inducer of phase I enzymes that was reported recently to have estrogenic properties. Only PCB congener 183 (2,2',3,4,4',5',6-heptachlorobiphenyl), which is also an inducer, was significantly associated with risk, with an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.4) in women with adipose levels >5.67 ng/g; the biological importance of this observation is unclear without confirmation in additional studies. Although neither the present nor other studies have provided convincing evidence of an association between body burden of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane and PCBs with cancer of the breast, these compounds are rated as "possible" and "probable" human carcinogens, respectively, by the International Agency for Research on Cancer. Investigations of associations with cancer at other sites should be carried out.     

Risk and aggressiveness of breast cancer in relation to plasma organochlorine concentrations.

Several organochlorines identified as "hormone mimics" were proposed as possible risk factors for breast cancer. We conducted a case-control study to assess breast cancer risk and disease aggressiveness in relation to plasma concentrations of several organochlorine compounds. Plasma lipid concentrations of 11 chlorinated pesticides and 14 polychlorinated biphenyl congeners were measured in 315 women newly diagnosed with breast cancer, 219 hospital-based controls, and 307 population controls from the Quebec City area (Canada). Concentrations of hormonally active organochlorines or their surrogates were compared between cases and controls as well as between groups of cases defined according to tumor size and axillary-lymph-node involvement. We found similar levels of organochlorines in cases and controls and no relationship between the relative risk of breast cancer and organochlorine exposure. However, the probability of lymph-node invasion among cases increased with exposure to 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene [p,p'-DDE; odds ratio, 2.54; 95% confidence interval (CI), 1.20-5.35; between the highest and the lowest tertiles]. Furthermore, p,p'-DDE exposure was associated with a dose-related increased relative risk of exhibiting both lymph-node involvement and a large tumor. Indeed odds ratio raised to 2.33 (95% CI, 0.94-5.77) for the second tertile relative to the first tertile and reached 3.51 (95% CI, 1.41-8.73) for the third tertile relative to the first tertile. Similar associations were noted with beta-hexachlorocyclohexane, oxychlordane, and transnonachlor. We conclude that exposure to persistent, hormonally active organochlorines during adulthood is not associated with breast cancer risk. The possibility that some organochlorines and especially p,p'-DDE may increase breast cancer aggressiveness deserves further attention.     

Serum levels of beta-hexachlorocyclohexane, hexachlorobenzene and polychlorinated biphenyls and breast cancer in Mexican women.

Information on the association between exposure to beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene (HCB) or polychlorinated biphenyls (PCBs) and the incidence of breast cancer is inconclusive. However, exposure to such compounds is a public health concern in Mexico and is subject to recent regulation. Serum levels of beta-HCH, HCB and PCBs were analysed in 95 histologically confirmed breast cancer cases and 95 hospital controls, 20-79 years of age, from Mexico City, enrolled between March 1994 and April 1996. After adjusting for established risk factors, there was no evidence of a relationship between beta-HCH, HCB and PCBs and breast cancer risk (OR for beta-HCH tertile 3 versus tertile 1: 1.05 95% CI 0.46-2.40; OR for HCB tertile 3 versus tertile 1: 0.46 95% CI 0.20-1.07; OR for PCBs 1.31 95% CI 0.33-5.21 for the high category of exposure). This study lends no support to the case for a role for beta-HCH, HCB or PCBs in breast cancer aetiology.     

Physical activity and risk of breast cancer in premenopausal women

Physical activity appears to be inversely related to risk of breast cancer, yet the results remain inconsistent. To evaluate this relation among premenopausal women and examine variation in risk according to level of obesity and use of oral contraceptives (OCs), the authors examined data from the Nurses' Health Study II. During 10 years of follow-up, 849 cases of invasive premenopausal breast cancer were confirmed. Physical activity was assessed by self-report at baseline and during follow-up using a validated questionnaire. Total physical activity was unrelated to risk of breast cancer. Women engaging in >or=27 metabolic equivalent (MET)-h week(-1) had a multivariate-adjusted relative risk (RR) of 1.04 (95% confidence interval (CI) 0.82-1.33) compared to those in the <3 MET-h week(-1) category. Among women with a BMI >or=30 kg m(-2), we observed a significant positive dose-response relation (P=0.04). Activity was unrelated to breast cancer risk at lower levels of BMI. A test for interaction between activity and BMI (<30, >or=30 kg m(-2)) was statistically significant (P=0.02). Among current OC users, higher activity was associated with a non-significantly lower risk of breast cancer (RR=0.59, 95% CI 0.30-1.16 for >or=27 vs <9 MET-h week(-1), P for linear trend=0.14). These results show no overall association between physical activity and risk of breast cancer among premenopausal women, but suggest that the effect of physical activity could be substantially modified by the underlying degree of adiposity. The potential interactions between physical activity, adiposity, and current use of OCs require further study.     

Oral contraceptives and colorectal cancer risk: a meta-analysis

Several studies have suggested an inverse association between use of combined oral contraceptives (OC) and the risk of colorectal cancer and here we present a meta-analysis of published studies. Articles considered were epidemiological studies published as full papers in English up to June 2000 that included quantitative information on OC use. The pooled relative risks (RR) of colorectal cancer for ever OC use from the 8 case-control studies was 0.81 (95% confidence interval (CI): 0.69-0.94), and the pooled estimate from the 4 cohort studies was 0.84 (95% CI: 0.72-0.97). The pooled estimate from all studies combined was 0.82 (95% CI: 0.74-0.92), without apparent heterogeneity. Duration of use was not associated with a decrease in risk, but there was some indication that the apparent protection was stronger for women who had used OCs more recently (RR = 0.46; 95% CI: 0.30-0.71). A better understanding of this potential relation may help informed choice of contraception.     

Exogenous hormone use and the risk of postmenopausal breast cancer: results from the Netherlands Cohort Study

The association between the use of exogenous hormones as either oral contraceptives (OC) or hormone replacement therapy (HRT) in relation to postmenopausal breast cancer incidence was examined in the Netherlands Cohort Study (NLCS) among 62,573 women aged 55 to 69 years. Information on these types of exogenous hormone use and other risk factors was collected by mailed questionnaire. During 3.3 years of follow-up, 471 incident breast cancer cases were identified. After adjustment for traditional breast cancer risk factors, the relative risk (RR) of breast cancer was 1.09 (95 percent confidence interval [CI]=0.79–1.48) for women who ever used OCs cf women who never used OCs. The relative rates (with CIs) for women who used OCs for a period < 5 years, 5–9 years, 10–14 years, and 15+ years were 0.97 (0.61–1.55), 1.20 (0.69–2.07), 1.03 (0.60–1.77), and 1.96 (0.99–3.89), respectively. The test for trend was not significant (P=0.13). There was no evidence of any association between the number of years between the first and the last use of OCs and breast cancer incidence. In the subgroup of women with first-degree relatives with breast cancer, the RR for breast cancer associated with ever use of OCs was 1.51 (CI=0.67–3.41), whereas in the remaining women, the RR was 0.97 (CI=0.73–1.27). Ever-use of HRT compared with never-use was not associated with an increase in breast cancer risk in the multivariate analysis (RR=0.99, CI=0.68–1.43). Also, the number of years of HRT use was not associated with an increased breast cancer risk (trend P=0.83), nor was the number of years between the first and the last use of HRT and breast cancer incidence. One subgroup of women in which the use of HRT seemed associated (but not significantly) with an increase in breast cancer risk was women with an induced menopause (RR=1.72, CI=0.95–3.12). The RR of breast cancer for women who had ever used both OCs and HRT, compared with women who never used these exogenous hormones was 1.00 (CI=0.51–1.94). From this study, it cannot be concluded that the use of exogenous hormones is a strong risk factor for the development of postmenopausal breast cancer.Since the acceptance of this paper, two other papers have been published on HRT and breast cancer. For HRT (estrogen alone), one supports our finding of no association (Stanford et al, JAMA 1995; 274: 137–42) and one did find a positive association for current use (Colditz et al, New Engl J Med 1995; 332: 1589–93), most pronounced in older women with longer durations of use. With regard to use of combined estrogen-progestin HRT, the results in both papers were comparable to those for estrogen alone. More research on (combinations of) types of hormones is needed.This work was supported by the Dutch Cancer Society.     

Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing

Oral contraceptive (OC) use in young women has been associated with an increased risk of breast cancer. This matched case-control study aims to elucidate the combined effects of OC use and genetic factors in a population-based series of BRCA1/2 mutation-tested early-onset breast cancers. A first invasive breast cancer was diagnosed in 259 women aged 40 years between 1990 and 1995 in the South Swedish Health Care Region. A total of 245 women were included in this study. Information on family history of cancer, reproductive factors, smoking and OC use was obtained from questionnaires or patient charts. Three age-matched controls per case were chosen from a prospective South Swedish cohort. Ever OC use and current OC use were not associated with breast cancer. Cases were more likely to have used OCs before age 20 years (adjusted odds ratio (OR) 2.10 (95% CI 1.32-3.33)) and before their first child (adjusted OR 1.63 (95% CI 1.02-2.62)). When stratified by age, the effect of early OC use was limited to women diagnosed prior to age 36 years (OR 1.53 (1.17-1.99) per year of OC use prior to age 20 years). The risks were similar for low-dose and high-dose OCs. The probability of being a BRCA1/2 mutation carrier was three times higher among cases who started OC use prior to age 20 years compared with cases who started at age 20 years or older or who had never used OCs. However, the duration of OC use was similar among cases with and without BRCA1/2 mutations. No association was seen with a first-degree family history of breast cancer. Each year of OC use prior to age 20 years conferred a significantly increased risk for early-onset breast cancer, while there was no risk associated with use after age 20 years.     

N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer.