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.     

Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women

Objective To assess postmenopausal breast cancer risk in relation to particular patterns of oral contraceptive (OC) use according to hormone replacement therapy (HRT) exposure.Methods Time-dependent Cox regression models were used to analyse information on postmenopausal women from a large-scale French cohort. Among a total of 68,670 women born between 1925 and 1950, 1405 primary invasive postmenopausal breast cancer cases were identified from 1992 to 2000.Results A non-significant decrease in risk of around 10% was associated with ever OC use as compared to never OC use in postmenopausal women. No significant interaction was found between OC and HRT use on postmenopausal breast cancer risk. Breast cancer risk decreased significantly with increasing time since first OC use (test for trend: p=0.01); this was consistent after adjustment for duration of use or for time since last use.Conclusion No increase in breast cancer risk was associated with previous OC exposure among postmenopausal women, probably because the induction window had closed. Some women may develop breast cancer soon after exposure to OCs, leading to a deficit of cases of older women. Further investigation is therefore required to identify young women at high risk.* Address correspondence to: F. Clavel-Chapelon, Equipe E3N-EPIC, INSERM “Nutrition, Hormones, Cancer”, Institut Gustave-Roussy, 94805 – Villejuif, France.     

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. CONCLUSIONS: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.     

Relation of regimens of combined hormone replacement therapy to lobular,ductal, and other histologic types of breast carcinoma

BACKGROUND: The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma. METHODS: A large, multicenter case-control study of Caucasian and African-American women who were diagnosed at age < 65 years with their first invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In-person interviews were conducted with 1749 postmenopausal patients, and their responses were compared with the responses of 1953 postmenopausal control women identified through random-digit dialing who met the study criteria of being postmenopausal at the time of diagnosis. Polytomous logistic regression was used to calculate the odds ratio (OR) as an estimate of the relative risk and to compute the 95% confidence interval (95%CI) associated with the use of various regimens of hormone replacement therapy (HRT) among women diagnosed with ductal breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a grouping of other histologic types of breast carcinoma. RESULTS: Ever use of unopposed estrogen therapy (ERT) was not associated with an increase in the risk of any histologic type of breast carcinoma. The risk of invasive lobular breast carcinoma and the risk of breast carcinoma of the grouping of other histologies increased among women currently using CHRT (OR, 2.2; 95%CI, 1.4-3.3; and OR, 1.9; 95%CI, 1.0-3.4, respectively). The risk increase was greater for the mixed lobular-ductal type than for the pure lobular type of breast carcinoma, although the difference was not statistically significant. There was some indication that >or= 5 years of continuous CHRT (>or= 25 days per month of progestin) was associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, 1.4-4.3) compared with sequential CHRT (< 25 days per month of progestin; OR, 1.5; 95%CI, 0.8-2.6). Current use of continuous CHRT was only moderately associated with risk of ductal breast carcinoma. CONCLUSIONS: Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age < 65 years.     

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.     

Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma

BACKGROUND: Observational studies and randomized trials have demonstrated that hormone replacement therapy (HRT) increases the recipient's risk of developing breast carcinoma. Because it is known that some breast malignancies are hormonally responsive and that others are not, it has been hypothesized that HRT may be associated with the development of estrogen receptor (ER)-positive/progesterone receptor (PR)-positive breast carcinoma more so than with the development of ER-negative/PR-negative breast carcinoma. METHODS: The Nurses' Health Study is a prospective cohort study that enrolled 121,700 female registered nurses ages 30-55 years in 1976. In the current study, the authors analyzed 2548 malignancies that developed among eligible postmenopausal women in that cohort between 1980 and 2000 and for which data on ER and PR status were available. RESULTS: Compared with women who had never used HRT, current long-term users of HRT were more likely to develop ER-positive/PR-positive breast carcinoma (multivariate risk ratio [RR], 1.80; 95% confidence interval [CI], 1.52-2.12) but were not any more likely to develop ER-negative/PR-negative disease (multivariate RR, 1.00; 95% CI, 0.72-1.39). This effect grew stronger with increasing duration of current HRT use and was also more pronounced among women with body mass index < 25 kg/m2. Furthermore, the association between HRT use and ER-positive/PR-positive disease was stronger among patients receiving combined HRT (CHRT) regimens, which included estrogen and progesterone, than among users of estrogen alone (ERT). In addition, tumors tended to develop more quickly in current users of CHRT than in ERT users. CONCLUSIONS: The finding that current users of HRT were more likely to develop ER-positive/PR-positive tumors than they were to develop ER-negative/PR-negative ones suggests that both endogenous and exogenous hormonal factors may influence breast tumor characteristics. In analyses of the effects of hormonal factors on breast tumor development, ER-positive/PR-positive tumors and ER-negative/PR-negative tumors should be considered separately from each other.     

Oral contraceptives, hormone replacement therapy and the risk of colorectal cancer.

The relationship between oral contraceptives (OCs), menopausal hormone replacement therapy (HRT) and the risk of colorectal cancer was investigated in a case-control study conducted in northern Italy between 1985 and 1992 on 709 women with incident colorectal cancer and 992 controls admitted to hospital for a wide spectrum of acute, non-neoplastic, non-digestive tract, non-hormone-related disorders. A reduced risk of colorectal cancer was observed in women who had ever used OCs [multivariate odds ratio (OR) = 0.58; 95% confidence interval (CI): 0.36-0.92]. The OR was 0.52 (95% CI 0.27-1.02) for use over 2 years. For women ever using HRT, the multivariate OR was 0.40 (95% CI 0.25-0.66). The risk was inversely related to duration of use, with ORs of 0.46 for 2 years or less and 0.25 for more than 2 years of use. No consistent pattern of trends was observed with time since first or last use. This study provides further evidence that OC and HRT do not increase, and possibly decrease, the risk of colorectal cancer. These results, if confirmed, would have important implications for the ultimate risk-benefit assessment of female hormone preparations.     

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.     

Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study.

Excess adiposity and hormone replacement therapy (HRT) are important contributors to postmenopausal breast cancer risk. HRT has been shown to modify the association between body weight and breast cancer risk, although few studies are sufficiently large to examine the risk of breast cancer associated with body mass index (BMI) and weight gain separately among current HRT users and nonusers. This study includes 1,934 incident breast cancer cases occurring among 62,756 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort. Age-adjusted incidence rates were calculated, and Cox proportional hazards models were used to examine the association of BMI and adult weight gain (since age 18 years) with breast cancer risk stratified by HRT use. Total adult weight gain strongly predicted breast cancer risk among former and never HRT users (P for trend < 0.0001). Weight gain of 21-30 pounds was associated with a rate ratio of 1.4 (95% confidence interval 1.1-1.8); rates doubled among women gaining >70 pounds compared with women who maintained their weight within 5 pounds of their weight at age 18. After accounting for weight gain, neither recent BMI nor BMI at age 18 were independent predictors of risk. Among current HRT users, no association was seen between breast cancer and either BMI or weight gain. Adult weight gain is strongly associated with postmenopausal breast cancer only among non-HRT users in this study. These data illustrate the importance of examining breast cancer risk factors separately by HRT use; the effects of other risk factors may be attenuated or obscured among women taking HRT.     

A pooled analysis of case-control studies of thyroid cancer¶ III. Oral contraceptives, menopausal replacement therapy and other female hormones

Objective: The relations between oral contraceptives (OC), hormone replacement therapy (HRT) for menopause, and other female hormone use and thyroid cancer risk was analyzed using the original data from 13 studies from North America, Asia and Europe.Methods: Based on 2,132 cases and 3,301 controls, odds ratios (OR) and the corresponding 95% confidence intervals (CI) were obtained by conditional regression models, conditioning on study and age at diagnosis, and adjusting for age, radiation exposure and parity.Results: Overall, 808 (38%) cases versus 1,290 (39%) controls had ever used OCs, corresponding to an OR of 1.2 (95% CI 1.0 to 1.4). There was no relation with duration of use, age at first use, or use before first birth. The OR was significantly increased for current OC users (OR=1.5, 95% 1.0 to 2.1), but declined with increasing time since stopping (OR=1.1 for >10 years since stopping). The association was stronger for papillary cancers (OR=1.6 for current users) than for other histologic types. No significant heterogeneity was observed across studies or geographic areas. Eight studies had data on HRT, for a total of 1,305 cases and 2,300 controls: 110 (8%) cases and 205 (9%) controls reported ever using HRT (OR=0.8; 95% CI 0.6 to 1.1). The ORs were 1.6 (95% to 0.9 to 2.9) for use of fertility drugs, and 1.5 (95% CI 1.1 to 2.1) for lactation suppression treatment.Conclusions: The studies considered in these analyses include most of the epidemiological data on the role of exogenous hormone use in the etiology of thyroid cancer, and they provide reassuring evidence on the absence of an association of practical relevance. The moderate excess risk in current OC users, if not due to increased surveillance for thyroid masses among OC users, is similar to that described for breast cancer, and would imply a role of female hormones on thyroid cancer promotion. There was no indication of increased thyroid cancer risk 10 or more years after discontinuing OC use.     

Use of Exogenous Hormones and Risk of Papillary Thyroid Cancer (Washington, United States)

Objectives: Greater incidence of thyroid cancer in women than men, particularly evident during the reproductive years, has led to the suggestion that female hormones may increase risk of this disease. We conducted a population-based case-control study in women aged 18 to 64 years in three counties of western Washington State (United States) to assess the relation of use of exogenous hormones, including oral contraceptives (OC) and hormone replacement therapy (HRT), to risk of papillary thyroid cancer.Methods: Of 558 women with thyroid cancer of the follicular epithelium diagnosed during 1988-94 who were identified as eligible, 468 (83.9 percent) were interviewed; this analysis was restricted to women with papillary histology (n = 410). Controls (n = 574) were identified by random digit dialing, with a response proportion of 73.6 percent. Logistic regression was used to calculate odds ratios (OR) and associated 95 percent confidence intervals (CI) estimating the relative risk of papillary thyroid cancer among users of exogenous hormones.Results: Among women aged 45 to 64 years, we observed no association of use of OCs or HRT with risk of papillary thyroid cancer. Among women less than 45 years of age, risk of papillary thyroid cancer was reduced in women who had ever used OCs (OR = 0.6, CI = 0.4-0.9); beyond the relation with ever-use, there was no further association with specific aspects of exposure such as estrogenic potency, latency, recency, age at first or last use, or use at the reference date.Conclusions: Our data do not support the hypothesis that use of exogenous estrogens increases the risk of female thyroid cancer. Cancer Causes and Control 1998, 9, 341-349     

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.     

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.     

Prospective study of exogenous hormone use and breast cancer in Seventh-day Adventists

Exogenous hormone use as either oral contraceptives (OC) or hormone replacement therapy (HRT) was evaluated in reference to subsequent breast cancer risk in a cohort study of 20,341 Seventh-day Adventist women, residing in California, who completed a detailed lifestyle questionnaire in 1976 and who were followed for 6 years. During the follow-up period, 215 histologically confirmed primary breast cancers were detected in the cohort. The mean age at diagnosis was 66 years, indicating a primarily postmenopausal case series. In this cohort, after taking into account potentially confounding variables, current use of HRT (in 1976) was associated with a 69% increase in breast cancer risk, which was statistically significant (RR = 1.69; CI = 1.12-2.55). However, there was no strong increase in risk with increasing duration of use of HRT. Subgroups of women who did experience HRT associated increases in breast cancer risk included those women who had ever used HRT (RR = 1.39; CI = 1.00-1.94) and those with no history of maternal breast cancer (RR = 1.45), those women with prior benign breast disease (RR = 2.80), and those women who experienced menopause at 44 years of age or later (RR = 1.56). There was no substantial increase in breast cancer risk associated with use of OC in this population, although among women with exposure to both OC and HRT there was a suggested increase in risk (RR = 1.42; CI = 0.71-2.85).     

Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy.

We investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with higher endogenous hormone levels, influences the use of hormone replacement therapy (HRT). The study included 749 postmenopausal women ages 44-75 years at baseline randomly selected from a larger multiethnic cohort. African-American, Japanese, Latina, and white women were included in the study. Women who carry the CYP17 A2/A2 genotype were about half as likely as women with the A1/A1 genotype to be current HRT users (odds ratio = 0.52; 95% confidence interval, 0.31-0.86). This association was present in all four racial/ethnic groups and for women above and below the median weight of 150 pounds. These findings suggest that the actual risk of breast cancer associated with HRT use may be higher than previously reported.     

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.     

Is use of hormone replacement therapy associated with increased detection of human papillomavirus and potential risk of HPV-related genital cancers?

Oral contraceptives (OC) are a risk factor for female genital cancers and in vivo studies have shown that progestins stimulate human papillomavirus (HPV) gene expression. A similar role for hormone replacement therapy (HRT) has received little evaluation. Cervical/vaginal specimens were obtained to detect HPV from postmenopausal women (n = 429) seeking annual gynaecologic care. HPV was detected in 14% of women and 4.4% had high-risk, oncogenic types. HPV prevalence was similar across current, past and never HRT users. After adjustment for HPV-related risk factors, current and past user status showed no increased viral detection compared with never users. HRT duration also did not elevate risk among current users. However, longer duration (adj. OR 1.5/year, 95% CI 1.0-2.3) and longer latency (adj. OR 1.2/year, 95% CI 0.9-1.7) among past users of oestrogen/progestin regimens were associated with greater risk. Overall use of HRTs was not associated with HPV detection or disease. However, past users of combination HRTs had significantly greater risk of HPV detection with longer HRT duration and latency, similar to OC-HPV findings. The recommendation that postmenopausal women continue HRTs long term may lead to an increased development of HPV-related diseases, of particular concern among those who discontinue HRTs and subsequent gynaecologic care for early cancer detection.     

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

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

Obesity and poor breast cancer prognosis: an illusion because of hormone replacement therapy?

High body mass index (BMI) and use of hormone replacement therapy (HRT) increase the risk of postmenopausal breast cancer. It has been shown that BMI modifies the effect of HRT, as its influence is most pronounced in lean women. We investigated the influence of BMI and HRT on prognosis in 2640 postmenopausal women diagnosed with breast cancer in Sweden in 1993–1995, taking into account HRT and mammography before diagnosis. Logistic and Cox regression were used. In non-users of HRT, obese women (BMI >30) compared with normal weight women (BMI <25) had a similar prognosis (hazard ratio (HR) 1.1, 95% confidence interval (CI) 0.8–1.6), despite larger tumours found in obese women. Obese HRT users had less favourable tumour characteristics and poorer prognosis compared with normal weight women (HR 3.7, 95% CI 1.9–7.2). The influence of BMI on breast cancer prognosis was similar whether diagnosed by mammographic screening or not. We found a similar prognosis of postmenopausal breast cancer-specific death regardless of BMI in non-users of HRT, but among HRT users obesity was associated with a poorer breast cancer prognosis.     

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.