Transformation of Breast Cancer in Taiwan

Transformation of Breast Cancer in Taiwan Chiun-Sheng Huang, MD, PhD, MPH President, the Breast Cancer Society of Taiwan Professor of Surgery National Taiwan University Hospital

More young breast cancers in Taiwan? 2010 Huang CS et al J Steroid Biochem Mol Bio Age-specific Breast Cancer Incidence 500 450 400 350 300 250 TW 1994 TW 1998 TW 2002 TW 2005 TW 2006 SEER 2002-2006 200 150 100 50 0 0 10 20 30 40 50 60 70 80

More young breast cancers in Taiwan? 2010 Huang CS et al J Steroid Biochem Mol Bio Age-specific Breast Cancer Incidence 500 450 400 350 300 250 TW 1994 TW 1998 TW 2002 TW 2005 TW 2006 SEER 2002-2006 200 150 100 50 0 0 10 20 30 40 50 60 70 80

More young breast cancers in Taiwan? 2010 Huang CS et al J Steroid Biochem Mol Bio Age-specific Breast Cancer Incidence 500 450 400 350 300 250 TW 1994 TW 1998 TW 2002 TW 2005 TW 2006 SEER 2002-2006 200 150 100 50 0 0 10 20 30 40 50 60 70 80

Westernization Lifestyle Since 1960 in Taiwan Increase of meat consumption Decrease of fertility rate 2006 Symposium COA/INRA Scientific Cooperation in Agriculture Adapted from http://csyue.nccu.edu.tw

Changes in Age at Menarche in Taiwan Age at Menarche (years) 18 15.8 16 16.7 16.5 15.5 14 12 10 8 6 4 2 14.7 You SL (unpublished data) 13.9 13.4 12.9 0 Birth Cohort 1911-1920 1921-1930 1931-1940 1941-1950 1951-1960 1961-1970 1971-1980 1981-1986

Environmental factors: nonylphenol (NP) Average daily NP intake in Taiwan is 4-fold and 8.5-fold higher than those in Germany and New Zealand Detected in 30% Taiwanese girls (urine), higher than white (4.6%) and black girls (8%) Urinary NP level inversely correlated with menarche age maternal-fetal transfer Lu YY et al, Environ Int. 2007 Chen ML et al, Chemosphere 2008 Chen ML et al, Chemosphere 2009

For DEHP (Bis(2-ethylhexyl) phthalate), 37% of the study population exceeded the tolerable daily intake established by European Union, and 85% exceeded the reference dose of the US.

Phthalate Exposure and Breast Cancer Risk: A Community-based Nested Case Control Study Manuscript in preparation

Phthalate Exposure and Breast Cancer Risk: A Longitudinal Community-based Nested Case Control Study Phthalate metabolites (μg/g Creatinine) MBzP MEP MEHP MEHHP MEOHP MnBP MiBP MMP Cases (N=126) Controls (N=253) No. (%) No. (%) Odds Ratio* (95% Confidence Intervals) P value 2.53 60 (47.6) 126 (49.8) 1.00 >2.53 66 (52.4) 127 (50.2) 1.11 (0.72-1.70) 0.65 16.50 35 (27.8) 99 (39.1) 1.00 >16.50 91 (72.2) 154 (60.9) 1.67 (1.04-2.68) 0.03 6.20 45 (35.7) 128 (50.6) 1.00 > 6.20 81 (64.3) 125 (49.4) 1.97 (1.25-3.10) 0.003 52.20 89 (70.6) 204 (80.6) 1.00 >52.20 37 (29.4) 49 (19.4) 1.68 (1.02-2.77) 0.04 14.20 39 (31.0) 99 (39.1) 1.00 >14.20 87 (69.0) 154 (60.9) 1.47 (0.93-23.4) 0.09 45.97 88 (69.8) 151 (59.7) 1.00 >45.97 38 (30.2) 102 (40.3) 0.63 (0.40-1.00) 0.04 12.63 113 (89.7) 202 (79.8) 1.00 >12.63 13 (10.3) 51 (20.2) 0.45 (0.23-0.87) 0.001 10.00 59 (46.8) 126 (49.8) 1.00 >10.00 67 (53.2) 127 (50.2) 1.13 (0.73-1.74) 0.58 * Odds ratios were adjusted for age, residence, years of cumulative estrogen exposure, and age at menarche.

Case-Control Study in Taiwan: reproductive factors can t explain the rapid increase of young female breast cancer All (n=694) Premenopausal (n=353) Postmenopausal (n=341) Age at menarche (years) P=0.05 P=0.89 P<0.001 > 13 1 1 1 = 13 1.35 1.03 2.87 < 13 1.69 1.06 7.84 No. of full-term pregnancies P=0.11 P=0.87 P=0.02 >2 1 1 1 1-2 1.11 1.1 2.22 0 1.24 1.21 5.69 Yang PS et al, Br J Cancer. 1997;75(5):752-6.

Aromatic Amines and N-Acetyltransferase 2 (NAT2) Aromatic amines are the environmental carcinogens existing in cigarette smoking, vehicle exhaust fumes, dyes, antioxidants, pesticides and can be detoxified and/or bioactivated by xenobiotic metabolizing enzymes, such as NAT2. Individuals can have different genotypes and be classified as rapid (increased bioactivation) or slow (decreased detoxification) of NAT2 acetylators

Logistic regression analysis of NAT2 genotype polymorphism and other risk factors in relation to breast cancer development Pre-menopausal women Post-menopausal women aor 95%CI aor 95%CI NAT2 polymorphism, Slow vs. rapid genotype 1.52 0.65-3.67 2.31 1.01-5.47 Age at menarche (years), 13 vs. >13 1.06 0.49-2.28 3.70 1.69-8.47 Age at 1st full-term pregnancy (years), nulliparity or 30 vs. <30 2.00 0.80-5.29 4.43 1.66-13.4 History of hormone replacement therapy, ever vs. never --- ---- 2.89 1.00-9.31 D19 6-1 Huang et al Int J Cancer 1999

Association between NAT2 slow acetylator genotype and breast cancer risk, stratified by HRT and BMI Pre-menopausal women post-menopausal women aor 1 (95%CI) aor 1 (95%CI) Use of HRT Never 1.5(0.7-3.7) 2.5(1.1-6.3) Ever --- 0.5(0.1-7.5) BMI, kg/m 2 <25 1.4(0.6-3.7) 6.5(2.1-11.6) 25 5.0(0.4-127) 0.7(0.1-3.1) A logistic regression model containing NAT2 genotype and other 4 risk factors (age at first D19 full-term pregnancy, history of smoking, 6-2 use of hormone replacement therapy and body mass index) was used

DNA adduct / mutation Biosynthesis Hydroxylation steroid Estrogen Catechol estrogen CYP17 CYP1A1 COMT Inactivation

Genotypic polymorphisms of estrogen-metabolizing genes and multiple risk factors for breast cancer Risk factor Multivariate-aOR 95%CI Estrogen-metabolizing gene CYP17(A 2 /A 2 vs. A 1 /A 1, A 1 /A 2 ) 1.23 0.67-2.28 CYP1A1(vt/vt vs. wt/wt, wt/vt) 1.79 0.86-3.78 COMT(L/L vs. H/H, H/L) 4.02 1.12-19.08 Age(years) 0.97 0.94-1.00 Family history of breast cancer 1.39 0.34-5.61 (Yes vs. No) Age at menarche( 13 vs. >13 years) 1.93 1.05-3.58 Age at first full-term pregnancy) 2.39 1.13-5.24 ( 30 or nulliparity vs. <30 years) History of hormone replacement therapy 4.47 1.58-14.76 (Yes vs. No)

Distribution of genotype polymorphisms of COMT in relation to breast cancer risk Genotype Cases (%) Control (%) OR(95%CI) aor(95%ci) a Premenopausal women H/H 29(60.4) 31(59.6) 1.00(ref) 1.00(ref) H/L 14(29.2) 18(34.6) 0.83(0.32-2.15) L/L 5(10.4) 3(5.8) 1.78(0.33-10.51) 2.00(0.46-10.36) Postmenopausal women H/H 37(56.9) 34(47.2) 1.00(ref) 1.00(ref) H/L 21(32.3) 37(51.4) 0.52(0.24-1.13) L/L 7(10.8) 1(1.4) 6.43(0.72-146) 9.34(1.27-193) a Risk factors adjusted for were age, family history of breast cancer, age at menarche, age at first full-term pregnancy, and history of hormone replace therapy.

Breast cancer incidence rates among Whites, Blacks, and JAHI in the United States (nine SEER areas) and Osaka, Japan Matsuno RK, Cancer Epidemiol Biomarkers Prev, 2007

Breast cancer incidence rates among Whites, Blacks, and JAHI in the United States (nine SEER areas) and Osaka, Japan during the years 1978 to 1997 Matsuno RK, Cancer Epidemiol Biomarkers Prev, 2007 White Black JAHI Osaka Mean age 63 57.7 61 53.5 Median age 64 57 62 51 Overall rate 87.6 80.0 72.4 21.8

Relative risk of breast cancer in relation to menopause based on 52705 cases, 108411 controls Lancet 1997; 350: 1047 Premenopausal Perimenopausal Postmenopausal By age at natural menopause (years) <35 35-39 40-44 45-49 50-54 55 By age at bilateral oophorectomy <35 35-39 40-44 45-49 50 RR 1.00 0.77 0.46 0.51 0.62 0.70 0.81 0.85 0.48 0.65 0.65 0.72 0.90

US Taiwan Unique trend of age-specific incidence rates of breast and uterus cancer in Taiwan Breast Cervix Uterus Ovary Lin CH et al, Int J Cancer. 2011 Jun 23 [Epub ahead of print]

Trend of histology of uterine cancer in Taiwan Endometrioid adenocarcinoma Serous/ Clear cell adenocarcinoma Type I endometrial cancer (estrogen dependent tumor) Type II endometrial cancer (estrogen unrelated tumor) Lin CH et al, Int J Cancer. 2011 Jun 23 [Epub ahead of print]

Age-specific incidence rates of IBC in Taiwanese and Caucasian Americans by birth cohort A Caucasian Americans T - Taiwanese YC Shen et al Cancer Epi Biomarkers Pre 2005

Cross-sectional age-specific breast cancer incidence rates JNCI 2015 published online April 13, 2015

Trends in age-standardized incidence rates of breast cancer by age group from 1988 to 2009 JNCI 2015 published online April 13, 2015

Longitudinal age-specific breast cancer incidence rates and corresponding incidence rate ratios. A) 1920 birth cohort. B) 1944 birth cohort. C) 1970 birth cohort. JNCI 2015 published online April 13, 2015

Female Breast Cancer Incidence Among Asian and Western Populations: More Similar Than Expected Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. Cross-sectional analyses that may be confounded by calendarperiod and/or birth cohort effects Longitudinal age-specific rates, extrapolated from the age-periodcohort model, were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The estimates for the most recent cohorts in Taiwan, South Korea, and Singapore actually showed later ages at onset than in the United States, and the breast cancer incidence rates in even surpassing the historically high rates in the United States JNCI 2015 published online April 13, 2015

Rising breast cancer incidence in Asia was largely attributable to birth cohort changes due to the adoption of a westernized lifestyle Calendar-period or screening effect can t be excluded, particularly in South Korea, Singapore, and Taiwan where population-based screening programs were implemented between the late 1990s and early 2000s. Women born between the 1960s and 1970s, who were in their 40s between 2000 and 2010, would be the first generation influenced by population-based screening programs. Rapid case ascertainment in a new and expanding cancer registry may also count. Low coverages of cancer registries in large territories such as China and the United States may limit the representative -ness of the results.

Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23637 breast cancer cases and 25579 controls Human Molecular Genetics, 2013, 2539 2550 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci identified by GWASs conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in East Asian women Taken together, these common genetic risk variants explain 10% of excess familial risk of breast cancer in Asian populations.

Time trend of ER expression by age group in Taiwan: data from two cohorts at NTUH P = 0.08 P < 0.001 P = 0.40 Cohort 1 (n=481): Huang Oncologist. 2008 Jul;13(7):751-60. Cohort 2 (n=1028): Lin Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14

Molecular subtype distributions among African Americans, non-african Americans and Taiwanese Age 50 years Age > 50 years Lin CH et al, Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14. Carey et al, JAMA. 2006;295:2492-2502

Correlation of Molecular Subtypes and Clinicopathological Characteristics Characteristics Luminal A (n=624 ) Luminal B (n= 101) HER2+/ER- (n=121 ) Basal-like (n=132) P value Age (mean) 51 50 52 54 0.006 Stage I 31% 21% 27% 27% 0.04 Stage II 47% 42% 43% 55% Stage III 17% 23% 18% 15% Stage IV 5% 3% 12% 3%

Correlation of Molecular Subtypes and Clinicopathological Characteristics Characteristics Lymph node status Luminal A (n=624 ) Luminal B (n= 101) HER2+/ER- (n=121 ) Basal-like (n=132) P value Positive 47 % 50 % 55% 31 % <0.001 Negative 53 % 50% 45% 69% Histology grade I 29% 15% 3% 7 % <0.001 II 59 % 57% 47 % 42% III 13 % 28% 51 % 51%

Chuang et al., APMIS 2014;122:699-707

Evolution of Breast Cancer Screening in Taiwan Phase I. 1995-1998 High-Risk Screening PE, Sono, Mammo, Hospitalbased Phase II. 1999-2001 Mass Screening PE+/-Sono Outreaching Phase III. 2002.7-2004.7 Two-Stage Screening 1. Questionnaire 2. Mammography Outreaching Phase IV. 2004.7~ Mass Screening Mammography National

Stages of Breast Cancers (2005 to 2011) US Taiwan 2005 2005 2008 2011 Stage 0 18% 10% 10% 14% Stage I 37% 27% 29% 31% Stage II 25% 38% 36% 32% Stage III 9% 18% 17% 16% Stage IV 3% 4% 6% 6% Stage unkown 7% 3% 2% 0%

Transformation of Breast Cancer in Taiwan Increased incidence of premenopausal or early-onset breast cancers could be due to lead-time bias (screening and easy access to breast examination). Western lifestyle and environmental factors will contribute to the increase of postmenopausal breast cancers.

Wen-Je Ko Taipei Mayor Professor of Surgery, NTUH He made a change

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