Breast cancer followed by corpus cancer: Is there a higher risk for aggressive histologic subtypes?

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1 Gynecologic Oncology 102 (2006) Breast cancer followed by corpus cancer: Is there a higher risk for aggressive histologic subtypes? John K. Chan a,, Michael R. Manuel a, Michael K. Cheung a, Kathryn Osann c, Amreen Husain a, Nelson N. Teng a, Anjali Rao a, Robert W. Carlson b, Alice S. Whittemore d a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford Cancer Center 875 Blake Wilbur Drive, MC 5827, Stanford, CA 94305, USA b Department of Medicine, Stanford University School of Medicine, Stanford Cancer Center, 875 Blake Wilbur Drive, MC 5827, Stanford, CA 94305, USA c Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine-Medical Center, 101 The City Drive, Orange, CA 92868, USA d Division of Epidemiology, Department of Health Research and Policy, HRP Redwood Building, Room T223, Stanford University, Stanford, CA 94305, USA Received 31 October 2005 Available online 17 February 2006 Abstract Objective. To analyze corpus cancer patients with a breast cancer history for risk of developing aggressive uterine histologic types. Methods. Corpus cancer patients with a history of breast cancer were identified from the Surveillance Epidemiology and End Results database from 1988 to Demographics, clinico-pathologic, and survival data were analyzed using Kaplan Meier and logistic regression analyses. Results. Of 52,109 women diagnosed with corpus cancer, 1922 had a history of breast cancer. Women with a history of breast cancer had a significantly higher proportion of uterine papillary serous carcinomas (UPSC) and sarcomas compared to those without a breast cancer history (9.4% vs. 6.3% for UPSC and 10.3% vs. 8.4% for sarcoma; P b 0.001). Patients with endometrioid or sarcoma of the uterus after breast cancer had significantly worse 5-year survivals than patients without a breast cancer history (84.4% vs. 90.5%; P b and 49.0% vs. 63.6%, P b 0.001, respectively). Older age, advanced stage, lack of surgery and radiation treatment, poor histologic types, and history of breast cancer were independent prognostic factors for poorer survival. Conclusion. In this study, the proportional incidence of UPSC and sarcoma was significantly higher in women with a breast cancer history. These findings highlight the association of breast cancer and high-risk corpus cancer subtypes Elsevier Inc. All rights reserved. Keywords: Breast cancer; Uterine cancer; Papillary serous; Sarcoma; Survival Introduction As the most common female and gynecologic cancers in the United States, breast cancer and corpus cancer are thought to share etiologic factors such as estrogen exposure and genetic predisposition. Multiple studies have confirmed an association between these cancers leading investigators to question whether a history of breast cancer increases the likelihood of developing high-risk corpus cancers such as uterine papillary serous Corresponding author. Fax: address: johnchan@stanford.edu (J.K. Chan). carcinoma (UPSC), sarcoma, or clear cell carcinomas. A previous study found that women with a prior history of breast cancer who subsequently develop endometrial cancer have a 2.6-fold increased risk of developing UPSC [1]. In reverse, the risk of breast cancer was significantly higher in women with a history of papillary serous as compared to endometrioid uterine cancer (25% vs. 3.2%, P = 0.001) [2]. Because of tamoxifen's estrogenic properties, several investigators have analyzed breast cancer patients who were treated with tamoxifen and subsequently developed uterine cancer [3 10]. Prior reports have stated that women who received tamoxifen were found to have an increased risk of more aggressive, non-endometrioid uterine histologic cell types /$ - see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.ygyno

2 J.K. Chan et al. / Gynecologic Oncology 102 (2006) [11]. In contrast, other studies did not find a difference in the risk of developing endometrioid vs. non-endometrioid histologic cell types after tamoxifen use. These conflicting reports in the literature were not only limited by small sample sizes, but many of the study cohorts were also derived from single academic institutions where there may be a disproportionate number of women with poor histologic cell types compared to the general population treated at community hospitals [1,2,4,12]. As such, we proposed to conduct a large, population-based study to determine whether women with a history of breast cancer who subsequently develop uterine cancer have an increased risk for developing aggressive histologic cell types. Materials and methods Demographic, clinico-pathologic, and survival information from all women who developed uterine cancer during the years were identified from the Surveillance Epidemiology and End Results (SEER) [13]. SEER is a national cancer surveillance program that collects information from all incident cancer cases in twelve U.S. geographic areas. Of 52,187 women diagnosed with corpus cancer (U-only group), 1922 had a history breast cancer (B-U group). Thirty-seven patients with a history of Paget's disease or inflammatory disease of the breast were excluded. In situ breast cancers were not included in this database. Forty-two patients who were diagnosed corpus cancer within 12 months from the presentation of their breast cancer were also removed from the analysis in order to reduce the likelihood of including women with a metastatic breast tumor. Factors including age of diagnosis, race, uterine tumor stage (International Federation of Gynecology and Obstetrics Staging), histologic cell type, grade, hormone receptor status, surgical treatment, radiation therapy, and survival time were extracted. To better characterize our patient population, the race classifications of the SEER program were categorized into four groups: Caucasians, African Americans, Asians, and Others. Asians were defined as Chinese, Japanese, Korean, Vietnamese, and Filipina. All other race and ethnicity classifications were defined as Others. To analyze trends in the study cohort and determine 5-year disease-specific survival, Chi-squared tests and Kaplan Meier analysis with log-rank tests were performed. The outcome of interest was death from endometrial cancer and time to death was censored in women who died from causes other than uterine cancer. The Cox proportional hazards model was used to assess the significance of multiple variables simultaneously. All data were analyzed using Intercooled Stata (Version 8.0; Stata Corporation, College Station, TX) and SAS (Version 6.12; SAS, Inc., Cary, NC). Two-tailed tests at P values less than 0.05 were considered significant. Results The patient characteristics of both study groups are depicted in Table 1. Women in the B-U group were diagnosed with their uterine cancer 5.9 years later than those in the U- only group. The mean age of diagnosis of corpus cancer in the B-U group was 69.7 ± 0.3 years while those in the U-only group was 63.8 ± 0.1 (P b 0.001). Irrespective of uterine histologic cell type, those in the B-U group remained significantly older (P b 0.001). 89.4% of the women in the B-U group were White compared to 86.6% U-only group (P = 0.003). There was no difference in the distribution of surgery treatment received by women in the B-U and U-only groups (93.2% vs. 93.8%, P = 0.26). We did not find a difference between the stage distribution of uterine carcinomas (Table 2) between the B-U and U-only groups Table 1 Patient and treatment data for uterine cancer Mean age (range) Breast Uterine (n = 1922) Uterine-only (n = 50,187) P value a 69.7 (36 99) 63.8 (1 102) P b Race distribution (n) White 1717 (89.4%) 43,459 (86.6%) P = Black 93 (4.8%) 3036 (6.1%) Asian 83 (4.3%) 2456 (4.9%) Other 29 (1.5%) 1047 (2.0%) Unknown 0 (0.0%) 189 (0.4%) Surgery No surgery 130 (6.8%) 3077 (6.1%) P = 0.26 b Surgery 1792 (93.2%) 47,104 (93.8%) Unknown 0 (0.0%) 6 (b0.1%) Radiation No radiation 1418 (73.8%) 35,653 (71.1%) P = 0.02 b Radiation 490 (25.5%) 14,023 (27.9%) Unknown 14 (0.7%) 511 (1.0%) a P value from Chi-squared tests of differences between the study groups. b Chi-squared test with 1 df, unknowns excluded. (P = 0.34). Over three-fourths of women were diagnosed with stage I uterine cancer in both groups (77.0% vs. 75.4%). However, a smaller proportion of women received adjuvant radiation in the B-U group compared to the U-only group (25.5% vs. 27.9%; P = 0.02). The distribution of histologic cell types between the two groups was significantly different (P b 0.001) with women in the B-U group presenting with a higher proportion of aggressive histologic cell types compared to those without a history of breast cancer. More specifically, women in the B-U group had a higher risk of developing UPSC (9.4% vs. 6.3%; P b 0.001) and sarcomas (10.3% vs. 8.4%; P b 0.001) compared to women in the U-only group. Given that there were only 32 patients with clear cell uterine cancer in the B-U group, it was difficult to detect a definitive difference between the two groups. Moreover, patients in the B-U group had a significantly higher likelihood of developing uterine grade 3 uterine cancers compared to those in the U-only cohort (25.5% vs. 21.9%; P b 0.001). Women who develop UPSC and sarcomas are typically older compared to those who present with endometrioid cancers. To determine if older age was responsible for the increase in incidence of aggressive histologies in the B-U group, we stratified our patients by 10- year age groups (60 69, 70 79, 80+) and found that the proportion of UPSC and sarcoma remained significantly higher in the B-U compared to the U-only group (P = for 60 69; P = for 70 79; and P = for 80+ age group). Although information on tamoxifen use was not available, we were able to obtain data on estrogen receptor status on 763 women in the B-U group; of these patients, 643 breast tumors overexpressed estrogen receptors. There were no significant differences in the distribution of uterine histologic cell types between those with a history of estrogen receptor positive vs.

3 510 J.K. Chan et al. / Gynecologic Oncology 102 (2006) Table 2 Uterine histology, stage, and grade distribution Breast Uterine (n = 1922) Uterine-only (n = 50,187) P value a Histology Endometrioid 1511 (78.5%) 42,033 (83.7%) P b b UPSC 180 (9.4%) 3174 (6.3%) Clear cell 32 (1.7%) 733 (1.5%) Sarcoma 197 (10.3%) 4217 (8.4%) Others 2 (0.1%) 30 (0.1%) Uterine stage Stage I 1479 (77.0%) 37,846 (75.4%) P = 0.34 Stage II 148 (7.7%) 3405 (6.8%) Stage III 113 (5.9%) 4079 (8.1%) Stage IV 182 (9.4%) 4857 (9.7%) Grade Grade (33.8%) 18,277 (36.4%) P b Grade (27.8%) 16,227 (32.3%) Grade (25.5%) 10,982 (21.9%) Unknown 247 (12.9%) 4701 (9.4%) a P value from Chi-squared tests of differences between the study groups. b Chi-squared test with 3 df, excludes Others histology. negative breast cancers (P = 0.88). The time interval between the diagnosis of breast cancer to a poor histologic uterine cancer such as UPSC, clear cell, or sarcomas, was approximately 12 months longer than to an endometrioid uterine cancer (7.9 vs. 6.9 year; P b 0.001). In the overall study group, the 5-year disease-specific survival of women with stage I II and III IV uterine cancer was 92.7% and 46.9%, respectively (P b 0.001). The 5-year disease-specific survival of those with endometrioid, clear cell, UPSC, and sarcoma were 90.3%, 67.4%, 63.0%, and 61.9%, respectively (P b 0.001; Fig. 1). The 5-year survival for the B-U group was 79.2% compared to 86.4% in those of the U-only group (P b 0.001; Fig. 2). Controlled for stage, the B-U group continued to have a worse survival compared to the U-only group with 5-year survival estimates at 85.1% vs. 93.0% (P b 0.001) for stage I II tumors and 41.4% vs. 47.1% (P b 0.001) for stage III IV disease. Stratified by histologic cell type, the B-U group had lower 5-year survival compared to the Fig. 1. Overall survival by histologic cell type. Fig. 2. Overall survival breast uterine group vs. uterine-only group. U-only group for endometrioid tumors (84.4% vs. 90.5%; P b 0.001) and sarcomas (49.0% vs. 63.6%; P b 0.001). However, there was no significant difference between those with B-U vs. U-only for clear cell cancer (71.0% vs. 67.3%; P = 0.92) and UPSC (62.3% vs. 61.9%; P = 0.93). In multivariate analysis of the overall study group, older age at diagnosis (P b 0.001), advanced stage disease (P b 0.001), grade 3 tumors (P b 0.001), UPSC or sarcoma histologic cell type (P b 0.001), lack of surgery or radiation therapy (P b 0.001), and a history of breast cancer (P b 0.001) remained as independent prognostic factors for poorer survival. Discussion In 2004, breast cancer was the most prevalent cancer in U.S. women with over 215,000 cases diagnosed, while corpus cancer was the most common gynecologic malignancy with over 40,000 cases [14]. These two cancers are thought to share etiologic factors such as estrogen exposure and genetic predisposition. Multiple studies have confirmed an association between these cancers, leading investigators to question whether a history of breast cancer increases the likelihood of developing high-risk uterine cancers such as uterine papillary serous carcinoma (UPSC), sarcoma, and clear cell histologic types. Gehrig et al. recently conducted a retrospective review of 54 women with a history of breast cancer who then developed uterine cancer and found that these patients have a significantly increased risk of developing UPSC as opposed to endometrioid uterine carcinoma [1]. In another retrospective series of 25 women, Geisler et al. also found that breast cancer developed in 3.2% of women with endometrioid carcinoma as compared to 25% of patients with UPSC [2]. This current study is the first large, population-based, multicenter study that has validated this association of poor histologic cell type uterine cancer. Prospective information on the relationship of two cancers is difficult to ascertain because clinical trials have typically excluded women with a previous history of a malignancy. As such, retrospective data are the only source for studying double-primary malignancies. Furthermore, this current study group is the largest series to date, including patients spanning across 12 regional cancer registries throughout the United States. As such, our study

4 J.K. Chan et al. / Gynecologic Oncology 102 (2006) eliminates the potential patient selection bias associated with studies derived from clinical trials or single academic institutions and allows for better representation of the general patient population. These studies raised the possibility of a genetic link between high-risk uterine cancers. Goshen et al. performed a DNA analysis for BRCA 1 and 2 on 56 women with UPSC, and the authors found no clear example of hereditary breast or ovarian cancer syndromes [15]. More importantly, none of these 56 women carried the BRCA mutation. They concluded that the association between UPSC and breast cancer is most likely due to mutations in other cancer predisposing genes. In another study of 23 HNPCC kindreds, Watson and Lynch found no increased risk of breast cancer despite the increase frequency of endometrial cancers identified in this cohort [16]. Thus, the possible genetic association between breast cancer and poor prognostic uterine cancer remains to be determined. Women with UPSC and sarcoma of the uterus typically present at an older age than those with endometrioid cancer. Since the patients in the B-U group were older, we initially thought that the association of poor prognostic histology uterine cancers after breast cancer might simply be a factor of age. However, after stratification by 10-year age groups, the proportion of sarcoma and UPSC remained significantly higher in the B-U compared to the U-only group, suggesting that the association of breast cancer and poor prognostic uterine cancer cannot simply be explained by the age differences observed in the two groups. The interval from the diagnosis of breast cancer to poor prognostic uterine cancer compared to the more common endometrioid corpus cancer was 1 year longer. The delay in the diagnosis of poor prognostic uterine cancer such as UPSC may be attributed to the lack of symptoms of vaginal bleeding in these women. Previous studies have revealed that 98% of women with endometrioid tumor histology present with postmenopausal bleeding compared to only 43% of women with serous tumor histology (P b 0.001) [1]. Small single institution retrospective series have shown conflicting results regarding the risk of developing high-risk uterine cancer after tamoxifen use [11,12]. Our study was limited by a lack of detailed adjuvant treatment information such as tamoxifen use after breast cancer. However, the database did provide information regarding breast cancer estrogen receptor status of breast cancer on 763 patients. Curtis et al. studied breast cancer patients from the SEER database and used hormone therapy as a surrogate for tamoxifen use. These authors confirmed that hormone therapy may increase the risk of developing malignant mixed müllerian tumors of the uterus [17]. In a retrospective study of 53 patients, Margriples et al. also found that women receiving tamoxifen for breast cancer who subsequently developed uterine cancer were at risk for developing poor histologic cell type endometrial cancers [11]. On the other hand, Barakat et al. evaluated 73 women with breast cancer who later developed uterine cancers and did not find a significant difference in the rate of endometrioid and nonendometrioid histologic cell types, regardless of tamoxifen use [12]. Similarly, the investigators from the National Surgical Adjuvant Breast and Bowel Project found no increased risk of poorly differentiated endometrial cancers in 24 breast cancer patients who subsequently developed uterine cancer after tamoxifen use [4]. In this large population-based study, the proportional incidence of UPSC and sarcoma was significantly increased in women with a prior history of breast cancer. Our results highlight the association of breast cancer and high-risk corpus cancer subtypes and raise the possibility of a genetic link between these malignancies. These findings could be useful in counseling high-risk women diagnosed with breast cancer, regarding the importance of routine gynecologic surveillance. Moreover, physicians should have an increased awareness of the association between breast cancer and high-risk corpus cancer subtypes. References [1] Gehrig PA, Bae-Jump VL, Boggess JF, Groben PA, Fowler Jr WC, Van Le L. Association between uterine serous carcinoma and breast cancer. Gynecol Oncol 2004;94: [2] Geisler JP, Sorosky JI, Duong HL, et al. Papillary serous carcinoma of the uterus: increased risk of subsequent or concurrent development of breast carcinoma. 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5 512 J.K. Chan et al. / Gynecologic Oncology 102 (2006) [14] Cancer Facts and Figures. American Cancer Society, Inc., Surveillance Research [15] Goshen R, Chu W, Elit L, et al. Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 2000;79: [16] Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993;71: [17] Curtis RE, Freedman DM, Sherman ME, Fraumeni Jr JF. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004;96:70 4.