Annals of Oncology Advance Access originally published online on September 4, 2007
Annals of Oncology 2008 19(1):150-155; doi:10.1093/annonc/mdm404
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epidemiology |
Menopause hormone replacement therapy and cancer risk: an Italian record linkage investigation
1 Department of Statistics; Unit of Epidemiology and Biostatistics, University of Milan-Bicocca
2 Mario Negri Institute of Pharmacological Research
3 Institute of Medical Statistics and Biometry, University of Milan
4 Research Center on Chronic Degenerative Diseases, University of Milan-Bicocca
5 Cancer Registry Division, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
6 Department of Morphological, Eidological and Clinical Sciences, Research Center for Reproductive Medicine, University of Pavia
7 Endocrinology and Internal Medicine Unit, Section of Gynaecological Endocrinology, Istituto di ricovero e cura carattere scientifico (IRCCS) Maugeri Foundation, University of Pavia, Pavia
8 Operative Unit of Territorial Health Services, Region Lombardia, Milan, Italy
* Correspondence to: Prof. G. Corrao, Dipartimento di Statistica, Università degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi 8, Edificio U7, 20126 Milano, Italy. Tel: +39-02-64485854; Fax: +39-02-64485899; E-mail: giovanni.corrao{at}unimib.it
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Abstract |
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Background: The effects of persistence with hormone replacement therapy (HRT) on the risk of hospitalization for cancer and of the route of HRT administration on the risk of breast and colorectal cancer were explored in a large cohort study.
Patients and methods: The 73 505 women residing in Lombardia (Italy), aged 45–75 years, who received at least one HRT prescription during 1998–2000 were followed until 2005. Among these, 3687 experienced cancer hospitalization. Proportional hazards model was fitted to estimate the association between cumulative HRT persistence and cancer risk.
Results: Compared with women who took HRT for <6 months, those exposed for >2 years showed hazard ratios (HR) of 0.78 (95% confidence interval 0.68–0.92) for colorectal cancer and 1.34 (1.13–1.58) for breast cancer. HR for breast cancer associated with long-term use of transdermal and oral HRT were, respectively, 1.27 (1.07–1.51) and 2.14 (1.43–3.21).
Conclusions: Evidence that long-term use of HRT is associated with increased risk of breast cancer and decreased risk of colorectal cancer is supplied from this study from a southern European population. Our findings indicate that transdermal therapy might have lower effect than oral therapy in increasing breast cancer risk.
Key words: cohort study, database, hormone replacement therapy, neoplasms, oral administration, transdermal administration
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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The relation between hormone replacement therapy (HRT) and cancer risk has been investigated by several observational studies. These showed increased risks of breast [1–5], ovarian [6–10] and endometrial cancer (for unopposed estrogens only) [11–16], whereas a protective effect on colorectal cancer risk has been reported [17–20]. The findings from the Women's Health Initiative (WHI) trial, including healthy women who received oral combined estrogen–progestin regimen, confirmed the increased breast cancer risk and the reduced incidence of colorectal cancer [21, 22].
Data for other cancers, including those of stomach [23, 24], liver [25, 26], pancreas [27], skin melanoma [28], uterine cervix [29–31], bladder [32, 33], kidney [34], brain [35, 36], thyroid [37, 38] and lymphatic and hematopoietic tissue [39–44], are limited and inconsistent.
Evidence from clinical studies shows important metabolic and biologic differences between oral and transdermal HRT [45–47]. Notwithstanding, there is still inconsistent evidence regarding the effect of long-term use of non-oral HRT on the risk of cancer, including breast and colorectum [48, 49].
We conducted a large population-based prospective cohort study to explore the association between use of HRT and the risk of several cancers. Other than to reproduce the evidence from literature in an observational setting indicative of the southern European clinical practice, the effects of oral and transdermal HRT on the risk of breast and colorectal cancer were compared.
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patients and methods |
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setting
The data used for this study were obtained from the health service databases of Lombardy region, one of the 20 regions of Italy. It has a population of about nine million, i.e. 16% of the Italian population, entirely covered by the National Health Service (NHS). An automated system of databases has been used since 1997 to collect data on the use of health services, including demographic and administrative data, hospital discharge and outpatient prescription of drugs reimbursable from the NHS. Different pieces of information are recorded for the beneficiaries of the NHS (practically the whole resident population) and can be linked together for each individual, using a unique personal identification code.
Procedures aimed at protecting personal data were enforced in order to protect privacy and to prevent the identification of individual data. In practice, each identification code was automatically converted to a unique and anonymous code, and the inverse process was prevented by the deletion of the conversion table.
cohort selection and follow-up
All women aged 45–75 years beneficiaries of the NHS residents in Lombardy represented the target population. According to the 2001 Italian Census, this population comprised of 1 744 857 individuals. Among these, those who received at least one HRT prescription from 1 January 1998 to 31 December 2000 were identified from the outpatient prescription drug database and were designed as eligible patients. HRT prescriptions included all drugs used in Italy to treat symptoms of menopause with different hormone regimens (estrogens or estradiol alone or conjugated with progestin) and route of administration (pills, ovules, gels, creams and patches).
Each woman accumulated person-years of follow-up from the date of the first recorded prescription of HRT (index date) to the earliest of the dates of hospitalization or death for any cause, migration or 31 December 2005.
Women who received at least one prescription of HRT in the period ranging from 1 January 1997 through index date, those previously diagnosed with cancer, and those who did not reach at least 6 months of follow-up were excluded. The remaining patients constituted the study cohort.
outcome ascertainment and exploring accuracy of diagnoses
The Regional hospital discharge database was used to identify cohort members who experienced at least one hospitalization for malignant neoplasm (International Classification of Diseases-9: 140–208) recorded as main cause of hospitalization. The earliest date of hospitalization was considered.
Hospitalization occurred among women belonging to the portion of the cohort residing in the Varese Province, were evaluated against cases traced from the population-based cancer registry of the Varese Province. Province of Varese is an Italian industrialized area localized in Lombardy between Milan and the Italian–Swiss border, with a resident population of 
800 000 inhabitants. Since 1978, this population is covered by cancer registration, and accuracy and completeness of the registered data have been carried out and published [50]. Because the register adopts standardized criteria for data collection and classification as the International Network of Cancer Registries [51], it can be considered a ‘gold standard’ for hospital discharge diagnoses.
exposure assessment
Drug types, dosages and number of canisters dispensed to each cohort member during follow-up were retrieved from the Regional outpatient prescription drug database, and used to construct the cumulative measure of HRT exposure. The conjugated estrogen dose equivalent was calculated for each dispensed canister (0.625 mg of conjugated estrogens were considered equivalent to 0.625 mg of esterified estrogens and to 0.05 mg of ethinyl estrogens [52]) and the theoretical duration of all prescribed canisters was calculated accordingly. For overlapping prescriptions, the individual was assumed to have refilled early and completed the first prescription before starting the second. An indicator of cumulative persistence with HRT during follow-up was constructed by summing the number of days with medication available and categorized according to progressively increasing exposure duration (
6 months, 7–12 months, 13–24 months and 
25 months). Other than for HRT as a whole, cumulative persistence according to administration route, that is transdermal (including ovules, gels, creams and patches) and oral route, was separately assessed.
data analysis
Cox proportional hazard regression was used to estimate hazard ratios (HRs), and to calculate their 95% confidence intervals, for the association between persistence with HRT and time of first hospitalization for malignancy [53]. The predictor variables of interest were the dummy factors constructed according to the categories of persistence with HRT medicaments, using the first category (i.e. women with <6 months spent with HRT treatment) as reference. As persistence can change over time, assessment of its effect requires properly accounting for the cumulative and varying nature of the measure. This was done by fitting the Cox model that include dummy factors expressed as time-dependent variables. With this approach, each subject's cumulative persistence is recalculated from the start of follow-up to the time of each outcome. Thus, the HR associated with a category of persistence is derived using persistence information concurrent to the observed outcome, rather than the persistence profile over the full length of follow-up [54].
Tests for linear trend were based on statistical significance of the regression coefficient of the persistence factor obtained by scoring the corresponding categories. The same procedure was used to estimate the relation between the categories of persistence with both transdermal and oral HRT, and the corresponding effects were compared by means of the normal approximation.
All the calculations were carried out using Proportional Hazards Regression (PHREG) procedure of the SAS package [55]. For all hypotheses tested, two-tailed P values <0.05 were considered significant.
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results |
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Data were obtained on 88 637 eligible women for whom at least one HRT prescription had been dispensed during 1998–2000. They represented 5.1% of the female population aged 45–75 years resident in Lombardy. Among eligible women, 15 132 were excluded because before the date of cohort entry they had already experienced at least one prescription of HRT and/or had been hospitalized for neoplastic disease and/or because they accumulated <6 months of follow-up. The 73 505 remaining women were included.
At entry, these women had a mean age of 57 years (Standard deviation 7.4 years) and more than 88% of them began their hormonal therapy via the transdermal route. During follow-up, the cohort accumulated 471 612 woman-years of observation, 93 638 women-years of exposure to HRT, and 1 609 989 HRT canisters were dispensed, including 1 253 543 transdermal products (5% ovules, 6% gels, 9% creams and 80% patches) and 356 446 oral products. Estrogens were dispensed as estradiol (82%), estriol (12%) or conjugated estrogens (6%).
The cohort generated 3687 hospitalizations for malignant neoplasms distributed for cancer site as indicated in Table 1. Other malignancies were not considered in this analysis owing to the small number of events (24 gallbladder cancers, 10 laryngeal cancers, 14 sarcomas, six Hodgkin's lymphomas and two leukemias). The positive predictive values obtained by comparison with data of the Varese Cancer Registry were 96% (colorectal cancer), 94% (pancreatic cancer), 85% (other malignant neoplasm of skin), 91% (breast cancer), 100% (endometrial cancer) and 90% (renal cancer). The other malignancies listed in Table 1 were not considered in this analysis owing to the small number of events generated by the portion of the cohort resident in the Province of Varese.
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Table 1 gives the dose–risk relation between persistence with HRT and risk of cancer hospitalization. Cancer risk as a whole was unrelated with persistence with HRT use. Significant trends with duration were observed towards decreasing risk of colorectal and endometrial cancers and increasing risk of breast cancer. There was no evidence that persistence with HRT is related with the risk of the other neoplasms.
Table 2 shows the effect of persistence with transdermal and oral HRT on the risk of hospitalization for selected cancers. Due to the small number of women-years with exposure to oral HRT, only colorectal and breast cancers were considered for this analysis. A pattern of decreasing risk of colorectal cancer with increasing persistence with both transdermal and oral HRT was observed, although the trends were not significant. There was no evidence that the route of HRT administration exerts different effects on the risk of colorectal cancer. The pattern of breast cancer showed increasing risks for both transdermal and oral HRT. However, the association was stronger for oral HRT than for transdermal one: the HR for >2 years of prescription was 1.27 for transdermal and 2.14 for oral preparations (P value for heterogeneity <0.01).
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discussion |
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This large population-based cohort study confirms the existence of an inverse relation between persistence with HRT use and risk of colorectal cancer, as well as of an increased risk of breast cancer with increasing HRT persistence. A significant inverse relation was observed for endometrial cancer, whereas no material association was observed for any of the other cancer sites investigated. Compared with transdermal exposure, oral HRT was more strongly associated with the risk of breast cancer.
We cannot distinguish the effect of unopposed estrogen therapy from that of combined estro-progestagen therapy since progestogen medicaments are not dispensed free of charge from the Italian NHS. However, unopposed estrogen therapy would be administered mainly to women who had undergone surgical menopause, and according to recent investigations, only 10% of Italian women has undergone hysterectomy [56]. Consequently, our findings mainly reflect the effect of estro-progestagen therapy, rather than of unopposed estrogen therapy.
There is convincing evidence that estro-progestagen therapy is inversely associated with colorectal cancer. A meta-analysis of 18 published observational studies indicated a 20% reduction in colon cancer among women who had ever used HRT compared with never users, and a 34% reduction among current or recent users [19]. Results were similar for rectal cancer. Our findings add evidence about this favorable effect.
Evidence that HRT increases the risk of breast cancer is given by a pooled analysis of individual data of 51 epidemiological studies [57], as well as by the WHI trial [21]. The increased risk of breast cancer among women with long-term HRT use has been also documented by some meta-analyses [2, 3, 58, 59]. The present findings, therefore, are in broad agreement with available evidence on HRT and breast cancer.
A meta-analysis of 29 observational studies showed a not significant risk reduction of endometrial cancer among users of combined regimens [11]. Neither WHI nor Heart and Estrogen/Progestin Replacement Study II (HERS II) trials found an increased endometrial cancer risk among users of combined HRT [21, 60]. In the Million Women study, a significant risk reduction was reported for women who used continuous combined therapy [16]. Likewise, a significant inverse relation of endometrial cancer risk with HRT persistence was found in the present study.
A moderate excess risk of ovarian cancer has been observed among HRT users [8–10]. In our study, a weak and not significant risk excess was found among women who used HRT for one or more years, which is therefore compatible with available evidence.
Estrogens are known to have immunomodulatory effects [61] and have been related to non-Hodgkin's lymphoma (NHL) [62]. Animal studies indicated that estrogen administration induces lymphoma [63]. The data on HRT and NHL in humans provide conflicting results, ranging from no association or even inverse association [40, 41] to positive associations [39, 42]. Our findings do not offer evidence that the risk of NHL varies according to the duration of HRT use.
There are limited epidemiological data on the association between HRT and cancers of stomach [23, 24, 43], liver [25, 26], pancreas [27, 43], uterine cervix [29–31], bladder [32, 33, 43], kidney [34, 43], brain [35, 36] and thyroid [37, 38, 43], as well as for skin melanoma [28] and multiple myeloma [43, 44]. Our findings do not offer evidence that the risk of these cancers varies along the categories of HRT persistence.
It has been reported that oral conjugated equine estrogen has more favorable changes than transdermal estradiol on circulating breast cancer risk biomarkers, but gives similar effects on mammographic density [64]. The Million Women Study [4], reported that, compared with never users, the risk of breast cancer in transdermal HRT users was only moderately lower than that of oral HRT. Oral and transdermal estradiol showed a similar risk of breast cancer according to a recent cohort study [65]. We found that users of oral HRT had a significantly higher risk of breast cancer than women who were treated with transdermal HRT. It has been reported that the risk reduction for colorectal cancer for transdermal HRT may be greater than that of oral HRT [49], but our data do not support that suggestion.
The main strengths of this study are the uniformly organized health care system allowing a large-scale population-based design, and the use of data on exposure that were collected before cancer diagnosis. Thus, recall bias is unlikely to have influenced data collection.
Misclassification of subjects according to their disease and exposure status due to errors in identification, diagnostic and therapeutic codings is a potential source of bias. It is unlikely, however, that our approach led to a relevant portion of uncaptured users of HRT and/or incident cases of cancer. Indeed, the prevalence of HRT users found in our study was very similar to that reported from the World Health Organization MONItoring of trends and determinants in CArdiovascular disease (MONICA) study for Italian women of the same age range [66]. Moreover, incidence rates of malignancies generated from our cohort were very similar to those estimated from data of the Italian Network of Cancer Registries for women residents in Lombardy of that same age range (http://www.tumori.net/it/banca_dati/query.php). Finally, good positive predictive values of hospital discharge diagnosis were found in the current study by comparison with the local Cancer Registry. Nonetheless, the absence of information about the extent of misclassification is a main source of systematic uncertainty in our estimates. However, nondifferential misclassification, i.e. exposure misclassification independent from the disease status, would most likely affect our estimates towards the null hypothesis [67].
A main pitfall of the current study concerns the inability to capture and control the effect of potential confounding factors, across the categories of persistence with HRT. Some risk factors, such as cigarettes smoking, alcohol drinking and reproductive history, and some comorbidity conditions, may be associated with the use of HRT [68, 69]. It is unlikely that smoking may act as a relevant confounder, since there was no evidence of a trend in risk for cancers known to be causally associated to smoking (such as, oral cavity, pharynx and lung) along the categories of HRT. We tried to reduce the effect of confounding by comparing users of HRT along the categories of persistence with HRT, rather than by comparing users and nonusers of HRT. However, we cannot exclude that some factors associated with treatment persistence might have affected our estimates.
These limitations notwithstanding this study confirms the favorable effect of long-term use of combined HRT against colorectal and endometrial cancers and the increased risk for breast cancer. It also indicates that, compared with oral HRT, long-term use of transdermal hormonal is associated with a lower risk of breast cancer. These data from a southern European population provide therefore useful information towards a more precise risk–benefit assessment of HRT. The clinical implications of this finding require additional studies in particular with low-dose HRT regimens.
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Italian Minister of the Education, University and Research (‘Fondo d'Ateneo per la Ricerca’ portion, years 2005 and 2006; PRIN portion, protocol no. 2005068001, year 2005).
Received for publication April 3, 2007. Revision received July 12, 2007. Accepted for publication July 16, 2007.
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