Obesity and Breast Cancer in a Multiethnic Population. Gertraud Maskarinec, MD, PhD University of Hawaii Cancer Center, Honolulu, HI

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1 Obesity and Breast Cancer in a Multiethnic Population Gertraud Maskarinec, MD, PhD University of Hawaii Cancer Center, Honolulu, HI

2 Background Breast cancer incidence remains lower in many Asian than Western countries Risk in Asian migrants to the United States has increased over several generations Excess body weight is a risk factor for postmenopausal breast cancer and predicts worse survival Persons of Asian ancestry appear to have a high risk to develop diabetes and other chronic diseases despite a relatively low body weight Question: Is the influence of adiposity on breast cancer risk and prognosis stronger in Asian/Asian American than in white women?

3 Outline Multiethnic Cohort Breast cancer incidence in Asians and Asian Americans Obesity rates in Asians and Asian Americans Obesity and breast cancer risk in Asians/Asian Americans BMI Weight gain Waist-hip ratio Breast cancer survival in Asians/Asian Americans Possible mechanisms Body fat distribution Adipokines Conclusions

4 Multiethnic Cohort Study Baseline , 26 page self-administered questionnaire Validated food frequency questionnaire Sent to residents of Hawaii and Los Angeles County Names were obtained through drivers license records, voter registration records, and Medicare files Limited to ages years Ethnic distribution of 215,251 participants Japanese American (26.4%) White (22.9%) Latino (22.0%) African American (16.3%) Native Hawaiian (6.5%) Other ancestry (5.8%) Short follow-up questionnaire after 5 years Biorepository collection in : N=67,594 (49.7% of eligible) Repeated FFQ after 10 years

5 MEC Questionnaire

6 Breast Cancer Incidence in Japanese Immigrants and Caucasians Kolonel et al. Japan Scientific Societies Press Incidence per 100, st Gen. 2nd Gen. Caucasian Japan Hawaii

7 Breast Cancer in Hawaii and Japan Japan Hawaii (Japanese) Hawaii (Caucasian)

8 Breast Cancer Risk - Multiethnic Cohort Pike et al. CEBP 2002 W AA NH JA L-US L-NUS Total All postmenopausal N 20,794 18,527 5,918 23,638 9,874 9,961 88,712 Cases ,757 RR IR* All women with natural menopause or bilateral oophorectomy N 14,079 9,527 3,636 16,576 5,930 5,616 55,364 Cases ,116 RR IR* *Adjusted to 1970 US Standard Population ages years

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11 Overweight by Ethnicity in Hawaii Maskarinec et al. Breast Ca Res & Treat 2006 (%) 100 Native Hawaiian Caucasian Japanese H: 62% to 72%, p = Study Year

12 Obesity in the Multiethnic Cohort Kolonel et al. Am J Epidemiol Men Women Haw J-A Cauc A-A Latino

13 BMI by Ethnicity - Multiethnic Cohort White et al. Int J Cancer Age 21 Baseline 0 White African Am Nat Hawaiian Japanese Latina

14 Diabetes Risk by BMI - MEC Maskarinec et al. Diabetes 2009 Caucasian Native Hawaiian Japanese American Hazard ratio <

15 Type 2 Diabetes in East Asians: Similarities & Differences with Populations in Europe & US Annals of the New York Academy of Science 2013

16 Breast Cancer Risk by BMI at BL White et al. Int J Cancer Overweight Obese P for interaction = 0.03 * 1.6 * * * * * 1 White African Am Nat Hawaiian Japanese Latina *p>0.05

17 Breast Cancer by Weight Gain since 21 White et al. Int J Cancer kg kg >22.7 kg * * * * * P for interaction = * * *p> White African Am Nat Hawaiian Japanese Latina

18 Breast Cancer by BMI & Weight Gain White et al. Int J Cancer >22.7 kg gain Obese * * * * White African Am Nat Hawaiian Japanese Latina Mutually adjusted plus other covariates *p>0.05

19 BMI & Postmenopausal Breast Cancer Risk Author Year Design Categories Risk 95% CI Asians Kuriyama 2005 CC per 5 kg/m , 6.92 Chow 2005 Cohort per 5 kg/m , 2.87 Iwasaki 2007 CC per 5 kg/m , 5.52 Wu 2007 Cohort per 5 kg/m , 1.93 Mathew 2008 Cohort per 5 kg/m , 1.67 Kawaii 2010 CC per 5 kg/m , 5.55 Suzuki 2011 Cohort per 5 kg/m , 1.59 White 2012 Cohort per 5 kg/m , 1.36 Multiple ethnic groups Renehan 2008 Meta per 5 kg/m , 1.19

20 BMI & Postmenopausal Breast Cancer Risk Author Year Design Categories Risk 95% CI Asians Kyogoku 1990 CC Q4 vs Q , 2.40 Hu 1997 CC >24 vs 21.4 kg/m , 4.55 Ng 1997 CC >27.5 vs 21 kg/m , 2.30 Tung 1999 CC >25 vs <20 kg/m , 3.24 Shu 2001 CC >28.0 vs <20.7 kg/m , 3.20 Hirose 2001 Cohort >25 vs <20 kg/m , 2.90 Wu 2006 Cohort >26.2 vs <21.6 kg/m , 1.34 Tian 2007 CC >24.45 vs <24.45 kg/m , 5.68 Suzuki 2013 Cohort 29 vs kg/m , 4.16 Shin 2009 CC >25 vs <20.9 kg/m , 2.20 Multiple ethnic groups Cheraghi 2012 Meta Overweight vs normal , 1.17 Cheraghi 2012 Meta Obese vs normal , 1.34

21 Weight Gain & Postmenopausal Breast Cancer Risk Author Year Design Categories Risk 95% CI Asians Kyogoku 1990 CC >4 kg/m , 2.10 Shu 2001 CC >5.65 vs. <1.15 kg , 4.20 Hirose 2001 Cohort >3 vs 0 kg/m , 1.70 Wu 2007 Cohort >20 vs 10 kg , 4.94 Shin 2009 CC 15 vs 0 kg , 2.40 Kawaii 2010 CC 12 vs <5 kg , 3.45 Suzuki 2011 Cohort 5 kg/m , 1.60 White 2012 Cohort per 5 kg , kg and BMI 24 vs Suzuki 2013 Cohort , 4.42 <10 kg and BMI<24 Multiple ethnic groups ER+/PR , 2.45 Vrieling 2010 Meta ER-/PR , 1.58

22 Waist Hip Ratio & Postmenopausal Breast Cancer Risk Author Year Design Categories Risk 95% CI Asians Ng 1997 CC >0.86 vs <0.75 cm , 14.2 Shu 2001 CC >0.835 vs < cm , 2.50 Wu 2006 Cohort >0.85 vs <77 cm , 1.20 Wu 2007 Cohort >0.84 vs <0.77 cm , 2.15 Mathew 2008 Cohort >0.85 vs <=0.85 cm , 0.97 Shin 2009 CC >0.83 vs <0.77 cm , 2.80 Other ethnic groups Tehard 2006 Cohort Whites , 1.28 Harvie 2007 Meta Multiple , 1.48

23 BMI & Breast Cancer Risk by ER Status Study ER+ ER- RR 95% CI RR 95% CI Iwasaki vs <19 kg/m Suzuki 2009 per 5 kg/m Kawaii vs <18.5 kg/m

24 Premenopausal Breast Cancer Risk Amadou et al. Obesity Reviews 2013 BMI WHR BMI: WHR: 1.05 Asians vs whites 1.19 Asians vs whites

25 Adiposity & Breast Cancer Survival Tao et al. American J Epidemiol, 2005 China DFS <21.23 kg/m % kg/m % 0.90 (0.7, 1.3) kg/m % 1.00 (0.7, 1.4) kg/m % 1.30 (1.0, 1.8) Kwan et al. BMC Cancer, 2012 Japan 25.8 vs 21.2-<23.3 kg/m 2 All 1.46 (0.81, 2.64) ER + or PgR (1.05, 23.4) ER-/PgR (0.38, 2.64) Caan et al. Cancer Epidemiol, Biomarkers & Prev 2012 US&China >10% weight gain US 1.03 (0.84, 1.26) China 1.25 (0.88, 1.77) Chan et al. Ann Oncology 2014 Meta-analysis Overweight 1.11 (1.06, 1.17) Obese 1.35 (1.24, 1.47) Per 5 kg/m (1.12, 1.25)

26 Breast Cancer Survival by Adiposity California Breast Cancer Survivorship Consortium Kwan et al. Am J Epidemiol 2014 BMI White Asian American N HR 95% CI N HR 95% CI Underweight , , 4.10 Normal weight Overweight , , 1.98 Obese , , 2.89 Severely obese , 1.61 Morbidly obese , 2.43 Waist-hip ratio White Asian American N HR 95% CI N HR 95% CI Q1 (<0.763) Q2 (0.763 <0.814) , , 2.83 Q3 (0.814 <0.867) , , 1.93 Q4 ( 0.867) , , 4.03

27 MEC - Breast Cancer-Specific Mortality Conroy et al. Breast Ca Res & Treatment 2011 HR Ethnicity BMI (kg/m 2 ) 2 P = 0.03 P < 0.04 P < Caucasian African Japanese Hawaiian Latino (n=70) American American (n=24) (n=49) (n=83) (n=46) < (n=53) (n=50) (n=81) (n=88) Models adjusted for age at diagnosis, breast cancer subtypes, stage, treatment, and family history of breast caner.

28 MEC - Breast Cancer-Specific Mortality Conroy et al. Breast Ca Res & Treatment Adjusted HR African American P interaction =0.53 Caucasian Japanese American 0.4 Hawaiian < Latino Models adjusted for age at diagnosis, breast cancer subtypes, stage, treatment, and family history of breast cancer.

29 Metabolic Pathways Linking obesity and Breast Cancer Risk Amadou et al. J Oncol 2013 Ethnic differences may exist for several pathways. Figure 5: Metabolic pathways linking obesity and breast cancer risk.

30 Visceral vs. Subcutaneous Fat Lim et al. Nutrition and Diabetes 2011

31 Visceral vs. Subcutaneous Fat Lim et al. Nutrition and Diabetes 2011 Japanese American (n=30) White (n=30) P value Participant Characteristics Age-adjusted mean Age Weight, kg Height, m <.0001 BMI (kg/m 2 ) DXA total fat mass, kg Body Fat Distribution Age- and total fat-adjusted mean DXA trunk-to-periphery fat ratio MRI % subcut fat/abdo area 33.4% 30.2% 0.21 MRI % liver fat (geometric mean) 5.8% 3.8% 0.06 MRI fatty liver (> 5.5%) 51% 24% 0.05

32 Ethnic Differences in Visceral Adipose Tissue : Filipino, White, and AA Women Araneta et al. Obesity 2005

33 Visceral Adipose Tissue in Asians Lear et al. Obesity 2007 VAT at given WC values, adjusted for age, in Europeans (white), Chinese (light gray), and South Asian (dark gray) women

34 Trunk to Periphery Fat Ratio (TPFR) in Mothers by Ethnic Group Morimoto et al. J Epidemiol 2012 p trend <0.01 TPFR p<0.01 p=0.04 p=0.40 Asian Part-Asian Mixed-Other Caucasian

35 Trunk to Periphery Fat Ratio (TPFR) in Daughters by Ethnic Group Morimoto et al. J Epidemiol 2012 p trend <0.001 TPFR p< p=0.02 p=0.01 Asian Part-Asian Mixed-Other Caucasian

36 ng/ml Leptin by Ethnicity and BMI in Premenopausal Women Conroy et al. Mediators of Inflammation 2011 p = < >35 BMI (kg/m 2 ) Caucasian (n=67) l Asian (n=74)

37 Adiponectin by Ethnicity and BMI in Premenopausal Women Conroy et al. Mediators of Inflammation 2011 µg/ml P <0.001 b < > 35 BMI (kg/m 2 ) Caucasian (n=67) l Asian (n=74)

38 Adipokines in Asians vs. White Postmenopausal Women Khan et al. Metabolism Adiponectin HMW ADP Leptin Soluble LR Chinese Japanese P<0.001 for all *Adjusted for age, smoking, waist circumference, physical activity, menopausal status, education

39 Leptin by Ethnicity & BMI Morimoto et al. Int J Obesity 2014 ng/ml p forja =0.01 African American Caucasian (reference) Native Hawaiian Latino 20 Japanese American 10 0 Normal weight Overweight Obese

40 Adiponectin by Ethnicity & BMI Morimoto et al. Int J Obesity 2014 μg/ml 20 p forja < Caucasian (reference) Native Hawaiian Latino African American Japanese American 0 Normal weight Overweight Obese

41 MEC - Adipokines and Breast Cancer Risk Ollberding et al. Ca Prev Res 2013 Quartiles Cases/ Controls Leptin OR (95% CI) Cases/ Controls Adiponectin OR (95% CI) Q1 182/ / Q2 210/176 Q3 158/176 Q4 156/ (0.96, 1.84) 1.74 (1.24, 2.44) 1.78 (1.19, 2.65) 169/ / / (0.87, 1.58) 0.92 (0.67, 1.27) 0.94 (0.66, 1.32) P for trend

42 Adiponectin and Breast Cancer Risk Minatoya et al. Breast Cancer 2013 Adiponectin Cases Controls OR (95% CI) OR (95% CI) < (58.5) 14 (31.1) , < (29.3) 12 (26.7) (12.2) 19 (42.2) 0.61 ( ) 0.15 ( ) 0.34 ( ) 0.06 ( ) P for trend 0.002* 0.001*

43 Conclusions Breast cancer risk and obesity rates have increased in Asians/Asian Americans The associations of BMI, weight gain, and WHR with breast cancer risk appear to be stronger in Asian/Asian Americans than in whites Suggestive evidence for breast cancer survival Obesity-related biomarkers may provide insight into biologic mechanisms; excess fat mass and visceral fat result in low production of adiponectin BMI has many limitations as a measure of adiposity Additional anthropometric measures, in particular from imaging, will be needed to understand the relation between ethnicity and adiposity

44 Acknowledgments MEC Investigators LN Kolonel BE Henderson L Le Marchand LR Wilkens MC Pike Faculty & Postdocs M Goodman SY Park U Lim SM Conroy NJ Ollberding Staff K White Y Morimoto & entire MEC staff The MEC-related research has been supported by many grants: R37 CA54281 (Kolonel) P01 CA (Kolonel) UM1 CA (Le Marchand/Wilkens/Henderson) P01 CA (Le Marchand) R25 CA90956 (Maskarinec) R21 DK (Maskarinec) P30 CA71789 (Carbone)