For the British Tamoxifen Second Cancer Study Group
Affiliation of authors: Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
Correspondence to: Professor Anthony J. Swerdlow, DSc, Section of Epidemiology, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK (e-mail: anthony.swerdlow{at}icr.ac.uk).
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ABSTRACT |
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INTRODUCTION |
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These uncertainties reflect the limited numbers of subjects in published studies, especially in analyses of long-term use and after long follow-up. So far, the largest published investigation had 324 case patients (1). We therefore conducted a larger casecontrol study in Britain, with a design intended to increase the numbers of subjects who had the potential for long-term exposure to tamoxifen, to investigate the relationships between tamoxifen treatment and the risk of endometrial cancer in premenopausal women, in long-term users of tamoxifen, and in women for several years after ending treatment.
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PATIENTS AND METHODS |
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We obtained the appropriate ethical approvals from the London School of Hygiene & Tropical Medicine Ethics Committee and numerous other ethics committees. We obtained anonymized listings of all women with breast cancer diagnosed from January 1, 1976, through December 31, 1996 (or to the most recent data year available from the cancer registry if earlier), from the population-based regional cancer registries of England, except for the Northern registry, and from the national cancer registries of Wales and Scotland. The listings included information on second cancers occurring in these women. The former Northern registry (now part of the Northern and Yorkshire registry), covering 5% of the population of Britain, was omitted because it was unable to identify the data necessary for the study. Women were eligible to be a case patient in the study 1) if they had a registered primary invasive (not in situ) breast cancer diagnosed from January 1, 1976, through December 31, 1996; 2) if they had no cancer (except non-melanoma skin cancer) previous to or concurrent with the breast cancer; and 3) if they had a registered primary endometrial cancer (invasive, not in situ) diagnosed from January 1, 1988, through December 31, 1996, at least 3 months after diagnosis of the breast cancer, with no other second malignancy except non-melanoma skin cancer or breast cancer occurring in the intervening period; and 4) if case notes could be located that covered the period from breast cancer diagnosis to endometrial cancer diagnosis. Although tamoxifen was introduced in the United Kingdom in September 1973, we restricted the study to patients treated from January 1, 1976, onward because we found in a pilot investigation that the prevalence of tamoxifen use was low before 1976, and so data collection for January 1, 1973, through December 31, 1975, would have been relatively inefficient. Similarly, we restricted the study to endometrial cancers occurring from 1988 onward to maximize the proportion of case notes that could be obtained and the proportion of subjects with long-term treatment and follow-up.
Control patients were women with breast cancer selected from the file of all patients diagnosed with incident breast cancers from January 1, 1976, through December 31, 1996. One control patient was randomly selected per case patient, with individual matching to case patients on 1) date of diagnosis of the primary breast cancer within 6 months; 2) age at diagnosis of the primary breast cancer within 6 months; 3) registry region of residence at the date of diagnosis of primary breast cancer; and 4) survival without second cancer, other than non-melanoma skin cancer or breast cancer, for at least as long after the diagnosis of breast cancer as the index duration (i.e., the time from breast cancer diagnosis to endometrial cancer diagnosis in the matched case patient). In addition, we required that 5) the control patient had not had a hysterectomy during the index period after breast cancer diagnosis and that 6) her case notes covered the period to the index date. Because criteria 5 and 6 could not be determined from the cancer registry file, we examined case notes for individuals who met control criteria 1 through 4. If criterion 5 or 6 was unfulfilled, a replacement control patient was chosen in the same way. This process was repeated if necessary.
In parallel with the endometrial cancer casecontrol study, we also conducted casecontrol studies of ovarian, colorectal, and liver cancers after breast cancer by use of the same data extraction forms and procedures. The control patients from these studies were selected by the same matching methods used for the endometrial cancer study, except that the matching ratio and the years of cancer incidence included varied by cancer site and that absence of hysterectomy was not a matching criterion. The control patients from these studies who had not had hysterectomies, therefore, met the general criteria to be control patients for the case patients in the endometrial cancer study, and we included all of the above-described control patients to maximize the data available for analysis.
For each patient, we attempted to locate the hospital case notes. When they were located, data were extracted on demographic details, identification of the general practitioner, tamoxifen treatment (start and stop dates and dosage for each period of treatment), other treatments (chemotherapy and radiotherapy) of the first primary cancer, abdominal and pelvic radiotherapy before the index date, occurrence of contralateral breast cancer, date of diagnosis of the first and second cancers, histologic type of the endometrial cancer, and potential confounding variables, including weight and height at diagnosis of the first cancer, parity, age at menopause, use of oral contraceptives and hormone replacement therapy, and, for control patients, hysterectomy. For case patients, the history was taken up to but not including the date of diagnosis of the second cancer; for matched control patients, the history was taken until the equivalent duration from diagnosis of the first primary (i.e., the index duration). For case and control patients for whom tamoxifen data from hospitals were incomplete, general practitioners were queried by mail for information that would validate and amplify hospital data. We could generally ascertain a definite date when tamoxifen treatment ended; however, when this date could not be determined with certainty, it was taken to be the date of last known treatment. The duration of tamoxifen use for patients who received the drug during two or more separate time periods was calculated by adding these periods together. The average daily dose of tamoxifen for those who changed dose over time was calculated as the average of the doses in the different periods weighted by the lengths of these periods. We also analyzed risks of endometrial cancer of different histologic subtypes, as categorized elsewhere (18,27).
We identified 825 case patients with endometrial cancer for whom full case notes were found and who met the study criteria. We also identified 208 provisionally eligible case patients from cancer registry records whose case notes could not be located or had insufficient information for this study. Not all of these patients would have been eligible if their notes were located. The 208 case patients who were excluded were similar to the 825 case patients with full case notes with respect to age. However, breast cancer was more often diagnosed before 1985 in the 208 excluded patients (46% of patients) than in the 825 included patients (33% of patients), and so they also were more likely to have a longer (5 years or more) index duration (64% and 60% of patients, respectively). For 813 of the 825 case patients with full case notes available, at least one matched control patient was found, and these 813 subjects became the case patients in our analyses.
Full case notes were obtained for a total of 1152 control patients. We also identified about 678 potential control patients from cancer registry records whose notes were sought but not found. Many of these 678 subjects may have been ineligible if the notes had been located, because records of a hysterectomy were in case notes, not in cancer registry records. These 678 subjects were similar to the 1152 control patients with available notes with regard to age, but their breast cancer was diagnosed more often before 1985 (46% of the 678 subjects; 29% of the 1152 subjects), and they were more likely to have index durations of 5 years or more (60% and 48%, respectively). Of the 1152 control patients with full case notes, 1067 were matched to the case patients with full case notes and, therefore, became the control patients in our analyses.
Statistical Analysis
To assess the relationship of tamoxifen treatment and other factors to the risk of endometrial cancer, we calculated odds ratios (ORs), as estimates of relative risks. Matching strata were created with all of the important variables (age and date of diagnosis of breast cancer, index duration, and area of the country). Odds ratios and 95% confidence intervals (CIs) were calculated, and tests of trend were conducted, by use of conditional logistic regression (28) with STATA version 8.2 (29). The trend tests were calculated with continuous actual values for individual subjects. Where required because of small numbers, exact P values and confidence intervals were calculated with LogXact version 5.0 (30). All statistical tests were two-sided.
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RESULTS |
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Although 423 of the 813 case patients developed endometrial cancer while they were still taking tamoxifen, the greatest relative risk was observed for patients who had ceased treatment within the last 2 months (OR = 7.7, 95% CI = 4.5 to 13.0). Because this increased risk is likely to be an artifact caused by symptoms associated with endometrial cancer that lead to discontinuing tamoxifen treatment, we reanalyzed the data by combining risk in patients still on treatment and risk in patients for the first 2 months after treatment ceased (Table 2). Increased risks of endometrial cancer were observed in all follow-up periods, although the risk increase was not statistically significant for the longest period (5 years or more) and risks tended to decrease statistically nonsignificantly with longer follow-up. After adjustment for duration of tamoxifen treatment, relative risk did not diminish in follow-up to 5 years or more.
Among each age group from that younger than 45 years to that 6574 years old, an increased risk of endometrial cancer was statistically significantly associated with tamoxifen treatment (Table 4). However, among the age group of 75 years or older, risk was not statistically significantly greater among those who received tamoxifen than among those who did not receive tamoxifen, although there was a statistically significant trend for the association of risk with treatment duration, as indeed there was in each of the younger age groups. Data on menopausal status were usually but not always recorded in the case notes (a menopausal status was recorded for 81% of case plus control patients younger than 55 years old at diagnosis of breast cancer). A statistically significantly higher risk of endometrial cancer was observed for tamoxifen users than for non-users, both for patients reported to be premenopausal (OR = 2.0, 95% CI = 1.1 to 3.4) and for patients who were reported to be premenopausal or who were aged younger than 45 years old and had not had an oophorectomy (OR = 2.0, 95% CI = 1.2 to 3.5; Table 4). The increased risk in postmenopausal patients was comparable to the risk in premenopausal patients, regardless of whether postmenopausal status was limited to those reported as such in the case notes (OR = 2.8, 95% CI = 2.0 to 3.9) or also included those determined to be postmenopausal by age (i.e., 55 years or older) (OR = 2.5, 95% CI = 1.9 to 3.3).
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DISCUSSION |
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A limitation of our study is that the proportion of patients omitted, because their case notes were unavailable, was greater than that in the data sets achieved in the previous largest studies (1,18). Some of this problem was caused by our focus on women treated many years ago, whose case notes had often been destroyed for policy reasons (e.g., closure of hospitals) that were not connected with treatment. One concern in studies that use case notes is that treatment and its duration can be underestimated if case notes are incomplete. However, it seems unlikely that our results were appreciably distorted for this reason because our results were unchanged when we restricted the analyses to subjects with a known end date of treatment and because, for variables examined previously, our findings were similar to previous findings from major published studies (1,18).
Another potential limitation is surveillance bias; that is, tamoxifen-treated women might be under greater surveillance for endometrial cancer than are other women with breast cancer, because endometrial cancer is a known side effect of tamoxifen treatment. Most of the cases of endometrial cancer in our study, however, occurred before 1994 when this side effect became widely accepted (1,6), and analyses restricted to cases diagnosed before 1994 showed a statistically significant association, with no smaller risk per year of tamoxifen use than for cases diagnosed subsequently. The strong durationresponse effect in our data would also be difficult to explain by surveillance bias because such a bias would be unlikely to increase substantially with time since first treatment. Furthermore, Bergman et al. (18) showed that endometrial tumors are diagnosed at a later stage and are associated with poorer survival in long-term tamoxifen users than in non-userswhereas the opposite would be expected if surveillance bias resulted in the observed increased risks. In addition, increased mortality from endometrial cancer has been associated with tamoxifen use (17). Results of previous studies (1,18) indicate that confounding by known risk factors does not appear to account for our results. Adjustment for non-tamoxifen risk factors also did not alter our risk estimates, but this is weak evidence, given our incomplete data on these factors.
Our data confirm that endometrial cancer risk is not associated with the dose of tamoxifen (2,1618,23), apparently even for the dose of 10 mg/day, a dose that has not been previously examined. Small numbers of subjects were taking this dose, however, and so the finding needs confirmation.
In contrast to dose, however, duration of treatment greatly affected risk in our study, as in most (1,10,1619,23) but not all (3) previous studies. The longest duration of treatment previously examined has been 5 years or more. Our study had more than seven times as many participants with 5 years or more of treatment as any previous study, and we found that risk increased steadily with increasing duration of tamoxifen treatment to the category with 10 years or more of treatment (median = 11 years). However, randomized trials for breast cancer have shown treatment benefit with tamoxifen of only up to 5 years, and longer treatment apparently does not increase the benefit (26,31). Two additional trials, however, are currently in progress (26). Among all control patients, 16% had received tamoxifen for 5 years or more; among control patients with information on at least 5 years of follow-up (i.e., those matched to case patients who had developed cancer after at least 5 years), 32% had received tamoxifen for 5 years or more. Because the control patients were matched on length of follow-up and were required not to have had a hysterectomy, they cannot be used directly to determine the proportion of patients in Britain who have received more than 5 years of tamoxifen treatment. However, our data suggest that it may be an appreciable proportion of patients.
Results of an early study of endometrial cancer risks after tamoxifen treatment for breast cancer (3) and of one of the two largest studies to date (18) suggested that risk was not increased if tamoxifen treatment was less than approximately 2 years. Our results, however, indicated that risks increase continuously with longer duration and do not have a threshold.
We found that the increasing risk of endometrial cancer associated with cumulative dose of tamoxifen is a reflection of the treatment duration and not of daily dose. The overall relative risks of endometrial cancer associated with tamoxifen treatment have varied between 0.6 and 7.5 in different studies (1,2,818,20) but were often based on small numbers of subjects. Given the large association of treatment duration with risk, there is little validity in comparing such risks without taking account of the distribution of treatment durations. The risk per year of treatment that we found (OR = 1.18, 95% CI = 1.14 to 1.23) was similar to that reported by the other largest studies [in Bernstein et al. (1), OR = 1.18 (95% CI = 1.08 to 1.28), and in Bergman et al. (18), we estimate that OR = 1.27].
Few studies have examined relative risks of endometrial cancer in tamoxifen-treated women as a function of age or menopausal status, and these have included only small numbers of premenopausal subjects, for whom conflicting results have been reported (1,7,8,14,20). Our data suggest that the risk needs to be considered clinically for both pre- and postmenopausal patients. Tamoxifen has different effects on estrogen levels in pre- and postmenopausal women, suggesting that it might also have different effects on endometrial cancer risks. In premenopausal women, tamoxifen stimulates the ovaries to synthesize estrogens and thus greatly increases the level of plasma estrogen (32). In postmenopausal women, however, tamoxifen slightly reduces the level of plasma estrogen and often increases the level of serum hormone binding globulin, and so free estradiol levels may be reduced in postmenopausal women (32,33). In premenopausal women, tamoxifen has antiestrogenic effects on the uterus, whereas in postmenopausal women, tamoxifen has estrogenic effects (32). Consequently, the finding that tamoxifen was associated with a comparable risk of endometrial cancer among pre- and postmenopausal patients in our study is surprising. A possible explanation is that in premenopausal women, the increased estrogen levels may override the antiestrogen effect of tamoxifen on the uterus, whereas in postmenopausal women, the antiestrogen effect of tamoxifen on the uterus may predominate, although such speculation is entirely post hoc.
Although one cannot calculate absolute excess risks from a casecontrol study, our relative risks indicate that the absolute excess risks must be much larger for older women than for younger women, because incidence rates of endometrial cancer in Britain increase steeply with age up to approximately 70 years (34).
With few exceptions (1,3,18), published analyses of the time course of endometrial cancer risks after tamoxifen have concerned patients who are currently receiving treatment or patients who are within 12 months of last treatment. The only analysis of risks 2 years or more after last treatment (18) found a statistically nonsignificantly increased relative risk for this period (RR = 1.2,95% CI = 0.6 to 2.2). An analysis of risks by time since breast cancer diagnosis, without information on length of treatment or end of treatment, found no diminution of risks after 10 years or more after diagnosis (20). We found that risks remained statistically significantly increased for 4 years and were statistically nonsignificantly increased beyond this period, suggesting that potentially elevated risk should be considered clinically for at least 4 years after the completion of tamoxifen treatment. The continuing increased risks after cessation of treatment also support the evidence, discussed above, that surveillance bias is not the reason for the increased endometrial cancer risks associated with tamoxifen treatment.
Results of most previous studies (16,18,20,24) indicate that tamoxifen treatment is associated with a much greater risk for mixed mesodermal tumors and sarcomas of the endometrium than for adenocarcinomas, although results of one analysis (24) did not agree. The potential high risk of mixed mesodermal tumors and sarcomas is important because of the poor prognosis of these tumors (18,20,35). In our analyses, the magnitude of risk was indeed different for different histologic tumor types (for mixed mesodermal tumors and sarcomas, OR = 13.5 [95% CI = 4.1 to 44.5], with a statistically significant trend for increased risk with greater treatment duration [Ptrend<.001]; for adenocarcinomas, OR = 2.1 [95% CI = 1.6 to 2.7], again with a statistically significant trend for increased risk with greater treatment duration [Ptrend<.001]). The relative risk for mixed mesodermal tumors was greater than that found in the previous study that calculated a relative risk (20), but the latter investigated only initial hormonal treatment (believed mainly to be with tamoxifen) and lacked follow-up of women moving out of the Surveillance, Epidemiology and End Results Program (SEER)1 catchment areas (20). The risk for clear cell tumors in our study, from smaller numbers of case patients, was increased statistically nonsignificantly with tamoxifen treatment, and treatment duration was not statistically significantly associated with risk of this histologic type. The evidence for an increased risk of uterine sarcoma associated with tamoxifen has led the U.S. Food and Drug Administration to issue a warning for tamoxifen, with a statement that the warning is most relevant to women taking the drug for prophylaxis of breast cancer (35). We note, in addition, that the risk of uterine sarcoma increases greatly with longer period of use.
As in previous studies (9,16,23), risk of endometrial cancer in women overall was greatly increased by prior pelvic radiotherapy. In the study by Sasco et al. (23), risk was no greater after treatment with tamoxifen in addition to pelvic radiotherapy than after such radiotherapy alone (23). However, in another, smaller study (9), risk was greatest for the two exposures combined. Our data were insufficient to distinguish between these two alternatives.
We also found a decreased risk of endometrial cancer after breast radiotherapy in women overall; it does not seem plausible that this result could be etiological. In principle, confounding seems a possible explanation, but on examination of the data we found no plausible confounder.
The increased risks of endometrial cancer associated with hormone replacement therapy and with greater postmenopausal weight and the reduced risk associated with smoking among all patients that we found are as expected because these are established risk factors (36). Our data on these factors were incomplete because they were mainly extracted from hospital case notes in which they may have had no essential clinical purpose. Nevertheless, because the information was recorded at the time of breast cancer diagnosis, it should not have been biased with respect to risk of subsequent endometrial cancer. It was insufficiently complete, however, to reach conclusions on interactions between the effects of hormone replacement therapy and of weight and that of tamoxifen.
In conclusion, the benefits of tamoxifen far outweigh the risks when used for 5 years or less for breast cancer treatment (6). However, our data show that the risk of endometrial cancer after tamoxifen treatment increases for up to at least 10 years of treatment, whereas current evidence suggests that tamoxifen treatment beyond 5 years does not add to its treatment efficacy. Trials to obtain further information on the effectiveness of long-term tamoxifen treatment are several years from completion (26); until the data are available, our results suggest that the associated risk of endometrial cancer makes treatment with tamoxifen beyond 5 years questionable.
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NOTES |
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The British Tamoxifen Second Cancer Study Group comprises Anthony J. Swerdlow, Michael E. Jones, David H. Brewster, MD (Scottish Cancer Intelligence Unit); David Forman, PhD (Northern & Yorkshire Cancer Registry & Information Service); Sara Godward, PhD (East Anglian Cancer Intelligence Unit); Anthony Moran, MB (North Western Cancer Registry); Gillian Lawrence, PhD (West Midlands Cancer Intelligence Unit); Henrik Møller, PhD (Thames Cancer Registry); Monica Roche, MBBS (Oxford Cancer Intelligence Unit); Paul Silcocks, MSc (Trent Cancer Registry); John A. Steward, PhD (Welsh Cancer Intelligence & Surveillance Unit); Julia Verne, PhD (South & West Intelligence Unit); and Lyn M I Williams, MD (Mersey & Cheshire Cancer Registry).
This research was supported by the Medical Research Council.
We thank the staff of the cancer registries and, in particular, Dr. T. Davies, Mrs. M. Page, Ms. C. Chester, Ms. J. Littler, Ms. J. Harvey, Ms. J. Evans, Ms. J. Harrison, Ms. P. Allgood, Dr. D. Etherington, Ms. J. Flaherty, Dr. J. Bell, Ms. J. Nicholas, Ms. C. Johnson, Mr. A. Waterhouse, Ms. S. Reynolds, Ms. J. Andrews, Mrs. S. Cook, Dr. A. Teale, Dr. L. Somervaille, Mrs. J. Stephenson, Ms. A. Ramsay, and Ms. C. Storer and the nurses from the Aetiological Epidemiology Team for facilitation and data extraction; the help of hospital and primary care clinicians and medical records staff throughout Britain in obtaining data; Ms. B. Peachey and Mrs. H. Nguyen for data entry; Professor S. Lakhani, Dr. G. Ross, and Professor M. Dowsett for advice; and Mrs. M. Snigorska for secretarial help.
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Manuscript received May 14, 2004; revised December 10, 2004; accepted January 6, 2005.
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