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.     

A case-control study of breast cancer and hormonal contraception in Costa Rica

By 1981, 11% of married women in Costa Rica ages 20-49 years had used depot-medroxyprogesterone acetate (DMPA) and 58% had used oral contraceptives (OCs). Since 1977, the Costa Rican Ministry of Health has maintained a nationwide cancer registry. These circumstances provided an opportunity for a population-based, case-control study of DMPA, OCs, and breast cancer in Costa Rica. Cases were 171 women ages 25-58 years with breast cancer diagnosed between 1982 and 1984; controls were 826 women randomly chosen during a nationwide household survey. Cases and controls were interviewed with the use of a standard questionnaire covering their reproductive and contraceptive histories. Logistic regression methods were used to adjust for confounding factors. While few cases or controls had ever used DMPA, DMPA users had an elevated relative risk (RR) estimate of breast cancer of 2.6 (95% confidence limits = 1.4-4.7) compared with never users. However, no dose-response relationship was found; even the group of women who had used DMPA for less than 1 year had an elevated RR estimate (RR = 2.3; 95% confidence limits = 1.0-5.1). In contrast, OC users had no elevation in RR compared with never users (RR = 1.2; 95% confidence limits = 0.8-1.8). The results of the DMPA analysis are inconclusive. Before decisions are made on whether to continue providing this effective contraceptive method, other ongoing studies will need to confirm of refute these findings.     

Oral contraceptive use and mammographic patterns.

High-risk mammographic patterns represent an increased risk of contracting breast cancer and may be used as a surrogate endpoint for the disease. We examined the relationship between oral contraceptive (OC) use and mammographic patterns among 3218 Norwegian women, aged 40-56 years. Information on ever OC use, duration, and age of first OC use and other epidemiological data were obtained through questionnaires. The mammograms were categorized into five groups. Patterns I-III were combined into a low-risk group and patterns IV and V into a high-risk group. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression and adjusted for age, menopausal status, parity, age at first birth, and body mass index. Women who reported ever having used OCs were 20% more likely (OR 1.27, 95% CI 1.0-1.6) to have high-risk mammographic patterns compared with those reporting never having used OCs. There was no dose response between different measures of OC use and high-risk patterns. Among nulliparous women, ever OC users were four times more likely (OR 4.65, 95% CI 2.1-10.3) to have high-risk patterns compared with never users. Our findings suggest that, especially among nulliparous women, ever OC use may exert its effect on breast cancer risk through changes in breast tissue, which can be observed on a mammogram.     

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.     

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.     

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.     

Combined oral contraceptives containing chlormadinone acetate and breast cancer: results of a case-control study.

The main subject of this hospital-based case-control study was the possible relationship between use of combined oral contraceptives (OCs) containing chlormadinone acetate and breast cancer. Analyses were based on data from 490 cases with newly diagnosed breast cancer and 1,223 controls and were separately performed for combined OCs with and without chlormadinone. For either of the combined OCs, risk was not elevated in ever users, did not increase with duration of use and did not change with time since initial exposure or with time since most recent use. However, the relative risk was increased in current users: RR = 1.72 (0.88, 3.36) for combined OCs with chlormadinone and RR = 1.42 (1.01, 2.00) for combined OCs without chlormadinone, which is, however, explained as a screening effect. These results show that chlormadinone as a constituent of combined OCs does not influence breast cancer risk.     

Oral contraceptives and breast cancer: results from an expanded case-control study

The relationship between oral contraceptives and breast cancer was evaluated among 2,022 cases and 2,183 controls participating in a multicentre breast cancer screening programme. Ever use of oral contraceptives was not related to breast cancer risk (RR = 1.0, 95% CI 0.9-1.2), and no overall patterns of increasing or decreasing risks were observed according to the duration of use, or time since first or most recent use. Although we had no women with extended periods of oral contraceptive use early in life, no evidence of adverse effects attributable to short-term use before age 25, before first live birth or during the perimenopausal period were observed. Further, oral contraceptives did not interact with other breast cancer risk factors, except among those with a history of two or more breast biopsies (RR = 2.0). Analyses by stage of disease revealed that risk was related to the duration of oral contraceptive use: greater than or equal to 5 years use was associated with reduced risk for in situ cancer (RR = 0.59) and increased risks for invasive cancers (RR = 1.5 and 1.4 respectively for small and large lesions). These data suggest that oral contraceptive effects may vary by stage of disease, but provide no overall evidence of an association between oral contraceptives and breast cancer.     

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.     

Active and passive smoking and breast cancer risk in middle-aged Japanese women

To examine the hypothesis that tobacco smoke is associated with the risk of female breast cancer, we estimated the relative risks of active and passive smoke in middle-aged Japanese women in a population-based prospective study. The cohort consisted of residents in 4 public health center areas, aged 40 to 59 years. A self-administered questionnaire survey was conducted in 1990. This analysis included 21,805 subjects, 180 of whom had developed breast cancer by December 31, 1999. When the reference was defined as never-active smokers without passive smoking, adjusted relative risks (RRs) were 1.9 (95% confidence interval [CI] = 1.0-3.6) in current active smokers, 1.2 (95% CI = 0.4-4.0) in ex-active smokers and 1.2 (95% CI = 0.8-1.6) in never-active smokers with passive smoking. The elevated risk for ever-smokers was clearly observed in premenopausal women at baseline (RR = 3.9, 95% CI = 1.5-9.9) but not in postmenopausal women (RR = 1.1, 95% CI = 0.5-2.5). In never-active smokers, the adjusted RR for passive smoking, residential or occupational/public tobacco smoke exposure was 1.1 (95% CI = 0.8-1.6). In premenopausal women, passive smoking increased the risk (RR = 2.6; 95% CI = 1.3-5.2) but not in postmenopausal women (RR = 0.7; 95% CI = 0.4-1.0). We conclude that tobacco smoking increases the risk of female breast cancer in premenopausal women.     

Hormone replacement therapy and risk of non-hodgkin lymphoma and chronic lymphocytic leukemia.

Our objective in this study was to evaluate whether the use of hormone replacement therapy (HRT) is associated with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). A cohort of 37,220 Iowa women ages 55 to 69 years in 1986 with no history of prior cancer was linked annually to a population-based cancer registry. Through 1998 (13 years of follow-up), 258 incident cases of NHL were identified, including 135 cases of diffuse NHL, 58 cases of follicular NHL, and 31 cases of small lymphocytic NHL. In addition, 63 cases of CLL were identified. Current and former use of HRT (primarily estrogen) and other cancer risk factors were self-reported on the baseline (1986) questionnaire. Compared with never users of HRT at study baseline, current [multivariate relative risk (RR), 1.4; 95% confidence intervals (CIs), 0.9-2.0) but not former (RR, 1.1; 95% CI, 0.8-1.4) users were at increased risk of NHL after adjustment for age and other confounding factors. This association was seen only in nodal NHL [RR(current), 1.5 (95% CI, 1.0-2.4); RR(former), 1.1 (95% CI, 0.8-1.6)] and was not apparent for extra-nodal sites. Of the common subtypes, there was a strong positive association with follicular NHL [RR(current), 3.3 (95% CI, 1.6-6.9); RR(former), 2.6 (95% CI, 1.4-4.7)], and women who were current users for more than 5 years had the highest risk (RR, 3.9; 95% CI, 1.8-8.6). There was no association with diffuse or small lymphocytic NHL, or with CLL. Most of the follicular NHLs were nodal (88%), and exclusion of extra-nodal sites slightly strengthened the association with HRT. For diffuse NHL, 64% of the cases were nodal, and there was no association of HRT with either nodal or extra-nodal sites. These data suggest that HRT is a risk factor for follicular NHL but not for diffuse or small lymphocyte NHL or CLL.     

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.     

Breast cancer with different prognostic characteristics developing in Danish women using hormone replacement therapy

The aim of this study is to investigate the risk of developing prognostic different types of breast cancer in women using hormone replacement therapy (HRT). A total of 10 874 postmenopausal Danish Nurses were followed since 1993. Incident breast cancer cases and histopathological information were retrieved through the National Danish registries. The follow-up ended on 31 December 1999. Breast cancer developed in 244 women, of whom 172 were invasive ductal carcinomas. Compared to never users, current users of HRT had an increased risk of a hormone receptor-positive breast cancer, but a neutral risk of receptor-negative breast cancer, relative risk (RR) 3.29 (95% confidence interval (CI): 2.27-4.77) and RR 0.99 (95% CI: 0.42-2.36), respectively (P for difference=0.013). The risk of being diagnosed with low histological malignancy grade was higher than high malignancy grade with RR 4.13 (95% CI: 2.43-7.01) and RR 2.17 (95% CI: 1.42-3.30), respectively (P=0.063). For breast cancers with other prognostic characteristics, the risk was increased equally for the favourable and non favourable types. Current users of HRT experience a two- to four-fold increased risk of breast cancer with various prognostic characteristics, both the favourable and non favourable types. For receptor status, the risk with HRT was statistically significantly higher for hormone receptor-positive breast cancer compared to receptor-negative breast cancer.     

Postmenopausal estrogen and progestin use in relation to breast cancer risk.

Epidemiological evidence now consistently supports a modest increase in breast cancer risk among women using postmenopausal hormones, usually estrogens.Less is known regarding how the addition of progestin affects breast cancer risk. The objective of this study was to investigate the type and duration of postmenopausal therapy and breast cancer risk. We performed a multicenter population-based case-control study set in Massachusetts, New Hampshire, and Wisconsin. The subjects were 5298 postmenopausal women (age range, 50-79 years) with a new diagnosis of invasive breast cancer from statewide tumor registries. For comparison, 5571 controls were randomly selected from population lists. Participants completed a structured telephone interview covering hormone use and breast cancer risk factors. Multivariable regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). The RR for breast cancer increased with longer durations of hormone use, about 2%/year for estrogen alone (RR, 1.02; 95% CI, 1.01-1.03) and 4%/year for estrogen-progestin use (RR, 1.04; 95% CI, 1.01-1.08). Estrogen-progestin use that was both recent and long term (>5 years in duration) was more strongly associated with breast cancer risk (RR, 1.57; 95% CI, 1.15-2.14) than similar use of estrogen alone (RR, 1.39; 95% CI, 1.17-1.65). In estrogen-progestin users, risks were similar for sequential and continuous use regimens but perhaps stronger for lobular than ductal breast cancer. Use of progestin alone was associated with a doubling of risk (RR, 2.09; 95% CI, 1.07-4.07 for ever use versus nonuse). Estrogen-progestin use, both sequential and continuous, appears to be more strongly associated with risk of breast cancer than use of estrogen alone.     

Active and passive smoking and the risk of breast cancer in women aged 36-45 years: a population based case-control study in the UK

Active smoking has little or no effect on breast cancer risk but some investigators have suggested that passive smoking and its interaction with active smoking may be associated with an increased risk. In a population based case-control study of breast cancer in women aged 36-45 years at diagnosis, information on active smoking, passive smoking in the home, and other factors, was collected at interview from 639 cases and 640 controls. Women were categorised jointly by their active and passive smoking exposure. Among never smoking controls, women who also reported no passive smoking exposure were significantly more likely to be nulliparous and to be recent users of oral contraceptives. Among those never exposed to passive smoking, there was no significant association between active smoking and breast cancer, relative risk (RR) of 1.12 (95% confidence interval (CI) 0.72-1.73) for past smokers and RR of 1.19 (95% CI 0.72-1.95) for current smokers, nor was there an association with age started, duration or intensity of active smoking. Compared with women who were never active nor passive smokers, there was no significant association between passive smoking in the home and breast cancer risk in never smokers, RR of 0.89 (95% CI 0.64-1.25), in past smokers, RR of 1.09 (95% CI 0.75-1.56), or in current smokers, RR of 0.93 (95% CI 0.67-1.30). There was no trend with increasing duration of passive smoking and there was no heterogeneity among any of the subgroups examined. In this study, there was no evidence of an association between either active smoking or passive smoking in the home and risk of breast cancer.     

Progestogen-only oral contraceptives and risk of breast cancer in New Zealand

Little is known about the influence of progestogen-only contraceptives on a woman's risk of breast cancer. This issue was examined in a national population-based case-control study 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. Use of progestogen-only pills was reported by 8.7 percent of all control subjects (and by 17.3 percent of those aged 25 to 34 years). The relative risk (RR) of breast cancer in women who had ever used progestogen-only pills was estimated to be 1.1 (95 percent confidence interval [CI]=0.73–1.5). In women aged 25 to 34 years, the RR was 2.3 (CI=1.2–4.3). Women who had started using progestogen-only pills within the last 10 years were at increased risk of breast cancer (RR=1.6, CI=1.0–2.4), whereas those who had first used them earlier were at significantly reduced risk (RR=0.44, CI=0.22–0.90). These findings are similar to results for depot medroxyprogesterone acetate, and a possible analogy with the influence of pregnancy is also suggested.The anthors are with the Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand. Address correspondence to: Dr Skegg, Department of Preventive and Social Medicine, University of Otago Medical School, P. O. Box 913, Dunedin, New Zealand. This research was supported by grants from the Medical Research Council of New Zealand and from the Special Program of Research, Development, and Research Training in Human Reproduction, World Health Organization.     

Contraceptive methods and induced abortions and their association with the risk of colon cancer in Shanghai, China

267400 female textile workers in Shanghai, who were administered a questionnaire at enrollment into a randomised trial of breast self-examination between October 1989 and October 1991, were followed up until the middle of 2000. Based on the 655 women who developed colon cancer, rate ratios (RRs) were estimated and trends in risk assessed using Cox Proportional Hazards Models. Risk was increased in women who used oral contraceptives for over 3 years (RR=1.56, 95% Confidence Interval (CI) 1.01-2.40). A possible increase in risk was also observed in women who received progestational injections during pregnancy (RR=1.24, 95% CI 0.95-1.62), but not in relation to the use of injectable contraceptives. A possible reduction in risk was associated with tubal ligation (RR=0.86, 95% CI 0.71-1.03) and ever having had an induced abortion (RR=0.84, 95% CI 0.71-1.00). No trends in risk were observed in relation to the duration of hormonal contraceptive use or the number of induced abortions. Additional studies of the possible roles contraceptives may play in the aetiology of colon cancer in women at low risk of this disease are warranted.     

Hormone replacement therapy and incidence of hormone-dependent cancers in the Norwegian Women and Cancer study

Increasing use of HRT over the last 2 decades could have contributed to the increasing incidence of cancer in women. Our aim was to investigate the relation between use of HRT and risk of hormone-dependent cancers in a Norwegian cohort of women. The Norwegian Women and Cancer (NOWAC) study is a representative, national, population-based cohort study. This report includes 35,456 postmenopausal women aged 45-64 years who answered a postal questionnaire in 1996-1998 providing information on reproduction, lifestyle and use of HRT. The women were followed up for cancer incidence. The main analyses were restricted to 31,451 postmenopausal women with complete information. Ever use of HRT was reported by 43.5% and current use, by 35% of the women. Current users had an increased risk of breast cancer (adjusted RR=2.1, 95% CI 1.5-2.5). The risk increased with increasing duration of use (ptrend < 0.0001). Using a regimen of continuous estrogen-progestagen implied an increased risk. Adjusted RRs associated with <5 and > or =5 years' duration of use were 2.6 (95% CI 1.9-3.7) and 3.2 (95% CI 2.2-4.6), respectively. The population-attributable risk of breast cancer due to current use of HRT was 27%. We found no significant increase in risk of ovarian cancer. Neither did we find users of estrogen-progestagen preparations to have any increase in risk of endometrial cancer. Our results suggest that HRT could be considered a major determinant for the increasing incidence of breast cancer in Norway.     

Androgen receptor (CAG)n and (GGC)n polymorphisms and breast cancer risk in a population-based case-control study of young women.

The androgen receptor (AR) is involved in the regulation of hormone-responsive genes and, as such, variation within the gene is hypothesized to play a role in breast cancer susceptibility. We therefore assessed the relationship between AR repeat variation and breast cancer in young women from the general population. Women diagnosed with breast cancer before age 45 years and age-matched controls, all participants in a population-based case-control study of breast cancer, were assessed for length variation in the (CAG)(n) and (GGC)(n) AR repeats within the AR gene. Results were generated from 524 cases and 461 controls. As per previous studies, (CAG)(n) repeat lengths of <22 were classified as short (S), and those of > or =22 were classified as long (L). For (GGC)(n) repeats, those < 17 were classified as short, and those > or = 17 were classified as long. Women with a cumulative (CAG)(n) repeat size of > or =43 showed a modest increase in risk for breast cancer [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7]. Women with a (GGC)(n) long (L) allele and those with a > or =33 cumulative repeat size had a decreased risk of breast cancer (OR, 0.7; 95% CI, 0.5-0.9). Among women homozygous for the (CAG)(n) short (S) allele and those with any (GGC)(n) L allele, an increased risk of breast cancer in relation to ever use of oral contraceptives [OCs; OR = 1.9 (95% CI, 1.0-3.6) and OR = 1.7 (95% CI, 0.9-3.5), respectively] was observed. An increased risk for OC use, however, was not observed among women with the CAG L or GGC S allele. This study, one of the first to examine both (CAG)(n) and (GGC)(n) in a population-based study for its relation to breast cancer risk, suggests a reduced risk in young women with (GGC)(n) repeat lengths of > or =17. In addition, these data suggest that AR repeat length may be partly responsible for the increased risk for early-onset breast cancer in women who use OCs, although these findings need replication in other populations.