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.     

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.     

Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden

BACKGROUND: The authors previously reported an increased risk of breast carcinoma with longer duration of hormone replacement therapy (HRT) use. It is unclear if different types of HRT confer different risks. METHODS: In this study, a population-based cohort of 29,508 women were interviewed during 1990-1992 to determine whether there are any differences in breast carcinoma risk according to different types and duration of HRT use. RESULTS: At the end of the follow-up period in December 2001, the cohort constituted 298,649 person-years. Slightly more breast carcinoma cases were seen (n = 556) than expected (n = 508.37; standardized morbidity ratio =1.09, 95% confidence interval [CI] = 1.00-1.19). Approximately 3663 women had ever used HRT. In Cox regression models, time to breast carcinoma in relation to duration and type of HRT use was analyzed, adjusting for age at menarche, age at first full-term pregnancy, parity, age at menopause, family history of breast carcinoma, and age at interview. In women with a natural menopause, a significantly higher risk was observed for longer duration of combined continuous HRT use compared with never users (hazard ratio [HR] = 4.60, 95% CI = 2.39-8.84). Nonsignificant elevated risks also were observed for longer combined sequential (HR = 2.23, 95% CI = 0.90-5.56), gestagen only (HR = 3.74,9 5% CI = 0.94-14.97), and estriol use (HR = 1.89, 95% CI = 0.81-4.39). No increased risk was seen in women after 5 years of nonuse. When studying women who ever used only one type of HRT, even more elevated HRs for gestagen-containing preparations were seen. The highest risks were associated with the combined continuous and gestagen-only therapy in women with >/= 48 months of use. Use of estradiol without progestins did not increase breast carcinoma risk significantly. The authors estimated the cumulative risk of breast carcinoma in a 50-year-old woman with gestagen-containing therapies for >/= 48 months, with a follow-up of 10 years, to be 7% (95% CI = 5.4-11.4%) compared with 2% (95% CI = 1.6%-2.9%) for never-users of HRT. CONCLUSIONS: Longer use of HRT containing progestins significantly elevates breast carcinoma risk whereas estradiol use does not. Continued use of progestins rendered the highest risks. The yearly risk of breast carcinoma for long-term users of progestins is of the magnitude of 50% the risk of a BRCA1 mutation carrier.     

A cohort study of reproductive factors and family history of breast cancer in southern Sweden

Background. Studies have been contradictory regarding the hypothesis that reproductive risk factors of breast cancer as parity and age at first full-term pregnancy (AFFP) operate differently in women with and without a family history of breast cancer. Methods. The overall tumour incidence and breast cancer incidence related to fertility factors were followed in a population based cohort of 29,508 women aged 25–65 when interviewed between 1990 and 1992 in south Sweden. At the end of the follow up in December 1999, the cohort constituted 226,611 person years. The risk of breast cancer in relation to reproductive factors were studied in women with at least one first degree relative with breast cancer and compared with women without a family history. Findings. A total of 1145 malignant tumours were seen and 1166.6 were expected (SIR = 0.98, 95% CI = 0.93–1.04). Slightly more breast cancer cases were seen 434 than expected 387.69 (SIR = 1.12, 95% CI = 1.02–1.23). A family history of breast cancer among a first degree relative was present in 1615 women. Forty-five breast cancers were seen among these women while 24.27 was expectecd (SIR = 1.85, 95% CI = 1.35–2.48). Nulliparous women with a family history of breast cancer had a higher risk of breast cancer, SIR = 1.76, 95% CI = 0.64–3.82, compared with nulliparous women without a family history, SIR = 1.13, 95% CI 0.99–1.29. Similarly women with parity 1–2 with a family history had a higher SIR = 1.81, 95% CI = 1.16–2.69 compared with women without a family history having 1–2 children, SIR = 1.13, 95% CI = 0.99–1.29. In women with 3 children those with a family history continued to have a high SIR = 1.98, 95% CI = 1.11–3.27 compared with women without a family history SIR = 0.90, 95% CI = 0.73–1.09. An early full-term pregnancy was protective in both groups. A higher risk than nulliparous women were seen after age 25 in the family history group and after age 30 in the sporadic cancer group. Interpretation. Women with a first degree family history of breast cancer do not experience the same protection from a high number of pregnancies as women without a family history. However, an early first full-term pregnancy seems to offer a substantial protection in the family history group if undertaken before age 20. This suggest that reproductive factors tend to operate differently in the two groups of women.     

Incidence of cancer among Nordic police officers

Police work may expose officers to various circumstances that have potential for increasing their risk of cancer, including traffic-related air pollution, night shift work and radiation from radars. In this study, we examined the incidence of cancer among Nordic male and female police officers. We utilize data from the Nordic Occupational Cancer (NOCCA) project, which linked census data on occupations from Finland, Iceland, Norway and Sweden to national cancer registries for the period 1961 to 2005. We report standardized incidence ratios (SIR) and 95% confidence intervals (CI) of selected cancers for each country by sex, age and calendar period. The cohort included 38 523 male and 1998 female police officers. As compared with the general population, male police officers had a 7% (95% CI: 4-9%) excess cancer risk, with elevated SIRs for various cancer sites, including prostate (SIR 1.19, 1.14-1.25), breast (SIR 1.77, 1.05-2.80), colon (SIR 1.22, 1.12-1.32) and skin melanoma (SIR 1.44, 1.28-1.60). Conversely, male police officers had a lower risk of lung cancer than the general population (SIR 0.72, 0.66-0.77). In female police officers, the SIR for cancer overall was 1.15 (0.98-1.34), and there was a slight excess of cancers of the breast (SIR 1.25, 0.97-1.59) and colon (SIR 1.21, 0.55-2.30). In conclusion, cancer incidence among the police officers was slightly higher than in the general population. Notably, SIRs were elevated for cancer sites potentially related to night shift work, namely colon, breast and prostate cancer.     

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.     

Cancer risk in women prenatally exposed to diethylstilbestrol

Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age- and calendar-year specific standardized incidence rate ratios (SIR), and age-adjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure.     

Cancer risk among Danish women with cosmetic breast implants

The available epidemiologic evidence does not support a carcinogenic effect of silicone breast implants on breast or other cancers. Data on cancer risk other than breast cancer are limited and few studies have assessed cancer risk beyond 10-15 years after breast implantation. We extended follow-up of our earlier cohort study of Danish women with cosmetic breast implants by 7 years, yielding 30 years of follow-up for women with longest implant duration. The study population consisted of women who underwent cosmetic breast implant surgery at private clinics of plastic surgery (n = 1,653) or public hospitals (n = 1,110), and a control group of women who attended private clinics for other plastic surgery (n = 1,736), between 1973-95. Cancer incidence through 2002 was ascertained using the Danish Cancer Registry. Risk evaluation was based on computation of standardized incidence ratios (SIR) and Cox proportional hazards models, adjusting for age, calendar period and reproductive history. We observed 163 cancers among women with breast implants compared to 136.7 expected based on general population rates (SIR = 1.2; 95% confidence interval [CI] = 1.0-1.4), during a mean follow-up period of 14.4 years (range = 0-30 years). Women with breast implants experienced a reduced risk of breast cancer (SIR = 0.7; 95% CI = 0.5-1.0), and an increased risk of non-melanoma skin cancer (SIR = 2.1; 95% CI = 1.5-2.7). Stratification by age at implantation, calendar year at implantation and time since implantation showed no clear trends, however, the statistical precision was limited in these analyses. When excluding non-melanoma skin cancer, the SIR for cancer overall was 1.0 (95% CI = 0.8-1.2). With respect to other site-specific cancers, no significantly increased or decreased SIR were observed. Similar results were found when directly comparing women who had implants at private clinics with women who attended private clinics for other plastic surgery, with rate ratios for cancer overall, breast cancer and non-melanoma skin cancer of 1.1 (95% CI = 0.8-1.6), 0.7 (95% CI = 0.4-1.3) and 1.5 (95% CI = 0.8-2.7), respectively. In conclusion, our study lends further support to the accumulating evidence that silicone breast implants are not carcinogenic. Reasons for the consistently reported deficit of breast cancer among women with breast implants remain unclear, whereas increased exposure to sunlight may explain the excess occurrence of non-melanoma skin cancer. We found no indication of delayed diagnosis of breast cancer due to the presence of breast implants.     

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).     

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.     

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.     

Breast cancer risk in monozygotic and dizygotic female twins: a 20-year population-based cohort study in Finland from 1976 to 1995.

This population-based study investigated the occurrence of breast cancer over a 20-year period in a cohort of monozygotic (MZ) and dizygotic (DZ) twins in Finland. Altogether, 13,176 female twins of known zygosity who were living in Finland at the end of 1975 were identified from the Finnish Twin Cohort Study and followed-up for cancer through the Finnish Cancer Registry for the years 1976-1995. Standardized incidence ratios (SIRs) were calculated, based on national cancer incidence rates. The relative risk of breast cancer for MZ twins compared to DZ twins was decreased [SIR(MZ)/SIR(DZ) ratio = 0.78; 95% confidence interval (CI), 0.58-1.0]; the decreased risk for MZ twins (SIR = 0.76; 95% CI, 0.58-1.0) accounted for this result, whereas the risk for DZ twins did not differ from the general population risk (SIR = 0.98; 95% CI, 0.84-1.1). There was no risk decrease among MZ twins in other cancers related to reproductive behavior; i.e., number of children and age at first birth seem not to explain the decreased risk of breast cancer. Our results, which are in line with earlier studies on the same topic, suggest that prenatal influences or postnatal behavioral factors may protect MZ female twins from breast cancer.     

Cancer risk after radiotherapy for breast cancer

Among women with breast cancer, we compared the relative and absolute rates of subsequent cancers in 1541 women treated with radiotherapy (RT) to 4570 women not so treated (NRT), using all registered in the Swiss Vaud Cancer Registry in the period between 1978 and 1998, and followed up to December 2002. Standardised incidence ratios (SIRs) and the corresponding 95% confidence intervals (CIs) were based on age- and calendar year-specific incidence rates in the Vaud general population. There were 11 lung cancers in RT (SIR = 1.40; 95% CI: 0.70-2.51) and 17 in NRT women (SIR = 0.76; 95% CI: 0.44-1.22), 72 contralateral breast cancers in RT (SIR = 1.85; 95% CI: 1.45-2.33) and 150 in NRT women (SIR = 1.38; 95% CI: 1.16-1.61), and 90 other neoplasms in RT (SIR = 1.37; 95% CI: 1.10-1.68) and 224 in NRT women (SIR = 1.05; 95% CI: 0.91-1.19). Overall, there were 173 second neoplasms in RT women (SIR = 1.54, 95% CI: 1.32-1.78) and 391 among NRT women (SIR = 1.13, 95% CI: 1.02-1.25). The estimates were significantly heterogeneous. After 15 years, 20% of RT cases vs 16% of NRT cases had developed a second neoplasm. The appreciable excess risk of subsequent neoplasms after RT for breast cancer must be weighed against the approximately 5% reduction of breast cancer mortality at 15 years after RT.     

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.     

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.     

Cancer occurrence after cosmetic breast implantation in Denmark

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973-1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17-2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76-1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78-1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5-2.2) among private clinic patients and 0.9 (95% CI = 0.4-1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted.     

Risk of second cancer among women with breast cancer

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI = 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR = 1.35), colorectal (SIR = 1.22), lung (SIR = 1.24), soft tissue sarcoma (SIR = 2.25), melanoma (SIR = 1.29), non-melanoma skin (SIR = 1.58), endometrium (SIR = 1.52), ovary (SIR = 1.48), kidney (SIR = 1.27), thyroid gland (SIR = 1.62) and leukaemia (SIR = 1.52). The excess of cancer after a breast cancer diagnosis is likely to be explained by treatment for breast cancer and by shared genetic or environmental risk factors, although the general excess of cancer suggests that there may be additional explanations such as increased surveillance and general cancer susceptibility.     

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.     

Hormone replacement therapy and incidence of central nervous system tumours in the Million Women Study

We examined the relation between the use of hormone replacement therapy (HRT) and the incidence of central nervous system (CNS) tumours in a large prospective study of 1,147,894 postmenopausal women. Women were aged 56.6 years on average at entry, and HRT use was recorded at recruitment and updated, where possible, about 3 years later. During a mean follow‐up of 5.3 years per woman, 1,266 CNS tumours were diagnosed, including 557 gliomas, 311 meningiomas and 117 acoustic neuromas. Compared with never users of HRT, the relative risks (RRs) for all incident CNS tumours, gliomas, meningiomas and acoustic neuromas in current users of HRT were 1.20 (95% CI: 1.05–1.36), 1.09 (95% CI: 0.89–1.32), 1.34 (95% CI: 1.03–1.75) and 1.58 (95% CI: 1.02–2.45), respectively, and there was no significant difference in the relative risks by tumour type (heterogeneity p = 0.2). In past users of HRT the relative risk was 1.07 (95% CI: 0.93–1.24) for all CNS tumours. Among current users of HRT, there was significant heterogeneity by the type of HRT with the users of oestrogen‐only HRT at higher risk of all CNS tumours than users of oestrogen–progestagen HRT (RR = 1.42, 95% CI: 1.21–1.67 versus RR = 0.97, 95% CI: 0.82–1.16) (heterogeneity p < 0.001). Among current users of oestrogen‐only and oestrogen–progestagen HRT, there was no significant heterogeneity by duration of use, hormonal constituent or mode of administration of HRT.