Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study.

BACKGROUND: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16alpha-hydroxyestrone (16alpha-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors. METHODS: 24,697 postmenopausal Danish women were enrolled in the "Diet, Cancer and Health" cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16alpha-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated for total and estrogen receptor-specific breast cancer and were stratified according to HRT use. RESULTS: A higher incidence of estrogen receptor-positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% CI, 0.69-1.45). The association between estrogen receptor-positive breast cancer and the 16alpha-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor-negative breast cancer, no significant associations were seen. CONCLUSIONS: The risk of breast cancer, in particular the estrogen receptor-positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.     

Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population.

PURPOSE: We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use. METHODS: From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers. RESULTS: Compared with nonusers, women using estrogen and progestin for >/= 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size 相似文献   

Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study

BACKGROUND: The goal of the current study was to investigate the relation between hormone replacement therapy (HRT) and breast carcinoma in a prospective study cohort. Particular attention was paid to the type of HRT used and to the association of HRT type with estrogen receptor status and tumor histology. METHODS: Between 1993 and 1997, a total of 29,875 women were enrolled in the Danish Cancer Society's prospective "Diet, Cancer and Health" study. Among 23,618 women who were assumed to be postmenopausal and for whom information on HRT use was available, we identified 423 cases of breast carcinoma over a median follow-up period of 4.8 years. Statistical analyses were based on the Cox proportional hazards model, with age serving as the time parameter. RESULTS: The breast carcinoma incidence rate ratio (IRR) was 2.22 (95% confidence interval [CI], 1.80-2.75) for users of HRT at baseline compared with women who never received HRT. Among HRT users (relative to nonusers), the IRR for estrogen receptor-positive tumors (2.38; 95% CI, 1.84-3.06) was greater than the IRR for estrogen receptor-negative tumors (1.56; 95% CI, 1.00-2.43). HRT use at baseline also was analyzed in relation to the incidence of lobular carcinoma and the incidence of ductal carcinoma; the adjusted IRR associated with HRT use was 3.53 (95% CI, 1.94-6.41) for lobular carcinoma and 2.10 (95% CI, 1.64-2.70) for ductal carcinoma. The likelihood of developing estrogen receptor-positive breast carcinoma was found to depend significantly on the type of HRT regimen used (P = 0.03), with women receiving continuous therapy having the greatest probability of developing estrogen receptor-positive disease. CONCLUSIONS: An increased breast carcinoma IRR was found to be associated with current HRT use. In addition, relative to other types of HRT regimens, continuous estrogen + progestin regimens were found to be associated with an increased risk of breast carcinoma, and particularly estrogen receptor-positive breast carcinoma.     

Smoking associated with hormone receptor negative breast cancer

Women who smoke have less favourable prognosis following breast-cancer diagnosis. Some studies suggest that this is due to a more advanced stage at diagnosis, on average. Our present aim was to assess whether smoking is associated with other prognostic markers as well, e.g., hormone receptor status, histopathology and tumour differentiation. The evaluation was based on 268 incident cases in a cohort of 10,902 women (35% smokers) followed for an average of 12.4 years. An immunohistochemical method on recuts of tumour tissue was used to assess hormone receptor status. One pathologist classified all tumours according to the WHO system, Nottingham grade and Nottingham Prognostic Index. The relative risk (RR) of oestrogen receptor-negative tumours was, for current smokers, 2.21 [95% confidence interval (CI) 1.23-3.96] and, for ex-smokers, 2.67 (95% CI 1.41-5.06) compared to never-smokers. Ex-smokers had an increased risk of progesterone receptor-negative tumours (RR = 1.61, 95% CI 1.07-2.41), but there were no other significant associations between smoking habits and oestrogen receptor-positive or progesterone receptor-positive or -negative tumours. The incidence of Nottingham grade III tumours was higher in ex-smokers than in never-smokers (RR = 2.03, 95% CI 1.17-3.54). In terms of histopathological type or Nottingham Prognostic Index, there were no significant differences between smoking groups. We conclude that smoking is associated with an increased occurrence of hormone receptor-negative tumours.     

Increased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy

Exposure to hormone-replacement therapy (HRT) has consistently been associated with an increased incidence of breast cancer, particularly of small tumours. Other tumour characteristics in relation to HRT have received less scientific attention. Our aim in this population-based prospective cohort study was to assess whether HRT is associated with an increased incidence of breast-cancer subgroups defined in terms of stage, type (according to the WHO system), Nottingham grade and the Nottingham Prognostic Index (NPI). Evaluation was based on a cohort of 5,865 post-menopausal women followed for an average of 9.8 years. Twenty percent of women reported current use of HRT at the time of the baseline interview. Record linkage with the Swedish Cancer Registry and local clinical registries identified 141 incident invasive breast-cancer cases. All tumours were reclassified by 1 pathologist. The incidence of breast cancer in HRT users was 377/10(5) and in non-users 221/10(5) person-years [relative risk (RR) = 1.72, 95% confidence interval (CI) 1.17-2.52]. This risk remained statistically significant after adjustment for established risk factors in a Cox proportional hazards analysis (RR = 1.66, 95% CI 1.12-2.45). Among HRT users, there was over-representation of cases with stage I tumours (adjusted RR = 2.33, 95% CI 1.44-3.76), of lobular carcinomas (RR = 4.38, 95% CI 1.60-12.0) and of tubular tumours (RR = 4.81, 95% CI 1.37-16.8). Nottingham grade I/II carcinomas (RR = 2.02, 95% CI 1.29-3.16) and cases with NPI < or = 3.4 (RR = 2.29, 95% CI 1.41-3.72) were similarly over-represented among HRT users. Incidence of breast cancer was increased in post-menopausal women who used HRT at baseline. Among HRT users, there was over-representation of tumours that, with regard to stage, type and grade, are associated with a favourable prognosis.     

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort was established in 1993, where all female nurses aged 45 years and above received a mailed questionnaire (n = 23,178). A total of 19,898 women returned the questionnaire (86%). The questionnaire included information on HRT types and regimens, reproductive history and lifestyle-related factors. Breast cancer cases were ascertained using nationwide registries. The follow-up ended on 31 December 1999. Women with former cancer diagnoses, women with missing information on HRT, surgical menopause, premenopausal, as well as hysterectomized women were excluded, leaving 10,874 for analyses. Statistical analyses were performed using Cox proportional hazards model. A total of 244 women developed breast cancer during follow-up. After adjustment for confounding factors, an increased risk of breast cancer was found for the current use of estrogen only (RR = 1.96; 95% CI = 1.16-3.35), for the combined use of estrogen and progestin (RR = 2.70; 95% CI = 1.96-3.73) and for current users of tibolone (RR = 4.27; 95% CI = 1.74-10.51) compared to the never use of HRT. In current users of combined HRT with testosterone-like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens (RR = 4.16, 95% CI = 2.56-6.75, and RR = 1.94, 95% CI = 1.26-3.00, respectively). An increased risk of breast cancer was noted with longer durations of use for the continuous combined regimens (p for trend = 0.048). The European traditional HRT regimens were associated with an increased risk of breast cancer. The highest risk was found for the use of continuous combined estrogen and progestin.     

A prospective study of smoking and risk of breast cancer in young adult women.

OBJECTIVES: To investigate the association between smoking and invasive breast cancers characterized by their estrogen receptor status in a large prospective study of mainly premenopausal women. METHODS: 112,844 women aged 25-42 years in 1989 were followed 10 years; questionnaire information on medical illnesses and risk factors was collected biennially and information on diet was collected in 1991 and 1995. During this period of follow-up (1,077,536 person-years), 1009 incident breast cancer cases were documented. RESULTS: In the multivariate-adjusted models, smoking status was not significantly related to overall breast cancer risk: compared with never smokers, the relative risks (RRs) were 1.18 [95% confidence interval (CI) 1.02-1.36] for past smokers and 1.12 (95% CI 0.92-1.37) for current smokers. Increasing duration of smoking before the first pregnancy was associated with a greater risk of breast cancer, although little increase was seen in the highest category: compared with never smokers, RRs were 1.42 (95% CI 1.10-1.83) for 15-19 years of smoking and 1.10 (95% CI 0.80-1.52) for >/=20 years of smoking (P for trend = 0.01). Smoking was related most strongly to the risk of estrogen receptor-positive breast cancers. For women who had smoked for >/=20 years, the RR of estrogen receptor-positive cancer was 1.37 (95% CI 1.07-1.74) and the RR of estrogen receptor-negative cancer was 1.04 (95% CI 0.71-1.53). For smoking before age 15, the RRs were 1.49 (95% CI 1.03-2.17) for estrogen receptor-positive cancer and 1.19 (95% CI 0.69-2.08) for estrogen receptor-negative cancer. CONCLUSIONS: Our results suggest that longer duration of smoking may be related to the risk of estrogen receptor-positive breast cancer but possibly less so for estrogen receptor-negative breast cancer.     

Red meat consumption during adolescence among premenopausal women and risk of breast cancer

BACKGROUND: Adolescence may be a period of increased susceptibility to breast cancer due to regular division of undifferentiated cells that occurs between puberty and first birth. Red meat consumption during early adult life has been associated with breast cancer, but intake during adolescence has not been examined prospectively. We aimed to assess the relationship between red meat intake during adolescence and premenopausal breast cancer. METHODS: We examined the incidence of invasive premenopausal breast cancer prospectively within the Nurses' Health Study II. A total of 39,268 premenopausal women who completed a validated 124-item food frequency questionnaire on their diet during high school, were followed for 7 years, from 1998 to 2005. Cox proportional hazards regression was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). RESULTS: 455 cases of invasive premenopausal breast cancer were diagnosed between 1998 and 2005. Compared with women in the lowest quintile of red meat intake during high school, the multivariate-adjusted RR for the highest quintile of intake was 1.34 (95% CI, 0.94-1.89; P(trend) = 0.05). A significant linear association was observed with every additional 100 g of red meat consumed per day (RR, 1.20; 95% CI, 1.00-1.43; P = 0.05). This association was more pronounced in hormone receptor-positive tumors (RR, 1.36; 95% CI, 1.08-1.70; P = 0.008) and was not significant in hormone receptor-negative tumors (RR, 0.99; 95% CI, 0.61-1.61, P = 0.97). CONCLUSION: Higher red meat intake in adolescence may increase the risk of premenopausal breast cancer.     

Progestagens use before menopause and breast cancer risk according to histology and hormone receptors

In a previous study, we found a positive association between premenopausal use of progestagens and breast cancer risk. We conducted the present study to assess the risk of breast cancers defined by their histology and hormone receptors status. We evaluated the association between progestagen-only intake (except for mini pills) before menopause and after the age of 40 years and invasive breast cancer risk in 67,057 women participating in the French E3N cohort study. Histologically confirmed invasive breast cancers (2,264) were identified through biennial self-administered questionnaires completed from 1992 to 2002. Risk estimates were calculated using the Cox proportional hazard model. We found an increased risk of lobular carcinoma associated with premenopausal use of progestagens among both current and past users [hazard ratio (HR), 1.51; 95% confidence interval (95% CI), 1.02-2.24 and HR, 1.38; 95% CI, 1.08-1.75, respectively]. Among current users, the use of progestagens for 4.5 years or more was associated with an increased risk of estrogen receptor-positive/progesterone receptor-positive carcinomas (HR, 1.68; 95% CI, 1.05-2.68), whereas current use of progestagens for <4.5 years was associated with an increase in the estrogen receptor-positive/progesterone receptor-negative carcinoma risk (HR, 1.61; 95% CI, 1.05-2.46). The premenopausal use of progestagens after the age of 40 years may be preferentially associated with the risk of lobular breast cancer and differentially affect the risk of breast cancer according to the hormone receptor status.     

Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case-control study

Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.     

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.     

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.     

Breast tumours following combined hormone replacement therapy express favourable prognostic factors

The aim of the present study was to evaluate the association between different types of hormone replacement therapy (HRT) and risk of specific breast cancer subgroups. A population-based prospective cohort study including 12,583 peri- or postmenopausal women were followed using record-linkage with national cancer registries. During an average follow-up of 4.5 years, 332 cases of invasive breast cancer were diagnosed. Tumour samples were available from 283 cases. These tumours were re-evaluated according to histological type, grade, and mitotic index. Evaluation of tumours included estrogen and progesterone receptor status (ERalpha, ERbeta and PgR), as well as expression of Ki67, HER2, cyclin D1 and p27. The incidence of breast cancer in current users of combined HRT (CHRT) was significantly higher than in non-users. The difference corresponded to an adjusted relative risk (95% confidence interval) of 3.01 (2.35-3.84) as obtained using a Cox's proportional hazards analysis. CHRT was associated with lobular tumours (3.48:1.99-6.10), grade 1 tumours (4.46:2.79-7.13) and tumours with a low mitotic index (4.35:2.99-6.34). CHRT was not related to any specific subgroup in terms of ERalpha-, ERbeta- or PgR-expression. CHRT was associated with low proliferating tumours, defined by the Ki67 index (3.58:2.60-4.93), HER2 amplified tumours (4.40:1.93-10.06), low expression of the oncogene cyclin D1 (3.14:2.32-4.23) and high expression of the tumour suppressor gene p27 (3.47:2.40-5.01). Use of estrogen-alone HRT (ERT) was not associated with any statistically significant risk of breast cancer. We conclude that the use of CHRT is associated with an increased incidence of breast tumours with comparatively favourable prognostic factors.     

Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk.

PURPOSE: Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors. METHODS: We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists' Collaborative Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models. RESULTS: Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months. Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15). CONCLUSION: Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases.     

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.     

Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC)

We examined prospectively the association between weight change during adulthood and breast cancer risk, using data on 1358 incident cases that developed during 5.8 years of follow-up among 40,429 premenopausal and 57,923 postmenopausal women from six European countries, taking part in the European prospective investigation into cancer and nutrition study. Multivariate Cox regression models were used to calculate hazard ratios according to weight change (kg), defined as the weight difference between age at enrollment and age 20 adjusted for other risk factors. Changes in weight were not associated with premenopausal breast cancer risk. In postmenopausal women, weight gain was positively associated with breast cancer risk only among noncurrent hormone replacement therapy (HRT) users (P-trend < or = 0.0002). Compared to women with a stable weight (+/-2 kg), the relative risk for women who gained 15-20 kg was 1.50 (95% confidence interval (CI) 1.06-2.13). The pooled RR per weight gain increment of 5 kg was 1.08 (95% CI 1.04-1.12). Weight gain was not associated with breast cancer risk in current HRT users, although, overall, these women experienced a much higher risk of breast cancer compared with nonusers. Our findings suggest that large adult weight gain was a significant predictor of breast cancer in postmenopausal women not taking exogenous hormones.     

A population-based cohort study of HRT use and breast cancer in southern Sweden

The overall tumour incidence and breast cancer incidence related to hormone replacement therapy (HRT) were followed in a population-based cohort of 29 508 women, aged 25-65 when interviewed in 1990-92. By the end of the follow up in December 1999, there were 226 611 person-years of observation. A total of 1145 malignant tumours were recorded (expected 1166.6; SIR = 0.98, 95% CI 0.93-1.04). There was a small excess of breast cancer with 434 observed and 387.69 expected (SIR = 1.12, 95% CI 1.02-1.23). Among about 3 663 ever users of HRT, there was no increase in overall tumour incidence (SIR = 0.98, 95% CI 0.86-1.12) but a significant excess of breast cancer (SIR = 1.35, 95% CI 1.09-1.64) compared with never users (SIR = 1.07, 95% CI 0.96-1.19). Breast cancer increased with increasing duration of use and for 48-120 months use the SIR was 1.92 (95% CI 1.32-2.70). There was no significant interaction with family history of breast cancer although an independent additive effect was suggested between HRT use and family history. In a Cox regression model time to breast cancer in relation to duration of HRT use was analysed adjusting for age at menarche, age at menopause, age at first full term pregnancy, parity and age at diagnosis. A significantly higher risk was seen for longer duration of HRT use compared with never users. No increased risk is seen in women beyond 5 years after stopping HRT. There was no interaction between previous use of oral contraceptives and later HRT use.     

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.     

Relationship between histamine2-receptor antagonist medications and risk of invasive breast cancer

BACKGROUND: Histamine(2)-receptor antagonist (H(2) blocker) medications are used to treat heartburn, gastroesophageal reflux disease, and ulcers. Some H(2) blockers, specifically cimetidine and ranitidine, also increase serum prolactin concentrations. Given the positive relationship between prolactin levels and postmenopausal breast cancer risk, use of H(2) blockers is a potential breast cancer risk factor. The few previous studies evaluating this association have been null but have been limited by small sample sizes, and none have evaluated risk by either histologic type or estrogen receptor/progesterone receptor status. METHODS: Combining data from two population-based case-control studies conducted in western Washington, we assessed the relationship between use of H(2) blockers and risk of different types of breast cancer among 1,941 cases and 1,476 controls 55 to 79 years old. Odds ratios and 95% confidence intervals (95% CI) were calculated using polytomous logistic regression. RESULTS: Current use of H(2) blockers overall, cimetidine, and famotidine was not associated with an increased risk of either invasive ductal or invasive lobular breast cancer. Current users of ranitidine had a 2.2-fold (95% CI, 1.1-4.3) increased risk of ductal carcinoma that was confined to a 2.4-fold (95% CI, 1.2-4.9) increased risk of estrogen receptor-positive/progesterone receptor-positive ductal carcinoma. CONCLUSIONS: Use of H(2) blockers in general is not associated with an increased risk of breast cancer, although current use of ranitidine may increase risk of hormone receptor-positive ductal carcinoma. Further studies to confirm this finding are warranted.