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ORIGINAL RESEARCH |
From the Departments of Oncology, Cancer Epidemiology, and Surgery, University Hospital, and South Swedish Regional Tumor Registry, Lund, Sweden.
Address reprint requests to: H. Olsson, University Hospital, Department of Oncology, Lund S-22185, Sweden; E-mail: hakan.olsson{at}onk.lu.se.
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ABSTRACT |
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METHODS: Baseline interviews were conducted from 1990 to 1992 in a population-based cohort of 29,508 Swedish women aged 25–65 years with no history of cancer. Cancer incidence in the cohort was assessed through December 31, 1999, with the Swedish Cancer Registry, the Population Census Registry, and the Cause of Death Registry.
RESULTS: When follow-up ended, the cohort included 226,611 person-years. A total of 1145 malignancies were diagnosed (observed), and 1166.6 were expected (standardized incidence ratio 0.98; 95% confidence interval [CI] 0.93, 1.04). Women who had experienced a natural menopause and had ever used HRT had no increased incidence of cancer overall (standardized incidence ratio 1.03; 95% CI 0.88, 1.19). Long-term HRT users who smoked had a decreased incidence of smoking-related cancers, such as the oral cavity, pharynx, hypopharynx, larynx, esophagus, lung, cervix, and bladder (standardized incidence ratio 0.24; 95% CI 0.08, 0.76). The effect was seen regardless of the type of HRT (progestin versus non–progestin-containing preparations) used and number of cigarettes smoked. The protective role of HRT for colon cancer was evident among both smokers and nonsmokers. An increased incidence of endometrial cancer was seen only for nonsmokers who used HRT.
CONCLUSION: Our data indicate that HRT use protects women against smoking-associated cancers. This effect occurs regardless of the type of HRT and the amount of smoking.
Approximately 40% of all Swedish women have used hormone replacement therapy (HRT) at some point in their lives. The positive health effects of HRT include a lower risk for osteoporosis1 and relief of menopausal symptoms, such as vaginal atrophy and hot flushes. Recently, the Women’s Health Initiative, a randomized, controlled trial, found an increase in overall morbidity among combined HRT users, and the study was stopped for safety reasons.2
It has long been known that HRT increases the risk of endometrial cancer,3 and a collaborative meta-analysis showed that HRT is associated with an increased risk of breast cancer as well.4 The increase in endometrial cancer has been seen mainly in association with unopposed estrogen use, because the addition of progestins has normalized the risk.5 The opposite might be true for breast cancer: Recent studies have suggested that preparations containing estrogen alone do not substantially increase the risk, whereas preparations containing both estrogen and progestin do.6–8
Little is known about the effects of HRT on the incidence of other malignancies. A recent meta-analysis suggested that HRT has a protective effect on colon cancer but no effect on the incidence of rectal cancer.9
In a previous investigation in which the present cohort was used,10 we found an increased incidence of breast cancer after 4 or more years of HRT use. The absolute risk seemed to be independent of other known risk factors for breast cancer, such as family history. The increase in risk disappeared within 5 years of HRT discontinuation. We also found that overall cancer incidence was not increased after HRT use.10
In the present investigation, we studied the incidence of cancer after HRT use in smokers and nonsmokers. We hypothesized that HRT use would favorably affect those epithelial tissues for which smoking is a carcinogen, such as the oral cavity, pharynx, hypopharynx, esophagus, larynx, lung, bladder, and uterine cervix. Specifically, HRT would maintain epithelial thickness and integrity, thus counteracting tumor development. Inherent in this hypothesis is the assumption that smoking-related tumors originate most often from the basal layer of the epithelium, which has lost the protective function of the more superficial epithelium.
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MATERIALS AND METHODS |
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The interview included questions regarding age at menarche, parity, age at first full-term pregnancy, age at menopause, type of menopause, oral contraceptive use (starting age, duration of use, brand use, age at last use), HRT use (starting age, duration of use, brand use, age at last use), family history of cancer (particularly breast cancer), constitutional factors, and alcohol and smoking habits. Women were shown a pictorial atlas featuring past and present HRT preparations as a memory aid. The women were asked about the average number of cigarettes smoked per day during various 5-year periods.
We used the unique personal identification number given at birth to every person in Sweden to collect information about cancer diagnoses, emigrations, and deaths in the cohort until January 1, 2000, from the Swedish Cancer Registry, National Cause of Death Registry, and the Population Census Registry. The Cancer Registry, founded in 1958, provides nearly complete coverage of the population.11 All cancer diagnoses were confirmed histologically or cytologically. Smoking-associated cancers were defined as the oral cavity, pharynx, hypopharynx, esophagus, larynx, lung, bladder, and uterine cervix.
Cancer incidence in the cohort was analyzed by the person-years method, with the national Swedish incidences for women used as reference, stratified by calendar year and 5-year age groups. Standardized incidence ratios were calculated as functions of the studied factors.
The women were followed from the date of interview until the third occurrence of a primary tumor, emigration, death, or January 1, 2000. Confidence intervals (CIs) for the standardized incidence ratios were calculated by assuming that the observed cancer cases followed a Poisson distribution. Hormone replacement therapy use and smoking habits in the cohort were also studied in a Cox regression model to adjust for known confounding factors. The assumptions for the Cox model were investigated and satisfied, and the covariates were evaluated by likelihood ratio tests. A trend test was used for different exposure levels. Only baseline information was used for assessing exposure in the analysis. Significance was defined as P < .05. All tests were two-tailed. Stata 7.0 (Stata Corp., College Station, TX) was used for statistical analyses.
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RESULTS |
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presents the baseline characteristics of the cohort.
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presents the incidence of each cancer type seen among ever-users of HRT in the cohort who had undergone a natural menopause. There was no increased incidence of cancer overall (standardized incidence ratio 1.03; 95% CI 0.88, 1.19). A significantly increased incidence was found for breast cancer (standardized incidence ratio 1.39; 95% CI 1.10, 1.74), and a decreased incidence was found for colon cancer (standardized incidence ratio 0.35; 95% CI 0.10, 0.89) among this subset.
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. Among women who had never used HRT, smokers had a higher risk than nonsmokers of smoking-related cancers. However, among women who had ever used HRT, smokers had lower smoking-associated cancer risks. For lung cancer, the risk was 7.5 times lower, and for cervical cancer it was 3 times lower, in nonsmokers compared with ever-smokers. Among smokers, a decreased risk of colon cancer was seen in women who used HRT compared with women who did not use HRT (P < .03). Hormone replacement therapy use lowered the risk of colon cancer regardless of smoking status. In smokers, HRT users experienced a lower risk of endometrial cancer, compared with nonsmoking HRT users. Use of HRT among smokers nonsignificantly lowered the risk for ovarian cancer. In contrast, smoking did not alter the increased breast cancer risk conferred by HRT. Smoking did not significantly increase breast cancer incidence among never-users of HRT. Smoking significantly increased the risk for malignant tumors (P < .006). The risk of cancer among smokers at smoking-associated sites, such as the oral cavity, pharynx, hypopharynx, larynx, esophagus, lung, cervix, and bladder, was decreased among long-term HRT users (48 months), compared with women who never used HRT (hazard ratio 0.24; 95% CI 0.08, 0.76) (Table 4). A significant trend indicated a stronger protective effect after longer HRT use (P < .006). Among never-smokers, HRT use did not significantly change cancer incidence at smoking-associated tumor sites.
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Including all women in the analysis (both women with a natural and an artificial menopause) gave essentially similar results as when only women with a natural menopause were included.
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DISCUSSION |
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Several mechanisms might account for the findings. Our results could be spurious, although the consistency in the effect between the various tumor types associated with smoking argues against such a possibility. Confounding factors also might account for our findings. Alcohol use may be such a factor, but the incidence of alcohol exposure in various models did not indicate that the findings could be accounted for by a residual alcohol effect (data not shown). Hormone replacement therapy might be underprescribed among heavy smokers owing to the risk of venous thromboembolism. This possibility seems unlikely, however, because HRT use was protective across all smoking categories. If the protective effect of HRT is real, the physiologic mechanism must be explained. Hormone replacement therapy might maintain mucosal integrity of epithelial surfaces (upper gastrointestinal tract, respiratory tract, and urinary tract) being exposed to the carcinogenic smoke products. The distance between an initiator and the epithelial stem cell may therefore be too great to allow tumor development. Whether estrogens and progestins exert such a protective effect outside the reproductive organs is currently unknown. Alternatively, the carcinogenic process itself may take longer in the presence of HRT. In the latter case, the effects of HRT might be only a postponement of tumor development rather than long-term protection. However, we have no molecular hypothesis to support this finding.
Previous studies addressing the incidence of smoking-related cancers among HRT users have been contradictory, showing either no effect2,12 or a protective effect of HRT.13,14 In recent reviews, Beral et al15 and La Vecchia16 stated that the data are inconclusive. Follow-up durations have been short, and a long-lasting effect may not yet be detectable. In the Women’s Health Initiative, combined HRT use showed no effect on lung cancer incidence after 5 years of follow-up.2 The longest duration of HRT use in our study was 48 months or longer. Whether 10 years or more of HRT use confers an even higher protective effect cannot be addressed at present with this cohort because of the small numbers. It is possible that the effect of HRT is underestimated because women who were classified as unexposed at enrollment may have started to use HRT during the follow-up period. The cohort is presently being reinterviewed, and future studies will examine this potential bias. Another limitation of our study is the small number of cases for the individual smoking-associated cancers, so we cannot yet assess whether there is a protective effect for all smoking-associated cancers.
Compared with another Swedish cohort investigating HRT use, the present investigation has the advantage of retrieving the HRT information by direct interviews and not by pharmacy prescriptions.12 Our subjects’ recall of HRT exposure was aided by a calendar and a pictorial atlas of brands prescribed in Sweden. Furthermore, the present cohort is population-based and is not limited to the use of certain pharmacies, hospitals, or attending mammography units.
The purpose of this report is not to advocate that women should smoke. Numerous studies have overwhelmingly implicated smoking as a risk factor for early death and the direct cause of many diseases. We recommend that women use HRT as appropriate by the evolving standard of care and refrain from smoking. However, smoking-associated cancers may be prevented or postponed by HRT use. Because this finding is new, it needs confirmation in future studies.
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Footnotes |
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doi:10.1016/S0029-7844(03)00564-7
Received July 22, 2002. Received in revised form February 3, 2003. Accepted April 24, 2003.
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REFERENCES |
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2. Investigators Writing Committee of the Women’s Health Initiative Randomized Clinical Trial. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002;288: 321–33.
3. Kelsey JL, Whittemore AS. Epidemiology and primary prevention of cancers of the breast, endometrium, and ovary. A brief overview. Ann Epidemiol 1994;4:89–95.[Medline]
4. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: Collaborative re-analysis of data from 49 epidemiological studies involving 51,977 women with breast cancer and 107,283 women without breast cancer. Lancet 1997;350: 1047–59.[Medline]
5. Pike MC, Ross RK. Progestins and menopause: Epidemiological studies of risks of endometrial and breast cancer. Steroids 2000;65:659–64.[Medline]
6. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328–32.
7. Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I. Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer 1999;81:339–44.[Medline]
8. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485–91.
9. Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: A meta-analysis. Obstet Gynecol 1999;93:880–8.
10. Olsson H, Bladström A, Ingvar C, Möller T. A population based cohort study of HRT use and breast cancer in southern Sweden. Br J Cancer 2001;85:674–7.[Medline]
11. Mattson B. Cancer registration in Sweden: Studies on completeness and validity of incidence and mortality registers. Stockholm, Sweden: Karolinska Institute, 1984, [doctoral thesis].
12. Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy—long-term follow-up of a Swedish cohort. Int J Cancer 1996;67:327–32.[Medline]
13. Gallus S, Bosetti C, Franceschi S, Levi F, Simonato L, Negri E, et al. Oesophageal cancer in women: Tobacco, alcohol, nutritional and hormonal factors. Br J Cancer 2001;85:341–5.[Medline]
14. Ettinger B, Friedman GD, Bush T, Quesenberry CP Jr. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol 1996;87:6–12.[Abstract]
15. Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol Biostat 1999;4: 191–210.[Medline]
16. La Vecchia C, Brinton LA, McTiernan A. Menopause, hormone replacement therapy and cancer. Maturitas 2001;39:97–115.[Medline]
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