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Endometrial cancer following breast cancer treatment: Tumor characteristics and predictors of survival
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Endometrial cancer following breast cancer treatment: Tumor characteristics and predictors of survival
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INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6a x 9* black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. ProQuest Information and Learning 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 800-521-0600 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ENDOMETRIAL CANCER FOLLOWING BREAST CANCER TREATMENT: TUMOR CHARACTERISTICS AND PREDICTORS OF SURVIVAL Copyright 2001 by Presley Ann Hays A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCES (APPLIED BIOMETRY AND EPIDEMIOLOGY) August 2001 Presley Ann Hays Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. U M I Number: 1409589 _ ___ (B) UMI U M I Microform 1409589 Copyright 2002 by ProQuest Information and Learning Company. A ll rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, M l 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UNIVERSITY O F SOUTHERN CALIFORNIA THE GRADUATE SCHOOL UNIVERSITY RARK LOS ANGELES. CALIFORNIA S 0 0 0 7 This thesis, written by under the direction of A .ex Thesis Com m ittee, and approved by a ll its members, has been pre sented to and accepted by the Dean of The Graduate School, in partial fulfillm ent of the requirements for the degree o f & Epidemiology Dt ma D ate August J^ JO O l THESIS COMMITTEE Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Dedication This thesis and my Masters degree would not have been possible without the support of my husband, Brett Thomas Whiddea I dedicate this to him. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table of Contents List of Tables/List of Figures................................................................................................................iv Abstract..................................................................................................................................................vi Introduction.............................................................................................................................................L Subjects and Methods Subject Identification and Eligibility............................................................................................. 2 Pathology Review............................................................................................................................ 3 Follow-up.......................................................................................................................................... 4 Statistical analysis........................................................................................................................... 5 Results..................................................................................................................................................... 7 Discussion.............................................................................................................................................31 References............................................................................................................................................35 iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. List of Tables/List of Figures Table 1. Characteristics of study population (n=324) and subset of patients with pathology material available (n=212)............................................8 Table 2. Endometrial cancer treatment characteristics of 324 patients with endometrial cancer following breast cancer in relation to stage of breast cancer............. 11 Table 3. Characteristics of 324 patients with endometrial cancer following breast cancer in relation to duration of tamoxifen use based on Cancer Registry records........... 12 Table 4. Characteristics of 290 patients with endometrial cancer following breast cancer in relation to hormone use based on Cancer Registry records..................... 13 Table 5. Characteristics of 316 patients with endometrial cancer following breast cancer in relation to body mass index (BMI) based on Cancer Registry records.............. 14 Table 6. Characteristics of 290 patients with endometrial cancer following breast cancer in relation to tamoxifen and/or ERT therapy based on Cancer Registry records... 15 Table 7. Degree of concordance between cancer registry review and pathology review......................................................................................................... 16 Table 8. Odds ratios (ORs) and 95% confidence intervals of endometrial cancer ride associated with treatment of breast cancer.................................. 17 Table 9. Factors influencing endometrial cancer-specific survival based on Cox proportional hazards models....................................................................... 32 Figure 1. Breast cancer-specific survival according to stage of breast cancer at diagnosis.................................................................................... 19 Figure 2. Breast cancer-specific survival according to tamoxifen treatment status for breast cancer..................................................................... 20 Figure 3. Breast cancer-specific survival according to tamoxifen treatment status and breast cancer stage........................................................... 21 Figure 4. Endometrial cancer-specific survival according to tamoxifen treatment for breast cancer status..................................................................... 22 Figure 5. Endometrial cancer-specific survival according to histology type of endometrial cancer.................................................................................24 Figure 6. Endometrial cancer-specific survival according to overall grade of endometrial cancer...................................................................................25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. List of Tables/List of Figures continued Figure 7. Endometrial cancer-specific survival according to histology type of endometrial cancer and tamoxifen treatment status for breast cancer.......................... 26 Figure 8. Endometrial cancer-specific survival according to overall grade of endometrial cancer and tamoxifen treatment status for breast cancer.......................... 27 Figure 9. Endometrial cancer-specific survival according to history of hormone replacement therapy........................................................................... 28 Figure 10. Endometrial cancer-specific survival according to BMI at breast cancer diagnosis......................................................................................29 Figure 11. Overall survival according to tamoxifen treatment status for breast cancer....30 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Presley Ann Hays Leslie Bernstein, Ph.D. ABSTRACT ENDOMETRIAL CANCER FOLLOWING BREAST CANCER TREATMENT: TUMOR CHARACTERISTICS AND PREDICTORS OF SURVIVAL Tamoxifen is widely prescribed as adjuvant therapy for women diagnosed with breast cancer. Many early studies of women developing endometrial cancer following breast cancer describe endometrial cancers from tamoxifen use that are well-differentiated, non-aggressive tumors with a good prognosis. PURPOSE: Compare tumor characteristics and survival patterns of women treated with tamoxifen and those not treated with tamoxifen. MATERIALS AND METHODS: 324 women diagnosed with endometrial cancer following breast cancer. RESULTS: There was no difference between the distributions of overall grade and histologic type among tamoxifen users compared to non-users. Endometrial cancer-specific survival among tamoxifen users did not differ compared to non-tamoxifen users. CONCLUSION: We found no evidence that tamoxifen induces more aggressive endometrial cancers in our cohort of patients, or that tamoxifen use affects breast cancer specific, endometrial cancer specific or overall survival. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION Tamoxifen is widely prescribed as adjuvant therapy for women diagnosed with breast cancer. It is a nonsteroidal hormone that acts as an anti-estrogen in breast tissue. Results of randomized clinical trials have shown that tamoxifen increases overall and disease-free survival of women with breast cancer, particularly those with estrogen receptor positive disease.[l-3] Because of the efficacy of tamoxifen in the treatment of breast cancer, a randomized controlled clinical trial of its use was undertaken in high risk women to determine whether it also reduced the risk of developing breast cancer. Results from this trial, the Breast Cancer Prevention Trial, showed that tamoxifen use decreased the incidence of estrogen receptor positive but not estrogen receptor negative breast cancer. [4] In addition to its anti-estrogen activity, tamoxifen exerts some estrogen-like effects on bone, the cardiovascular system and the endometrium. Tamoxifen apparently has beneficial effects on bone density and lipid profiles;[5] however, the unopposed estrogen-like activity of tamoxifen on the endometrium has led to endometrial polyps and increased risk for developing endometrial cancer. [6-9] This adverse effect is presumably due to an increase in proliferative activity, [7,10] with the majority of endometrial cancers associated with tamoxifen use having characteristics similar to estrogen induced tumors. [11,12] Early studies of the effects of unopposed estrogen on the endometrium have suggested that estrogen-induced endometrial neoplasms are typically well-differentiated, of low grade and early stage.[13] Endometrial carcinomas related to tamoxifen have been presumed to develop in a similar manner.[10] Many early studies of women developing endometrial cancer following breast cancer describe endometrial cancers from tamoxifen use that are well-differentiated, non- aggressive tumors with a good prognosis.[l 1,14, IS] Yet, a retrospective study from the Yale Tumor Registry by Magriples and associates] 16] and, more recently, a case-control study from the Netherlands,[17] reported that women taking tamoxifen tend to have more poorly 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. differentiated tumors associated with a poor prognosis. These studies have concluded that tamoxifen induces a more aggressive type of endometrial cancer than is observed in the absence of this treatment. Rather than acting as an estrogen agonist, these investigators suggest that tamoxifen may have a different mechanism of action on the endometrium, resulting in tumors with an aggressive histology not typical of exogenous estrogens. As tamoxifen is being considered as a breast cancer chemo-preventive agent for high- risk women, it is important to know whether women taking tamoxifen are at risk of developing more aggressive endometrial cancers and whether the survival patterns of those who do develop endometrial cancer differ according to whether they have been treated with tamoxifen. Using a population-based cohort of 324 women diagnosed with endometrial cancer at least 6 months following a first primary breast cancer diagnosis, we investigated histologic characteristics of the tumors and survival of women treated with tamoxifen, and compared them with those of women who were not treated with tamoxifen. Additionally, we compared the distributions of histology characteristics and survival for women by estrogen replacement therapy status and body size, two factors that modified the effects of tamoxifen on the risk of endometrial cancer in our case- control study. [9] SUBJECTS AND METHODS Subject Identification and Eligibility Eligibility criteria for selection of case and control patients have been previously described. [9] Case patients were women diagnosed with endometrial cancer at least six months following a diagnosis of invasive breast cancer. The dates of accrual of endometrial cancer diagnoses for eligible patients were July 1978 through June 1993. Case patients were identified through population-based Surveillance, Epidemiology and End Results (SEER) registry systems in Los Angeles County (n=228), Atlanta (GA) (n=14), Iowa (n=50) and Seattle-Puget Sound 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (WA) (n=32). Control patients were randomly selected from a roster of breast cancer patients and were individually matched to each case patient on registry, year of birth, year of diagnosis, race and stage of breast cancer at diagnosis. Control patients were required to have had an intact uterus throughout the “at risk” interval defined by the dates of breast cancer and endometrial cancer diagnosis of the case patient to whom they were matched. They were also required to be alive on the last day of that time interval. Neither cases nor controls could have had a cancer diagnosis prior to their initial breast cancer, nor could they have any cancer diagnosis other than breast cancer in the interval at risk. Medical records were abstracted and telephone interviews were conducted (whenever possible, with patients or their next-of-kin) to confirm study eligibility and to obtain detailed information on breast cancer treatment and exposures possibly related to endometrial cancer risk (such as body weight, height, use of oral contraceptives and hormone replacement therapy, smoking history and history of diabetes). We recorded details of dose and duration of chemotherapy, radiation therapy and tamoxifen therapy. The standing height and weight of each patient was obtained from the medical record at the time of her breast cancer diagnosis. Breast cancer stage was classified as localized if pathology and surgical reports indicated no nodal involvement or metastatic disease and as non-localized if disease extended to the lymph nodes or was metastatic. Pathology Review Paraffin-embedded endometrial cancer tissue blocks and diagnostic slides were requested from the pathology laboratories where each of the 324 original endometrial cancer diagnoses was made. We were able to obtain specimens for 222/324 (68.3%) endometrial cancer patients. When blocks were provided, they were sectioned serially and the first section was stained using hematoxylin and eosin for histologic assessment When tissue blocks were 3 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. not available, unstained slides were requested and used for pathology review. The main reason pathology materials could not be obtained for 102 cases was the length of time since the endometrial cancer diagnosis; some laboratories retain specimens only for a fixed period of time. The same pathologist (MP) reviewed all specimens and characterized the histopathology of the tissue block provided. After the slides were determined to be adequate for diagnosis, the behavior of the specimen was categorized as: no abnormality, benign hyperplasia, carcinoma in- situ, or invasive cancer. Histology was classified according to the following classifications: endometrioid adenocarcinoma, villoglandular adenocarcinoma, serous papillary adenocarcinoma or other adenocarcinoma, leiomyosarcoma, malignant mixed mullerian tumors (MMMT), miillerian adenosarcoma, endometrial stromal sarcoma, clear cell carcinoma, or other type of histology. Overall histologic grade was classified by FIGO (International of Gynecologic and Obstetrics) standards as low, intermediate, high or other grade. [18] The presence or absence of other endometrial pathology including the type of hyperplasia (none, simple, complex or atypical) and the presence of polyps was also recorded. The pathologist was blinded to the tamoxifen status and other exposure history of the cases. Histologic classification as recorded by the SEER registries and grade as abstracted from the original diagnostic pathology reports were also recorded. Follow-up Each of the SEER registries conducts follow-up activities on cancer patients to determine length of survival, cause of death (coded to version 9 or 10 of the International Classification of Diseases) and date of death. In Los Angeles County, these activities were not initiated until 1992. However, Los Angeles County registry records have been routinely linked to California state mortality records since 1972. Additionally, during the interview process, we verified follow-up information for Los Angeles County patients. We also followed these 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. patients using tracing resources, including a nationwide credit agency (Experion), change of address records, and records of the California Department of Motor Vehicles. All patients were followed through December 31,1999. Causes of death were assigned according to the cause of death on the death certificate and grouped as due to breast cancer, endometrial cancer or other causes. Statistical analysis For statistical analyses, we collapsed the endometrial cancers into three histology groups: (1) endometrioid adenocarcinomas; (2) clear-cell carcinomas and papillary serous carcinomas; and (3) malignant mixed mullerian tumors (MMMT) and sarcomas of the endometrium. These same groupings were used in the report of Bergman etal.[ 17] Based on the review, one case was excluded as it appeared that the malignancy was of endocervical origin, most likely originating in the cervix. We conducted analyses based solely on case patients to examine the effects of tamoxifen treatment on histologic subtype and grade as well as survival. We also evaluated the effects of prior use of estrogen replacement therapy (ERT) and body mass index (BMI) on these outcome measures. Tamoxifen use was classified as no use, less than 2 years of use and greater than or equal to 2 years of use for these analyses. For analyses of estrogen replacement therapy, we compared users to non-users. BMI was calculated as weight (kg) divided by the square of height (M). We retained the two BMI categories used in Bernstein et al.,[9] classifying women as having high BMI (> 24.5 kg/M2 ) or low BMI (<24.5 kg/M2 ) based on the median BMI observed among the control patients. Analyses of histology and grade were conducted using all cases (n=324) and using those cases included in the pathology review (n=212). In analyses based on this subgroup of cases, in addition to histology type and grade, the presence and type o f hyperplasia and the 5 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. presence of polyps was recorded. The histology characteristics based on exposure to tamoxifen, ERT or high BMI were compared using either the chi-square test or Fisher’s exact test. The Kappa statistic was estimated as a measure of the degree of concordance between the registry diagnosis and that of the study pathologist. Excellent agreement was categorized as a Kappa statistic equal to or above 0.75, good agreement was between 0.74 and 0.41, and poor agreement was considered to be less than or equal to 0.40.[19] A weighted Kappa statistic was used when the relative seriousness of the different kinds of disagreements were specified, otherwise an unweighted Kappa statistic was used. All p-values presented are 2-sided. Survival from breast cancer, endometrial cancer and overall survival according to duration of tamoxifen use, hormone use and BMI was studied in all 324 cases. Survival curves were compared using the log-rank test statistic. In addition, Cox’s proportional-hazards models were fit to examine the effects of tamoxifen duration, hormone use and BMI on the survival from breast and endometrial cancer controlling for other possible prognostic factors including age at breast cancer diagnosis, age at endometrial cancer diagnosis, breast cancer treatments, stage of breast cancer at diagnosis, and histological classification and grade of endometrial cancer. Conditional logistic regression methods were used to assess the relative odds (and 95% confidence intervals) of developing each of the three histologic subtypes of endometrial cancer associated with exposure to tamoxifen. The original case-control matching was retained in these analyses which were based on the 324 case patients and the 671 control patients in the study.[9] For each histologic subtype, we examined the trend in risk with increasing exposure by modeling months of tamoxifen use as a continuous variable in each of the analyses. We also compared a model with no specification by histologic subtype to that where the subtype was specified to determine whether any of the trends in risk associated with tamoxifen use for the 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. three subtypes differed from the others (a 2-degree of freedom test for heterogeneity based on twice the absolute difference in the log-likelihoods for the two models). Logistic regression analyses, survival analysis and Cox proportional hazards analyses were conducted using the Epilog software package (version 2.1 for DOS). RESULTS All patients (n=324) and the subset of patients available for pathology review (n=212) are presented in Table I. The specimens available for pathology review were representative of the entire study group in terms of registry source, age and year of endometrial cancer diagnosis, months between initial breast cancer and endometrial cancer diagnosis, months of follow-up since endometrial cancer diagnosis, vital status at the end of follow-up and treatment characteristics for breast cancer (Table 1). The majority of patients were from the Los Angeles based registry (70.3%, Table 1). The median age at endometrial cancer diagnosis was 70 years (range, 44-94 years) and the majority of women were post-menopausal (90.1%). The median time between the initial breast cancer and endometrial cancer diagnosis was 37 months (range, 6-162 months) and the median time of follow up since endometrial cancer diagnosis was 85 months (range, 9 days-251 months). A total of 146 cases reported using tamoxifen as treatment for breast cancer prior to their endometrial cancer diagnosis, with a median time for tamoxifen use of 26 months (range, 12 days-110 months). The median time from the initiation of tamoxifen treatment to diagnosis of endometrial cancer was 36 months (range, 6-162 months). 188 cases had died at the end of follow-up; of these, 58 cases (30.9%) died from breast cancer, 42 cases (22.3%) died from endometrial cancer, and 73 cases (38.8%) died from other causes. The cause of death was not recorded by the cancer registry for 15 cases (8.0%). The other causes of death included cardiovascular disease (12.8%), myocardial infarction (3.7%), stroke (3.2%) or other cancer (5.9%). 7 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Characteristics of study population (n=324) and subset of patients with pathology material available (n=212) A ll patients Pathology review Characteristic___________________________ n (%)________ n (%) SEER* Registry Atlanta 14(4.3) 10 (4.7) Iow a 50 (15.4) 30 (14.2) Los Angeles 228 (70.4) 158(74.5) Seattle-Puget Sound 32 (9.9) 14 (6.6) Age at endometrial cancer diagnosis, y <50 9 (2.8) 7 (3.3) 50-59 38(11.7) 26 (12.3) 60-69 119(36.7) 74 (34.9) 70-79 108 (33.3) 78 (36.8) >80 50 (15.4) 27 (12.7) Year of endometrial cancer diagnosis 1978-1981 12 (3.7) 6 (2.8) 1982-1985 40 (12.3) 26 (12.3) 1986-1989 129 (39.8) 91 (42.9) 1990-1993 143 (44.1) 89 (42.0) Months between intital breast cancer and endometrial cancer diagnosis <24 70(21.6) 55 (25.9) 24-59 154(47.5) 104 (49.1) >60 100 (30.9) 53 (25.0) Months of follow-up since endometrial cancer diagnosis <24 62 (19.1) 41 (19.3) 24-59 66 (20.4) 42 (19.8) >60 196 (60.5) 129 (60.8) Status at end of follow-up Alive 136 (42.0) 91 (42.9) Dead 188 (58.0) 121 (57.1) Cause of death Breast cancer 58 (30.9) 41 (33.9) Endometrial cancer 42 (22.3) 25 (20.7) Other cancer 1 1 (5.9) 5 (3.9) Coronary vascular disease 24 (12.8) 15 (12.4) Myocardial infarction 7(3.7) 2(17) Stroke 6 (3.2) 2(17) Other 25 (13.3) 19(15.7) Cause not recorded 15(8.0) 12 (9.9) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1 (continued) Characteristic A ll patients n(%) Pathology review n (% ) Proportion of deaths by age <50 5/9 (20.0) 5/7(71.4) 50-59 9/38 (23.7) 7/26 (26.9) 60-69 56/119(47.1) 32/74 (43.2) 70-79 79/108 (73.1) 56/78(71.8) >80 39/50 (78.0) 21/27 (77.8) Treatment of breast cancer Radiotherapy 102(31.5) 74 (34.9) Chemotherapy 76 (23.5) 52 (24.5) Tamoxifen 146 (45.1) 101 (47.6) *SEER= Surveillance, Epidemiology, and End Results Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2 presents the endometrial cancer treatment characteristics for all 324 cases. The majority of case patients were diagnosed with localized breast cancer (198,61.1%) or regional breast cancer (121,37.3%) and 5 (1.3%) were diagnosed with distant breast cancer. Of the cases with localized breast cancer, 74.8% did not take tamoxifen and 93.4% did not receive chemotherapy. 76.2% of the regional and distant breast cancer cases took tamoxifen, with a similar distribution among cases taking tamoxifen for less than 2 years (44.8%) and cases taking tamoxifen for greater than or equal to 2 years (35.2%). Tamoxifen use and chemotherapy treatment were both statistically significantly related to breast cancer stage (both p<0.00001, Table 2). Radiation therapy was not significantly related to stage of breast cancer (p=0.19). The distributions of overall histologic grade and histologic type among tamoxifen users were not statistically different from those of non-users (p=0.42 and p=0.74, respectively, Table 3). The distribution of hyperplasia differed significantly according to tamoxifen use (p=0.0009). However, the presence of polyps was not statistically different among tamoxifen users and non users (26.7% vs. 32.3% respectively, p=0.43). The distribution of women who had used estrogen replacement therapy did not differ from that of non-users for overall histologic grade or histology type. Patients who took estrogen replacement therapy were less likely than non-users to have atypical hyperplasia (12.5% vs. 28.9%, p=0.039, Table 4). BMI was unrelated to overall grade or histology type (p=0.68 and p=0.87, respectively, Table 5). Examination of overall grade, histology type and presence of hyperplasia and polyps according to exposure to tamoxifen and estrogen replacement therapy showed no differences in the distribution of these characteristics except for hyperplasia (p^0.017, Table 6). There was good concordance between pathology records at the time of endometrial cancer diagnosis and pathologist review, with a weighted kappa statistic of 0.56 for overall FIGO grade and an un-weighted kappa of 0.54 for histologic type (Table 7).[19] 10 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2. Endometrial cancer treatment characteristics of 324 patients with endometrial cancer following breast cancer in relation to stage of breast cancer. Number and percent given in table. Stage of Breast Cancer Characteristic Localized Non-iocalized Tamoxifen Use* No 148 (74.8) 30 (23.8) Yes 49 (24.7) 96 (76.2) p<0.0001 < 2 years 23 (46.9) 43 (44.8) > 2 years 26 (53.1) 53 (55.2) Chemotherapy** No 183 (93.4) 60 (48.8) Yes 13(6.6) 63(51.2) p<0.0001$ Radiotherapy* No 139(70.9) 80 (64.0) Yes 57(29.1) 45 (36.0) p=0.19 * Including one patient with unknown duration of tamoxifen use ** Excluding 5 patients with unknown chemotherapy treatment 4 Excluding 3 patients with unknown radiation treatment * Chi square p-values 1 Fisher's exact p-value 11 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3. Characteristics of 324 patients with endometrial cancer following breast cancer in relation to duration of tamoxifen use based on Cancer Registry records. Number and percent given in table. Characteristic No tamoxifen (ns178) i <2yrs (n«66) > _2 yrs (n=79) Total tamoxifen (n=146)** p-value” Overall histologic grade (FIGO) Low Intermediate High 64 (35.9) 77 (43.3) 37 (20.8) 25 (37.9) 26 (39.4) 15 (22.7) 28 (35.4) 28 (35.4) 23 (29.1) 53 (36.3) 54 (37.0) 38 (26.0) p=0.42 Histologic type* Endometrioid adenocarcinoma Clear cell and papillary serous M M M T and sarcomas of the endometrium 144(81.4) 21 (11.8) 12 (6.8) 52 (78.8) 10(15.1) 4(6.1) 61 (77.2) 11 (13.9) 7 (8.9) 113(77.4) 21 (14.4) 1 1 (7.5) p=0.74 Hyperplasia* None Simple, Complex Atypical (n=93) 49 (52.7) 23 (24.7) 21 (22.6) (n=32) 1 1 (34.4) 15(46.9) 6 (18.7) (n=43) 14 (32.6) 20 (46.5) 9 (20.9) (n=75) 25 (33.3) 35 (46.7) 15(20.0) p=0.009 Polyps Present Not present 30 (32.3) 63 (67.7) 5(15.6) 27 (84.4) 15 (34.9) 28 (65.1) 20 (26.7) 55 (73.3) p=0.43 * One patient excluded based on pathology review, endocervical lesion most likely ** Including one patient with unknown duration of tamoxifen use * Based on a total of 168 patients: 112 pathology specimens unavailable for review, 44 specimens not sufficient for hyperplasia/polyps review * Chi square p-values for no tamoxifen vs total tamoxifen 12 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 4. Characteristics of 290* patients with endometrial cancer following breast cancer in relation to hormone use based on Cancer Registry records. Number and percent given in table. Characteristic No estrogen replacement (re*i55) Estrogen replacement (n«135) p-value* Overall histologic grade (FIGO) Low 57 (36.8) 47 (34.8) Intermediate 69 (44.5) 53 (39.3) High 29 (18.7) 35 (25.9) p=0.32 Histologic type** Endometrioid adenocarcinoma 126(81.3) 108 (80.0) Clear cell and papillary serous 20 (12.9) 17 (12.6) M M M T and sarcomas of the endometrium 9 (5.8) 10 (7.4) p=0.86 Hyperplasia* (n=83) (n=72) None 34(41.0) 34 (47.2) Simple, Complex 25 (30.1) 29 (40.3) Atypical 24 (28.9) 9 (12.5) p=0.039 Polyps Present 25 (30.1) 20 (27.8) Not present 58 (69.9) 52 (72.2) p=0.75 * 34 patients excluded due to unknown estrogen replacement status ** One patient excluded based on pathology review, endocervical lesion most likely originating 4 Based on a total of 155 patients: 112 pathology specimens unavailable for review, 23 specimens not sufficient for assessment of hyperplasia and polyps review *Chi square p-value for no estrogen replacement vs estrogen replacement 13 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5. Characteristics of 318* patients with endometrial cancer following breast cancer in relation to body mass index (B M I) based on Cancer Registry records. ___________________Number and percent given in table.___________________ Characteristic Low BMI (n*126) High BMI (n-189) p-value* Overall histologic grade (FIGO) Low 46 (36.5) 67 (35.3) Intermediate 48 (38.1) 81 (42.6) High 32 (25.4) 42 (22.2) p=0.68 Histologic type** Endometrioid adenocarcinoma 101 (80.2) 149 (78.8) Clear cell and papillary serous 17 (13.5) 25 (13.2) M M M T and sarcomas of the endometrium 8 (6.4) 15(7.9) p=0.87 * 8 patients excluded due to unknown BM I status ** One patient excluded based on pathology review, endocervical lesion most likely originating in the cervix *Chi square p-value for low BMI vs high BM I Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 6. Characteristics of 290* patients with endometrial cancer following breast cancer in relation to tamoxifen and/or ERT therapy based on Cancer Registry records. Number and percent given in table. No Both Tamoxifen or Tamoxifen Tamoxifen ERT only ERT only or ERT Characteristic (n=97) (n=58) <n*64) <n=71) p-value* Overall histologic grade (FIGO) Low Intermediate High 34 (35.1) 44 (45.4) 19 (19.5) 23 (39.7) 25 (43.1) 10 (17.2) 23 (35.9) 28 (43.8) 13 (20.3) 24 (33.8) 25 (35.2) 22(31.0) p=0.55 Histologic type** Endometrioid adenocarcinoma Clear cell and papillary serous M M M T and sarcomas of the endometrium 79(81.4) 11 (11.3) 7(7.2) 47(81.0) 9(15.5) 2 (3.5) 53 (82.8) 8 (12.5) 3(4.7) 55 (77.5) 9 (12.7) 7(9.8) p=0.80 Hyperplasia* None Simple, Complex Atypical (n=50) 25 (50.0) 12 (24.0) 13(26.0) (n-33) 9 (27.3) 13 (39.4) 11 (33.3) (n=36) 20 (55.6) 10 (27.8) 6 (16.7) (n-36) 14 (38.9) 19 (52.8) 3 (8.3) p=0.017 Polyps Present Not present 17(34.0) 33 (66.0) 8 (24.2) 25 (75.8) 10(27.8) 26 (72.2) 10 (27.8) 26 (72.2) p=0.80 * 34 patients excluded due to unknown ERT status ** One patient excluded based on pathology review, endocervical lesion most likely & Based on 155 patients: 112 pathology specimens unavailable for review, 23 speciemens not sufficient for hyperplasia/polyps review * Chi square p-value comparing all 4 columns 15 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 7. Degree of concordance between cancer registry review and pathology ____________________________ review*________________________ Overall grade Based on Pathology review Based on Cancer Registry records Low Intermediate High Low 53 32 5 Intermediate 12 38 7 High 2 8 35 K**=0.56 Histologic type Based on Pathology review Clear cell and MMMT and Based on Cancer Endometrioid papillary sarcomas Registry records adenocarcinoma serous of the endometrium Endometrioid adenocarcinoma 149 17 2 Clear cell and papillary serous 3 8 1 MMMT and sarcomas of the endometrium 2 0 10 KSO.54 * Based on 192 patients: 112 pathology specimens unavailable for review, 20 specimens not sufficient for review ** Weighted Kappa used due to ordinal ranking of grading system 1 Unweighted Kappa Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 8. Odds ratios (ORs) and 95% confidence intervals of endometrial cancer risk associated with treatment of breast cancer Duration of tamoxifen therapy Exposure ________ None < 24 months > 24 months p-value** Histologic type of endometrial cancer No. of case patients/ No. of control subjects* Adenocarcinoma 144/347 52/109 61/84 Serous or papillary cell 21/49 10/23 11/11 M M M T or Sarcomas 12/24 4/9 7/9 OR (95% Cl) Adenocarcinoma 1.0 (referent) 1.25(0.79-1.97) 2.04 (1.27-3.27) p=0.0022 Serous or papillary cell 1.0 (referent) 0.82 (0.24-2.82) 3.78 (0.95-14.99) p=0.034 M M M T or Sarcomas 1.0 (referent) 0.76 (0.17-3.34) 3.97 (0.39-40.89) p=0.23 Overall histologic grade (FIGO) No. of case patients/ No. of control subjects* Low 64/136 25/53 28/46 Intermediate 77/197 26/53 28/27 High 37/89 15/35 23/31 OR (95% Cl) Low grade 1.0 (referent) 0.99 (0.50-1.96) 1.39 (0.69-2.78) p=0.16 Intermediate grade 1.0 (referent) 1.38(0.72-2.63) 3.48 (1.67-7.27) p=0.0037 High grade 1.0 (referent) 0.97 (0.42-2.23) 2.37 (0.99-5.70) p=0.024 ‘Control subjects are breast cancer patients who were individually matched to each endometrial cancer case on exact birth year, exact year of diagnosis, race, SEER registry and summary stage of breast cancer “p-value for histologic type trend based on actual months of tamoxifen use; test for heterogeneity of trends, X 2 (2df)=1.48, p=0.48 “p-value for overall grade trend based on actual months of tamoxifen use; test for heterogeneity of trends, X 2 (2df)=0.31, p=0.86 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 45% of the case patients and 37% of controls had used tamoxifen. We previously reported that the unadjusted relative risk of endometrial cancer for women who had taken tamoxifen compared with those who had not was 1.55 (95% Cl 1.11-2.17[9J). The risk of developing adenocarcinoma of the endometrium increased 18% per year of tamoxifen use (95% Cl 6%-32%). Risk of developing serous or papillary cell carcinoma of the endometrium increased 27% (95% Cl 9%-59%) per year of tamoxifen use and the risk of developing sarcoma or MMMT of the endometrium increased 95% (95% Cl 65%-482%) per year of tamoxifen use. Although the magnitude of the increase in risk appears to vary by histology type, these trends in risk did not differ statistically (test for homogeneity of trends, X2 (2df)=1.48, p=0.48). The risk of developing a low-grade endometrial carcinoma increased 14% per year of tamoxifen use and the risk of developing an intermediate-grade or a high-grade endometrial carcinoma increased 24% per year of tamoxifen use. These trends in risk by overall grade also did not differ statistically (test for homogeneity of trends, X2(2df)=0.31, p=0.86). Breast cancer-specific survival differed according to breast cancer stage (p<0.0001) (Figure 1). Patients diagnosed with localized breast cancer had significantly longer survival than those diagnosed with non-localized breast cancer (p<0.0001). Breast cancer-specific survival also differed according to tamoxifen use (p=0.0002, Figure 2). The breast cancer specific probabilities of survival did not differ according to tamoxifen treatment status within categories of breast cancer stage (Figure 3) (localized disease: p=0.45; non-localized disease: p=0.23). Survival probabilities did differ between stages however (localized vs. non-localized disease: p=0.0001). Endometrial cancer-specific survival among tamoxifen users did not differ compared to non-tamoxifen users (p=0.54, Figure 4); however cases who took tamoxifen for less than or equal to 2 years had slightly greater survival probabilities than cases who took tamoxifen for 18 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 1. Breast cancer-specific survival according to stage of breast cancer at diagnosis. H .80 p < 0.0001 1 11 180 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 2. Breast cancer-specific survival according to tamoxifen treatment status for breast cancer. S u n M f m >5yrs m M ,L£2yrs 40 p= .0002 Ti»#(«9ene») Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 3. Breast cancer-specific survival according to tamoxifen treatment status and breast stage. $un**i •T.STG ♦T.STGJ.3 Ip < 0 0001 222 ti l Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 4. Endometrial cancer-specific survival according to tamoxifen treatment status for breast cancer. 10ft M P = 1 1 1 m 148 I t M f t n M M f t Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. greater than 2 years. Endometrial cancer-specific survival for patients who took tamoxifen for 2-5 years had slightly better survival compared to patients who took tamoxifen for more than 5 years; however, the survival curves converged 75 months after breast cancer diagnosis (not shown). The cumulative probabilities of endometrial cancer-specific survival differed by histology type of the tumor (p<0.0001. Figure 5) and grade (p<0.0001, Figure 6). However, within histology group or within grade, survival did not differ by tamoxifen exposure (Figures 7 and 8). Endometrial cancer-specific survival did not differ among patients who had or had not used hormone replacement therapy (p=0.32, Figure 9) or among patients classified into high versus low BMI (p=0.21, Figure 10). For all causes of death, the overall survival was better for those patients who did not take tamoxifen than for those who did (p=0.007, Figure 11); however, when patients diagnosed with breast cancer prior to 1985 were excluded from the analysis, tamoxifen use was no longer predictive of overall survival (p=0.845, not shown). Using multivariate Cox proportional hazards modeling to assess predictors of breast cancer specific survival, we found that increasing age at breast cancer diagnosis, being treated with chemotherapy, prior use of hormone replacement therapy for at least 2 years (relative to no use), and non-localized breast cancer were significantly associated with increased risk of dying; however, neither tamoxifen use nor radiotherapy treatment for breast cancer were associated with risk of dying from breast cancer. In analyses of endometrial cancer specific survival, tamoxifen use was associated with a non-significant reduction in risk of dying, whereas increasing age at endometrial cancer diagnosis, intermediate or high FIGO grade, and histological classification other than adenocarcinoma were significant predictors of risk in 23 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 5. Endometrial cancer-specific survival according to histology type of endometrial cancer. SovM 1 JW .Serous & pap cd L ____ ^ M T & Sarcomas p< 0.0001 1t1 222 Uni* (norths) 24 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 6. Endometrial cancer-specific survival according to overall grade of endometrial cancer. SinM tan to p< 0.0001 40 ■ 1 1 1 14# 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 7. Endometrial cancer-specific survival according to histology type o f endometrial and tamoxifen treatment status for breast cancer. v.V •T.Serous & pap cd & Sarcomas _-t.Serous & pap cei FM M M T s Sarcomas p< 0.0001 1 1 1 IB S 222 Tim (norths) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 8. Endometrial cancer-specific survival according to overall grade of endometrial and tamoxifen treatment status for breast cancer. ♦Tjn» V -L ■ r jm m Ip <0.0001 X ■ 1 4 8 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 9. Endometrial cancer-specific survival according to history of hormone replacement therapy SunM im N o ' 40 P = 3b m m m at D nfejM M to} Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 10. Endometrial cancer-specific survival according to body mass index (BMI) at breast cancer diagnosis. t t t . M M P= 21 ti l m 185 T im # (worthy Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 11. Overall survival according to tamoxifen treatment status for breast cancer. Sunm* M p= .0 0 7 1 1 1 1 « S m T iM O M n R u ): Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. multivariate analysis (Table 9). Neither chemotherapy nor radiation therapy for breast cancer treatment affected endometrial cancer survival (logrank test p-values: p=0.220 and, pN).434, respectively). DISCUSSION Tamoxifen therapy for breast cancer is associated with a significant and substantial increase in endometrial cancer risk.[l, 7-9,17] In this study we have extended the results of Bernstein et al.[9] to examine the risk of endometrial cancer according to breast cancer stage at diagnosis and predictors of endometrial tumor characteristics and survival following the endometrial cancer diagnosis. Although pathology review was not available for all patients in our study, the subset of patients who were available for pathology review were representative of the entire case series for every variable studied based on cancer registry and interview information. The overall grade and histological type of endometrial cancer diagnosed in breast- cancer patients did not vary according to tamoxifen treatment status, similar to the reports of Fomander et al.,[14] Fisher,[1] and van Leeuwen.[8] Moreover, contrary to the reports of Bergman et al.[17] and Magriples,[16] the endometrial tumors in tamoxifen-treated patients were not more aggressive nor were they associated with a shorter survival. Tamoxifen has specific effects on the female reproductive system; it acts as an estrogen agonist on the vaginal epithelium and endometrium of postmenopausal women. [20] Reports of increased incidence of polyps, hyperplasia and endometrial carcinoma in women treated with tamoxifen compared to controls are consistent with this estrogen agonist effect.[7, 14, 21,22] Lahti et al.[21] concluded that long-term tamoxifen use was associated with larger uterine size, thicker endometrium and endometrial polyps in postmenopausal breast cancer patients receiving tamoxifen. Both endometrial polyps and the presence of hyperplasia may develop in the presence of endogenous or exogenous estrogenic activity. In contrast, we found that endometrial 31 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 9. Factors influencing endometrial cancer-specific survival based on ______________ Cox Proportional Hazards models_______________ Relative Hazard (95% Cl) Exposure Unadjusted Adjusted* Tamoxifen use None 1.0 (referent) 1.0 (referent) < 2 years 0.58 (0.22-1.52) 0.58(0.22-1.53) > 2 years 0.92 (0.44-1.91) 0.66 (0.31-1.38) Age at diagnosis of endometrial cancer 1.05 (1.02-1.09) 1.07(1.03-1.11) Overall FIGO grade Low 1.0 (referent) 1.0 (referent) Intermediate 6.65 (1.51-29.24) 5.14(1.16-22.86) High 31.81 (7.54-134.27) 21.50 (4.94-93.68) Histologic type Adenocarcinoma 1.0 (referent) 1.0 (referent) Serous or papillary cell 2.68 (1.25-5.75) 1.78 (0.82-3.90) M M M T or Sarcomas 5.39 (2.42-11.99) 3.47 (1.44-8.37) * All factors in table included in a single model Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. cancer patients who had taken tamoxifen in our study tended to have less atypical hyperplasia and polyps than those not taking tamoxifen. Tamoxifen is believed to act on the endometrium in a manner similar to that of unopposed estrogen.[l 1] Endometrial cancers that develop in the presence of unopposed estrogen tend to exhibit low-grade, early stage lesions with a favorable prognosis.[13] The majority of endometrial cancers associated with tamoxifen use have characteristics similar to estrogen stimulated tumors.[l 1] Our data found a large majority of endometrial cancers following breast cancer that were low to-intermediate grade endometrial adenocarcinomas. The grade and histology distributions of patients treated with tamoxifen did not differ from those who did not take tamoxifen (Table 3). Contrary to Magriples et al.[16] and Bergman et al.,[17] we did not find that the endometrial carcinomas occurring in patients who took tamoxifen had more aggressive tumor characteristics or resulted in a shorter survival. Breast cancer-specific survival probabilities were significantly greater for cases diagnosed with localized breast cancer stage compared to cases diagnosed with regional or distant breast cancer. Among tamoxifen users, cases who used tamoxifen for less than 2 years had significantly smaller survival probabilities than cases who never used tamoxifen, or used tamoxifen for more than 2 years. We believe this is due to the use of tamoxifen as secondary therapy among women whose breast cancer had progressed and that it is unrelated to tamoxifen use. 93% of the case patients in this series were diagnosed and treated for breast cancer before 1990 with substantial numbers prior to 1987 when tamoxifen was not as frequently prescribed as adjuvant therapy. Because of our unexpected finding that women who used tamoxifen for two years or less were more likely to die of their breast cancer than woman with longer use and those not treated with tamoxifen, we reviewed several factors related to the treatment of the 23 women in 33 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. this categoiy who died of their disease. In addition to their year of breast cancer diagnosis, we examined their breast cancer stage at diagnosis, whether they received tamoxifen as adjuvant therapy or as treatment for recurrence and whether they had taken tamoxifen after their breast cancer diagnosis. We identified 6/20 patients who continued tamoxifen therapy after their endometrial cancer diagnoses. We did not routinely collect information on or after the date of endometrial cancer diagnosis and do not know whether 3 patients in this group continued tamoxifen use. In addition, 4 women classified as having taken tamoxifen for 2 years or less had actually used tamoxifen for less than 2 months- so that this exposure category represents a wide range of exposures to tamoxifen prior to a woman’s death due to breast cancer. The risk of endometrial cancer associated with tamoxifen use did not vary statistically according to histology group ex' grade. Similarly, endometrial cancer-specific survival probabilities did not vary according to tamoxifen exposure status, although a more aggressive histology type and a higher overall grade of endometrial cancer were independent predictors of endometrial cancer-specific survival. In conclusion, we find no evidence that tamoxifen preferentially induces more aggressive endometrial cancers in our population-based cohort of patients diagnosed with endometrial cancer following their breast cancer diagnosis, or that tamoxifen use affects breast cancer specific, endometrial cancer specific or overall survival. 34 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. References 1. Fisher B, C.J.P., Redmond C K, Fisher E R, Wickerham D L, Cronin WM, et al., Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. Journal of the National Cancer Institute, 1994.86: p. 527-37. 2. Group, E.B.C.T.C., Tamoxifen for early breast cancer: an overview o f the randomised trials. The Lancet, 1998. 351: p. 1451-67. 3. Anteby E Y, Y.S., Weissman A, Degani S, Caspi B, Appelman Z, Hochner- Celnikier D, Sonographic evaluation o f the uterus in postmenopausal women receiving tamoxifen: characterization o f mid-uterine abnormalities. European Journal of Obstetrics and Gynecology and Reproductive Biology, 1996.69: p. 115-9. 4. Fisher B, C.J.P., Wickerham D L, Redmond C K, Kavanah M, Cronin W M, et al., Tamoxifen for prevention o f breast cancer: report o f the National Surgical Adjuvant Breast and Bowel Project P-l Study. Journal of the National Cancer Institute, 1998. 90: p. 1371-88. 5. Love R R, M.R.B., Barden H S, Epstein S, Newcomb P A, Jordan V C, Carbone P P, Demets D L, Effects o f tamoxifen on bone mineral density in postmenopausal women with breast cancer. New England Journal of Medicine, 1992. 326: p. 885-6. 6. Killackey M A, H.T.B., Pierce V K., Endometrial adenocarcinoma in breast cancer receiving antiestrogens. Cancer Treatment Rep, 1985.69: p. 237-8. 7. Fornander T, R.L.E., Cedermark B, Mattsson A, Skoog L, Theve T, Askergren J, Glas U, Silfversward C, Somell A, Wilking N, Hjalmar, M, Adjuvent tamoxifen in early breast cancer: occurrence o f new primary cancers.The Lancet, 1989. i: p. 117-20. 35 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8. van Leeuwen F E, B.J., Coeberg J W, Kiemeney L A, Gimbrere C H, Otter R, et al., Risk ofendometrial cancer after tamoxifen treatment o f breast cancer. The Lancet, 1994.343: p. 448-52. 9. Bernstein L B, D.D., Cerhan J R, Schwartz S M, Liff J, McGann-Maloney E, Perlman J A, Ford L, Tamoxifen therapy for breast cancer and endometrial cancer risk. Journal of the National Cancer Institute, 1999.91(19): p. 1654-62. 10. Gusberg S B, Tamoxifen for breast cancer: associated endometrial cancer. Cancer, 1990.65: p. 1463-4. 11. Barakat R R, W.G., Curtin J P, et al., Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence o f adverse histologic features. Gynecol Oncol., 1994.55: p. 164-68. 12. Barakat R R, Tamoxifen and endometrial neoplasia. Clinical Obstetrics and Gynecology, 1996.39: p. 629-40. 13. Elwood J M, B.D.A., Clinical and pathologicalfeatures and survival o f endometrial cancer patients in relation to prior use o f estrogens. Gynecol Oncol, 1980. 10(173-87). 14. Fomander T, H. A., Moberger B, Descriptive clinicopathologic study o f 17 patients with endometrial cancer during or after adjuvent tamoxifen in early breast cancer. Journal of the National Cancer Institute, 1993.85(22): p. 1850-55. 15. Peters-Engl C, M.M., Danmayr E, Mirau M, Alth G, Leodolter S, Endometrial cancer after tamoxifen treatment: a descriptive study o f 25 breast cancer patients who subsequently developed endometrial cancer. Anticancer Research, 1996.16: p. 3241-6. 16. Magriples U, N.F., Schwartz P E, Carcangiu M L, High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. Journal of Clinical Oncology, 36 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1993.11(3): p. 485-90. 17. Bergman L, B.M.L.R., Gallee M P W, Hollema H, Benraadt J, van Leeuween F E, and the Comprehensive Cancer Centres ALERT Group, Risk and prognosis o f endometrial cancer after tamoxifen fo r breast cancer. The Lancet, 2000. 356: p. 881- 87. 18. Kurman R J, Blaustein's Pathology o f the Female Genital Tract. Fourth ed. 1994, New York: Springer-Verlag. 19. Fleiss J L, Statistical Methods fo r Rates and Proportions. Second ed. 1981, New York: John Wiley & Sons. 218. 20. Ismail S M, Pathology o f endometrium treated with tamoxifen. Journal of Clinical Pathology, 1994.47: p. 827-833. 21. Lahti E, B.G., Kauppila A, Apaja-Sarkkinen A, Taskinen P J, Laatikainen T, Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstetrics and Gynecology, 1993.81(660-64). 22. Neven P, V.I., Controversies regarding tamoxifen and uterine carcinoma. Current Opinion in Obstetrics and Gynecology, 1998.10: p. 9-14. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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Hays, Presley Ann
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Endometrial cancer following breast cancer treatment: Tumor characteristics and predictors of survival
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