IJC International Journal of Cancer

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1 IJC International Journal of Cancer The emerging epidemic of estrogen-related cancers in young women in a developing Asian country Ching-Hung Lin 1 *, Yong-Chen Chen 2,3 *, Chun-Ju Chiang 2, Yen-Shen Lu 1,4, Kuan-Ting Kuo 5, Chiun-Sheng Huang 6, Wen-Fang Cheng 7, Mei-Shu Lai 2, San-Lin You 3,8 and Ann-Lii Cheng 1,4 1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan 2 Graduate Institute of, College of Public Health, National Taiwan University, Taipei, Taiwan 3 Institute of Life Sciences, School of Public Health, National Defense Medical Center, Taipei, Taiwan 4 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan 7 Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan 8 Genomics Research Center, Academia Sinica, Taipei, Taiwan The incidence of breast and genital tract cancers is increasing among Taiwanese women, but the age specificity and histopathological features of these cancers have not been determined. We used a descriptive epidemiological method and data from the Taiwan Cancer Registry ( ) to examine secular trends in the age-specific incidences of female breast cancer, three major female genital tract cancers and the histopathological subtypes of these cancers. Age-specific incidence rates in the United States ( ) were used as an external reference, and the incidence rates of all malignancies and of malignant brain tumors were used as internal references. We found that age-adjusted incidence rates of female breast, uterine, and ovarian cancers increased in Taiwan from 1979 to 2007, whereas the incidence of cervical cancer decreased after The largest increase was observed for ductal and lobular carcinomas of the breast and endometrioid carcinomas of the uterus and ovary in women 55 years, all of these tumors show a high prevalence of hormone receptor expressions. In addition, hormone-receptor-positive rates of breast cancer were uniquely higher in younger, as opposed to older, Taiwanese women. These findings indicate that estrogen-related cancers rapidly emerge in young women in Taiwan and that incidence rates are catching up with that of women living in the United States. The incidences of breast and gynecological cancers are thought to differ significantly between Asians and Caucasians. For example, the frequency of cervical cancer has been reported to be significantly higher among residents of Southeast Asian, when compared to non-asian, countries. 1 3 In contrast, breast, uterine and ovarian cancer frequencies are reported to be significantly lower in most parts of Asia when compared to other regions. 4 In recent decades, however, the incidences of breast, uterine and ovarian cancer have been increasing in certain rapidly developing Asian countries such as Singapore, Korea, Key words: estrogen, cancer, young women, Asia Additional Supporting Information may be found in the online version of this article *C-H.L. and Y-C.C. contributed equally to this work. Grant sponsor: National Center of Excellence for Clinical Trial and Research; Grant number: DOH99-TD-C DOI: /ijc History: Received 3 Mar 2011; Revised 15 May 2011; Accepted 3 Jun 2011; Online 23 Jun 2011 Correspondence to: Ann-Lii Cheng, Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei 10016, Taiwan, Tel.: þ (ext ), Fax: þ , alcheng@ntu.edu.tw Japan and Taiwan Previous age-period-cohort analyses revealed a much stronger birth cohort effect on the incidence of breast cancer for Taiwanese and Japanese, when compared to Caucasian American, women. 7,8,11 This stronger birth cohort effect was found to correlate directly with a rapid increase in the incidence of early-onset breast cancer in Taiwan and Japan. Similar to that of breast cancer, the incidence of uterine cancer in Japan has increased in women less than 40 years of age. The incidence of ovarian cancer has also increased markedly in Japanese women over 60 years of age, whereas the incidence of cervical cancer has declined significantly among Japanese women aged years. 9 Whether the agespecific incidence changes of these cancers exist in other Asian countries, however, remains to be determined. Taiwan has become increasingly industrialized since the 1960s. In our study, the cancer registration system in Taiwan, established in 1979, was utilized to ascertain whether the unique age-specific changes in female breast and genital cancer incidence reported for Japanese women are observed in Taiwanese women. More importantly, because each form of cancer is pathologically and clinically distinct, the histopathological subtypes of emerging female breast and genital tract cancers observed in Taiwanese women were classified to gain a better understanding of their etiology.

2 2630 Emerging epidemic of estrogen-related cancers Material and Methods Sources of data Annual age-specific incidence rates of female breast, cervical, uterine and ovarian cancers in Caucasians in the United States ( ) were obtained from the Cancer Incidence in Five Continents (CI5), Volumes 5 to 9 ( Corresponding age-specific incidence data for Taiwanese subjects ( ) were obtained from the Taiwan Cancer Registry data profiles. Data for invasive cancers, but not for in situ cancers, were included in our study. The National Cancer Registry in Taiwan was launched in 1979 to collect information for all cancer cases from hospitals with 50 or more beds. The registry was considered to be complete and accurate, with the percentage of cases based on death certificate only (DCO) as low as 1.5%; in 2007, the DCO percentages for female breast, cervical, uterine and ovarian cancers were lower than 0.5%, and the percentages of morphological verification (diagnosis based on microscopic or cytological analysis of a tissue specimen) of female breast, cervical, uterine and ovarian cancers were greater than 99%. 12 For analyses, 5-year groupings were used to evaluate the influence of age; for the calendar year, data were grouped into five 5-year intervals ( ) for the United States and one 4-year interval ( ) and five 5-year intervals ( ) for Taiwan. Year of birth was calculated from the year of diagnosis and age at diagnosis; ten 5-year birth cohorts ( ) for the United States and fourteen 5- year birth cohorts ( ) for Taiwan were analyzed. Incidences of all malignancies and of malignant brain tumors as internal references The incidences of all malignancies and of malignant brain tumors were used as internal references to avoid the potential bias due to incomplete cancer registry data. Environmental factors have the capacity to influence the incidence of all malignancies whereas the development of brain tumors is only weakly associated with lifestyle changes or exposure to common environmental contaminants. 13 For example, an earlier investigation utilizing data from the Taiwan Cancer Registry with malignant brain tumor incidence as a control variable revealed that the incidence of childhood hepatocellular carcinoma decreased after hepatitis B vaccination. 14 Classification of histopathological subtypes of breast, cervical, uterine, and ovarian cancers in Taiwanese women The corresponding International Classification of Diseases for Oncology morphology codes for classification of histological subtypes are listed in Table 1. Histopathological subtypes were classified according to the World Health Organization Classification of Tumors (Tumours of Breast and Genital Organs, Pathology and Genetics) as follows: for breast cancer ductal carcinoma, lobular carcinoma, mucinous carcinoma, medullary carcinoma, metaplastic carcinoma, other epithelial tumors and fibroepithelial tumors; for cervical cancer squamous cell carcinoma, adenocarcinoma, other adenocarcinomas, other epithelial tumors, mesenchymal tumors and mixed epithelial and mesenchymal tumors; for uterine cancer serous adenocarcinoma, clear cell adenocarcinoma, endometrioid adenocarcinoma, other epithelial tumors, mesenchymal tumors, mixed epithelial and mesenchymal tumors and gestational trophoblastic disease; and for ovarian cancer serous carcinoma, mucinous carcinoma, endometrioid carcinoma, other epithelial tumors, sex cord-stromal tumors and germ cell tumors. 15 Hormone receptor status of breast cancer in Taiwanese women Data on estrogen receptor (ER) and progesterone receptor (PR) expressing breast cancers in different age groups were obtained from the Taiwan Cancer Database (TCDB), which was initiated in 2003 by the Bureau of Health Promotion, Department of Health, Taiwan. Data for this database were collected prospectively by a breast cancer treatment committee at each participant hospital (including National Taiwan University Hospital). Thirty-two hospitals had become participants in this program by Data were collected from 12,436 patients and included in the TCDB between January 1, 2005, and December 31, TCDB coverage was 87.7% for all forms of invasive breast cancer in Taiwan. Statistical analysis Age-specific incidence rates of all malignancies, of malignant brain tumors and of breast, cervical, uterine and ovarian cancers for both the United States and Taiwan were plotted against the period of diagnosis. The percentage change within each diagnostic period was then compared to that within the diagnostic period. Age-adjusted incidence rates were calculated using the direct standardization method and the world population in 2000 as the standard population. Trends in age-specific incidence rates of breast, cervical, uterine and ovarian cancers, subdivided by histological subtype and birth cohort, were assessed by visual inspection. The chisquare test was used to compare frequencies of hormone receptor expression in breast cancers between age groups (535, 35 50, or >50 years). Results Incidences of all malignancies and of malignant brain tumors The age-adjusted incidences of all malignancies and of malignant brain tumors in Taiwan increased in the beginning of 1979 and reached plateau values after 2003 but in the United States both have remained constant since 1983 (Fig. 1 and Supporting Information Table 1). The age-specific incidences of all malignancies and of malignant tumors in Taiwan increased significantly in women aged >60 years and after were found to be similar to the corresponding incidences in the United States (Fig. 1).

3 Lin et al Table 1. Histology classifications of breast, cervical, uterine and ovarian cancers and percentage of each histology subtype in the whole study cohort Subtype ICD-9 Percentage 1 Breast cancer Ductal carcinoma 8022, 8035, 8500, 8521, Lobular carcinoma Mucinous carcinoma 8470, 8480, 8481, Medullary carcinoma 8510, Metaplastic carcinoma 8070, 8071, 8072, 8073, 8074, 8560, 8572, 8575, Other epithelial tumors 8200, 8314, 8315, 8502, 8530, 8550, 8522, 8523, 8524, , 8201, 8211, 8260, 8503, 8450, 8013, 8041, 8401, 8246, Fibroepithelia tumors Mesenchymal tumors 8800, 8801, 8805, 8810, 8850, 8851, 8852, 8853, 8854, , 8857, 8858, 8890, 8894, 8896, 9120, 9580, 9150 Cervical cancer Squamous cell carcinoma 8051, 8052, 8070, 8071, 8072, 8073, 8074, 8075, , 8082, 8083, 8084 Adenocarcinoma 8005, 8140, 8144, 8210, 8260, 8261, 8262, 8263, , 8380, 8384, 8441, 8460, 8470, 8480, 8481, 8482, 8490, 9110 Other epithelial tumors 8012, 8013, 8015, 8020, 8041, 8200, 8240, 8246, 8249, Mesenchymal tumors 8004, 8800, 8801, 8805, 8810, 8890, 8894, 8896, 8910, 8930, Mixed epithelial and mesenchymal tumors 8950, 8951, 8980, 8981, Uterine cancer Serous adenocarcinoma Clear cell adenocarcinoma Endometrioid adenocarcinoma 8262, 8380, 8382, 8383, Other epithelial tumors 8015, 8020, 8021, 8041, 8043, 8052, 8070, 8071, 8072, , 8074, 8075, 8120, 8255, 8323, 8480, 8482 Mesenchymal tumors 8800, 8801, 8890, 8891, 8896, 8930, Mixed epithelial and mesenchymal tumors 8933, 8934, 8950, Gestational trophoblastic disease 9100, Ovarian cancer Serous carcinoma 8441, 8460, 8461, Mucinous carcinoma 8470, 8471, 8480, 8481, 8482, Endometrioid carcinoma 8380, 8381, 8382, 8383, Clear cell carcinoma 8310, Other epithelial tumors 8005, 8020, 8021, 8070, 8071, 8072, 8073, 8074, , 8076, 8078, 8323, 9000 Sex cord-stromal tumors 8590, 8600, 8620, 8621, 8630, 8631, 8632, 8634, Germ cell tumors 9060, 9064, 9065, 9070, 9071, 9072, 9080, 9081, 9082, 9083, 9084, 9085, 9090, 9100, 9101, The percentage of histology subtypes which fulfilled the WHO histological classification criteria. A total of 8.7% of breast cancers, 10.2% of cervical cancers, 40.9% of uterine cancers and 31.5% of ovarian cancers among the whole study cohort were excluded because the histology codes were invalid or were not specified. Incidences of breast, cervical, uterine, and ovarian cancers When compared to the United States in , the ageadjusted incidence rate of cervical cancer was higher and the age-adjusted rates of breast, uterine and ovarian cancers were lower in Taiwan in (Fig. 1 and Supporting Information Table 1). After 1979 in Taiwan, however, a rapid and continuous increase in the age-adjusted incidence of breast and uterine cancers was observed; an age-adjusted increase in the incidence of ovarian cancer was also observed but was found to decrease with time. By contrast, these age-adjusted incidences have not changed significantly in the United States since The age-adjusted incidence of cervical cancer

4 2632 Emerging epidemic of estrogen-related cancers Figure 1. Age-specific incidence rates of whole malignancies and malignant brain tumors by calendar year in Taiwan (a) and the United States (b) and by birth cohort in Taiwan (c) and the United States (d). declined after 1998 in both Taiwan and the United States; in Taiwan, this decline was more marked in than in previous periods. Age-specific incidence rates by calendar year and by birth cohort As shown in Figure 2a, the age-specific incidence rates of breast and uterine cancers differed significantly between the United States and Taiwan. In Taiwan, the age-specific incidence rates of both cancers were described by bell-shaped curves with peak incidences occurring at approximately years of age. In the United States, the incidence rates of these cancers increased steadily with age and reached plateau values at years of age. In Taiwan, a significant decline in cervical cancer incidence at age <60 years was observed in and contributed to age-specific changes between 1979 and The age at which the peak incidence of cervical cancer was observed in Taiwan was 55 years in and 70 years in In contrast, the incidence of cervical cancer in the United States has declined gradually in women >50 years of since 1978, and the age at which the peak incidence of cervical cancer was observed in this country declined from 60 years in to 40 years in For ovarian cancer, the agespecific incidence increased steadily with age, reaching plateau values at years in both Taiwan and the United States. For cohorts born in Taiwan after 1938, the birth cohort agespecific incidences of breast, uterine and ovarian cancer increased gradually whereas that of cervical cancer decreased gradually (Fig. 2b). By contrast, no significant birth cohort effect for age at onset of all four cancers was observed for women in the United States. For Taiwanese women born after 1938, the slopes of the breast and uterine cancer incidence curves became increasingly steeper, indicating that the risk of early onset breast and uterine cancers had been rapidly increasing. As can also be seen in Figure 2b, the incidence rates of breast and uterine cancers in women <40 years of age have been approaching those for Caucasian American women since In the latest period examined ( for Taiwanese subjects and for Caucasian Americans), breast cancer incidences for Taiwanese women aged years (25.75 per 1,000,000) and years (60.8 per 100,000) were remarkably close to those for Caucasian women aged years (24.20 per 100,000) and years (60.14 per 100,000). The uterine cancer incidences for Taiwanese women aged years (3.50 per 100,000) and years (5.90 per 100,000) were also close to those for Caucasian women aged years (2.78 per 100,000) and years (5.75 per 100,000). Age-specific incidence rates by histological subtype in Taiwan The age-specific incidence rates of breast, cervical, uterine and ovarian cancers by histological subtype and calendar

5 Lin et al Figure 2. Age-specific incidence rates of breast, cervical, uterine and ovarian cancers by calendar year in Taiwan and US (a) and by birth cohort in Taiwan and the United States (b). year in Taiwan are shown in Supporting Information Figure 1. Findings for the three major histological subtypes of each cancer are shown in Figure 3. The main subtypes significantly increasing in incidence were: for women aged 55 years, ductal and lobular carcinomas (breast cancer), endometrioid adenocarcinoma (uterine cancer) and endometrioid carcinoma (ovarian cancer); for women aged >60 years, mucinous carcinoma (breast cancer) and serous and clear cell adenocarcinomas (uterine cancer); for women aged years, serous adenocarcinoma (ovarian cancer). The main subtype decreasing in incidence was squamous carcinoma (cervical cancer); the decrease was observed for subjects aged 60 years. Hormone receptor status according to age group Table 2 presents the ER and PR status of breast cancers by age group according to data obtained from the TCDB in (n ¼ 12,436). Younger patients (50 years of age) had a higher prevalence of ER-positive (68% vs. 58%, p < 0.001) and PR-positive (63% vs. 50%, p < 0.001) tumors when compared to older (>50 years) patients. The youngest group (<35 years) also had a significantly higher prevalence of tumors with ER (65% vs. 58%, p < 0.001) and PR (55% vs. 50%, p ¼ 0.014) expression when compared to older (>50 years) patients. Discussion Findings of the present report reveal that the incidences of breast, uterine and ovarian cancers during the last 28 years have been increasing rapidly in Taiwan but have increased to a much slower extent in the United States. Of particular importance is the finding that the greatest increases in breast and uterine cancer rates occurred in young Taiwanese women. Uniquely bell-shaped age-specific incidence curves were observed which differed significantly from those for Caucasian American women and which persisted throughout the entire period of the study. The main subtypes increasing in incidence in young Taiwanese women were endometrioid carcinomas of the uterus and ovary and ductal and lobular carcinomas of the breast. For breast cancers, both ER-positive

6 2634 Emerging epidemic of estrogen-related cancers Figure 3. Major histology subtypes of breast (a), cervical (b), uterine (c) and ovarian cancers (d) by calendar year in Taiwan. and PR-positive rates were uniquely higher in younger, when compared to older, Taiwanese women. Taken together, these findings provide strong support for a rapid increase in the incidence of estrogen-related malignancies in young women in Taiwan. To avoid or reduce potential bias due to incomplete cancer registry data, the incidences of all malignancies and of malignant brain tumors were selected as reference controls. The incidence rates of these reference controls had been approaching plateau values in Taiwan after Cervical cancer declined after 1998 in both Taiwan and the United States, and screening programs likely account for the reduction in incidence. During the period of in Taiwan, the incidence of breast and uterine cancers was found to increase to a much greater extent than that of the reference controls or of ovarian cancer. As shown in Supporting Information Table 1, breast and uterine cancer incidence rates in rose 69 and 94%, respectively, above the baseline incidences in and were much higher than the incidence rates of all malignancies (28%), of malignant brain tumors (14%) and of ovarian cancer (37%).

7 Lin et al Table 2. Hormone receptor status of breast cancer according to age group in Taiwan between 2005 and 2006 No. (%) No. (%) <35 years years 50 years >50 years p 1 ERþ 449 (65) 3,727 (68) 4,176 (68) 3,635 (58) <0.001 ER 244 (35) 1,756 (32) 2,000 (32) 2,625 (42) PRþ 379 (55) 3,528 (64) 3,907 (63) 3,114 (50) <0.001 PR 314 (45) 1,955 (36) 2,269 (37) 3,146 (50) 1 Comparison between 50 and >50 years. The curves describing age-specific breast and uterine cancer incidence rates in Taiwan were uniquely bell shaped, differing significantly from those describing age-specific breast and uterine cancer incidence rates in the United States and from those describing age-specific incidence rates for all malignancies, for brain tumors, and for ovarian cancer in Taiwan. However, these bell-shaped curves were similar to those describing age-specific breast cancer incidence rates in Singapore, Korea and Japan and that describing the age-specific uterine cancer incidence rate in Japan. 5 7,9 In previous analyses, a significant increase in early-onset breast cancer incidence was observed in Taiwan in , 8 and an increase in the incidence of breast and uterine cancers was observed in Taiwan which continued after 1998 with the largest segment of that increase occurring in younger women. The age at which the peak incidence of breast cancer and uterine cancer was observed in Taiwan was at years from 1979 to To avoid potential bias due to inaccuracy of the histological classification of tumors in a registry data, only histological classifications that fulfilled WHO criteria were used in our study. Although 8.7% of breast cancers, 10.2% of cervical cancers, 40.9% of uterine cancers and 31.5% of ovarian cancers were excluded because of invalid or unspecified histological codes, the distributions of histology subtypes (Table 1) were generally consistent to previous reports in Asia. For example, the low frequency of lobular carcinoma in our study was consistent with previous reports in Korea 16 and Japan. 17 The age-specific time trends of histological subtypes revealed a significant increase in ductal and lobular carcinoma of the breast, endometrioid adenocarcinoma of the uterus, and endometrioid carcinoma of the ovary in women aged 55 years (Fig. 3). Epithelial subtypes of uterine cancer (endometrial cancer) can be estrogen dependent (Type I) or estrogen independent (Type II). Type I endometrial cancer is characterized by an endometrioid histology whereas the Type II form is characterized by a high-grade histology (usually serous or clear-cell) and more aggressive behavior. 18,19 Ovarian endometrioid carcinomas almost always resemble endometrioid carcinomas of the endometrium, express the ER and the PR, are frequently low grade, and are considered to be associated with estrogen exposure. 20 In our study, the incidence of endometrioid carcinomas of both the uterus and ovary increased rapidly in women aged 55 years; the increase was more dramatic for women with the uterine cancers. The incidence of ovarian serous carcinoma, another subtype characterized by high ER and PR expression, 20,21 also increased more rapidly in younger than in older women although the age-specific incidence curve was not clearly bell shaped. In contrast, the incidence of Type II endometrial cancer increased rapidly in older women (>60 years; Fig. 3). In addition to histology subtypes, we analyzed the frequency of ER and PR expressions by age groups to further characterize the pathological features of breast cancer in young women in Taiwan. Unlike the findings of a similar analysis involving African-American and Caucasian American patients with breast cancer, 22 analysis of TCDB data in (n ¼ 12,436) showed that young (50 years) breast cancer patients had a significantly higher prevalence of ER- and PR-positive tumors than did their older (>50 years) counterparts. Even very young (<35 years) breast cancer patients, who have been consistently characterized by a higher proportion of ER-negative tumors in Western countries, 23,24 had a significantly higher prevalence of ERand PR-positive tumors than did older (>50 years) patients in Taiwan. To investigate the time trend of ER-positive breast cancer incidence, we analyzed two published cohorts of patients with breast cancer diagnosed at National Taiwan University Hospital. The first cohort (breast cancer diagnosed in ) included participants in a study of association between CYP19 TTTA repeat polymorphism and prognosis. 25 The second cohort included consecutive patients with breast cancer diagnosed in The methods and cut off point used for ER positivity (tumors with 10% positively stained nuclei by immunohistochemistry) were the same in these two cohorts. Compared to that in first cohort, ER positive rate was significantly increased in young patients (age 50 years) in second cohort (Supporting Information Fig. 2). These observations strongly support the hypothesis that most forms of early-onset breast cancer emerging in Taiwan are hormone-receptorpositive. The rapid increase in the incidence of early-onset hormone-receptor-positive breast cancer and of endometrioid carcinomas of uterus and ovary in young Taiwanese women suggests that these subjects are at increased risk for estrogenrelated malignancies. Etiologies may involve excess estrogen from either endogenous or exogenous sources. Taiwan has become increasingly industrialized since the 1960s. With westernization of lifestyle, Taiwanese women born after the 1960s have adapted to higher caloric and higher fat diets, undergo an earlier menarche, have drastically reduced fertility rates, and have delayed childbearing These factors are associated with prolonged reproductive stimulation by endogenous estrogen and have been linked to an increasing incidence of breast cancer in Taiwan and Western countries.

8 2636 Emerging epidemic of estrogen-related cancers Beyond endogenous estrogens, certain industrial environmental pollutants with estrogenic effects may also be causative and deserve further investigation. For example, plastic trash bags have been used to transport hot foods in Taiwan for several decades. Nonylphenol is an estrogenic degradation product of alkylphenol polyethoxylates, which have been used widely for the manufacture of plastic wrappings. Findings of a recent study revealed that the average daily intake of nonylphenol by Taiwanese subjects was 4-fold higher than that by Germans and 8.5-fold higher than that by New Zealanders. 30 In addition, high concentrations of estrogenic steroid pollutants in water and of polycyclic aromatic hydrocarbons in the air have been reported in Taiwan Genetic components, particularly those genes involving estrogen synthesis or metabolism, may also play a role in the emergence of estrogen-related malignancies in young Asian women and have not been systemically analyzed in this population. Determining the responsible environmental factors or gene-environment interactions leading to carcinogenesis in younger women with estrogen-related malignancies in Taiwan and other rapidly developing countries in Asia represents a challenging and important objective. 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