New Insights into Breast Cancer Risk Reduction

Transcription

1 New Insights into Breast Cancer Risk Reduction November 10, 2013 Rowan T. Chlebowski Professor of Medicine David Geffen School of Medicine at UCLA Chief, Division of Medical Oncology and Hematology Harbor-UCLA Medical Center

2 Outline Asia vs. Western Incidence Lifestyle Factors Menopausal Hormone Therapy Chemoprevention agents Future

3 Age Specific Incidence Rate for Breast Cancer by Countries Toi et al. Jpn J Clin Oncol 2010;40(Supl 1):i13-i18

4 Age-Adjusted Breast Cancer Mortality Increased over 100% in Korea and Japan from 1980 Levels In USA, in same interval, screening mammography and adjuvant therapy has decreased breast cancer mortality from 32 to 23 per 100,000 females (28% decrease) Zhang et al. Europ J Cancer Prev 2012;21: , Siegel et al. CA: A Cancer J for Clinicians 2012;62:10

5 Hypothesis The difference between breast cancer mortality rates in U.S. and Asia Countries: U.S. Asia 23 / 100,000 females/yr 9 / females/yr Largely related to life style differences with endogenous estrogen and insulin mediation

6 Breast Cancer Target in Prevention Trials: Tumor Growth Kinetic Model Parameters in model (based on clinical findings): 200- day doubling time, 1.16 cm detection threshold, and 7% result tumor prevalence Model used to calculate the percentage of breast cancer in the WHI E+P trial during 5.6 years of intervention which were either novo (6%) or established but preclinical (94%) Breast cancer chemoprevention in prevention trials is mostly therapy of preclinical breast cancers Santen et al. Journal of Steroid Biochemistry & Molecular Biology (2013) [Epub ahead of print]

7 Breast Cancer Prevention: Hypothesis As current breast cancer prevention studies likely reflect therapy mostly of preclinical breast cancer Any therapy with efficacy in the adjuvant breast cancer setting or an contralateral breast will reduce breast cancer incidence Only issue is the side effect profile and cost

8 Outline Asia vs. Western Incidence Lifestyle Factors Menopausal Hormone Therapy Chemoprevention agents Future

9 Country-by-Country Breast Cancer Death Rate by Estimated Dietary Fat Intake Carrol, et al. Can Med Assoc J 1968;98(12):590-4

10 Dietary Fat Intake and Breast Cancer Recurrence Women s Intervention Nutrition Study (WINS) Women yrs Early breast cancer Surgery +/- RTx Systemic therapy* Dietary fat intake 20% of calories Randomization 60:40 within 365 days from 1 o surgery n=2437 Dietary Intervention (n=975) to reduce fat intake maintaining nutritional adequacy Control (n=1462) Median follow-up 60 months * Tamoxifen required, chemorx optional for ER+; chemorx required for ER-. Chlebowski RT, Blackburn GL, Thomson CA, et al J Natl Cancer Inst 2006;98:1767

11 PATIENTS (%) Women s Intervention Nutrition Study (WINS): Clinical Outcomes Relapse-Free Survival HR 0.76 ( ) P=0.03 Overall Survival Subgroups (108 months follow-up) Group N HR, 95% CI 15 Control Diet All ( )** Absolute difference:1% 3% 3% 3% 4% 7% months follow-up Follow-Up Time (Years) ER+, PR ( ) ER+, PR ( ) ER-, PR ( ) ER-, PR ( )*** [P=0.003] Dietary Intervention Increased Relapse-Free Survival Chlebowski RT, Blackburn GL, Thomson CA, et al J Natl Cancer Inst 2006;98:1767 Chlebowski RT, Blackburn GL, Hoy MK, et al Proc Amer Soc Clin Oncol 26; Abstract 522, 2008

12 The Women s Health Initiative (WHI) WHI is a multi-component study designed to address determinants of major chronic disease in women Clinical Trials = 68,132 DM CaD HT 48,835 27,347 36,282 Observational Study = 93,676 Total cohort = 161,808 Includes 4 clinical trials (2 Hormone Therapy, Dietary Modification, Calcium Plus Vitamin D), n=68,132 and an Observational Study, n=93,676 DM=Dietary modification; CaD=Calcium plus vitamin D; HT=Hormone therapy

13 WHI Dietary Modification Trial: Breast Cancer Incidence in 48,835 Randomized Postmenopausal Women For breast cancer mortality 27 vs 53, HR 0.77 ( ), P=.07 Incidence by Baseline Fat Intake % energy from fat (kcal) HR (95% CI) HR 0.91 ( ), P=.09 1,727 total diagnoses < (0.79, 1.20) 27.9 < (0.89, 1.30) Prentice RL, Caan B, Chlebowski RT et al. JAMA 2006;395: < (0.70, 1.03) > (0.64, 0.95) Interaction p value = 0.04 Lower breast cancer incidence with higher entry fat intake

14 High and Low Fat Dietary Intake, Recurrence, and Mortality After Breast Cancer Diagnosis 1893 early stage breast cancer patients with 349 recurrences and 372 deaths after 11.8 years Baseline (11-39 month post diagnosis, food frequency questionnaire) Those consuming larger amounts of high-fat dairy had higher breast cancer mortality (P trend = 0.05) and higher all-cause mortality (P trend < 0.001) Kroenke et al. J Natl Cancer Inst 2013 [Epub Mar 14, 2013]

15 Meta-Analysis of 76 Studies: Physical Activity and Breast Cancer Incidence in Postmenopausal Women Physical activity: Postmenopausal OR 0.75 (95% CI ) Premenopausal OR 0.80 (95% CI ) Intensity Low OR 0.82 (95% CI ) High OR 0.78 (95% CI ) Weight Loss: OR 0.81 (95% CI ) Hardefeldt, Edirmanne, Eslick. Cancer Res 2012;72 (24 suppl); S

16 Breast Cancer Outcome and Change in Physical Activity from Before to after Breast Cancer Diagnosis in WHI Cohort of Postmenopausal Women Total N (n=2776) No change/inactive (n=958) Increase/active (n=1121) Decrease/inactive (n=697) Deaths N=46 N=69 N=53 Ageadjusted HR Multivariate -adjusted ( ) 1.01 ( ) ( ) 1.06 ( ) HR=hazard ratio Adjusted for age, stage, ER, PR, grade HER2, ethnicity, WHI study arm, previous hormone therapy use, time from diagnosis to physical activity assessment, BMI, diabetes, alcohol, smoke, total calories and percentage calories from fat, and servings of fruit and vegetables. Irwin, McTiernan..Chlebowski. Cancer Prev Res 2011;4(4):522-9

17 Early Stage Breast Cancer Randomized Lifestyle Trials with Weight Loss Study Number Women s Intervention Nutrition Study (WINS) 2437 The German SUCCESS-C Study (only a subset randomized to lifestyle trial) ~ 1000 DIANA 5 (Diet and Androgens) Trial 1208 The Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA) 338 Villarinnied Tumori 2012;98:1-18 Chlebowski, Blackburn, Thompson, et al. J Natl Cancer Inst 2006;98: Andergassen Neugebauer, Salem, et al. Breast Care (Basel) 2010;5(6): Ligibel, Segal, Pond, et al. SABCS Proc 2011;P

18 Dog Ownership and Physical Activity (PA) Minutes PA, mean (SD) Dog Status Physical activity (wk) Owner Non-owner P-value Total PA (minutes) (SD) 322 (338) 267 (312) <0.001 Total walking (minutes) 150 (175) 111 (144) <0.001 Cross-sectional survey of 1800 adults 1 Odds of achieving sufficient physical activity and sufficient walking remained 57% to 72% higher among dog owners (P<0.05) after adjustment for sociodemographic neighborhood, social environment and intrapersonal factors Comparable results from survey of Cutt, Giles-Corti, Knuiman et al Am J Public Health 2008;98: Reeves, Rafferty, Miller, Lyon-Callo. J Phys Activty and Health 2011;8:436-44

19 Outline Asia vs. Western Incidence Lifestyle Factors Menopausal Hormone Therapy Chemoprevention agents Future

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21 WHI Hormone Program Design Postmenopausal women with prior hysterectomy N= 10,739 CEE (Conjugated equine estrogens) mg/d Placebo Postmenopausal women with no prior hysterectomy N= 16,608 CEE mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d Placebo

22 Estrogen Plus Progestin and Estrogen-Alone Influence on Breast Cancer in the WHI Randomized Clinical Trials Estrogen plus Progestin Placebo (in combination arm) HR (95% CI) = 1.25 (1.07, 1.46) HR (95% CI) = 0.77 (0.62, 0.95) Estrogen Alone Placebo (in estrogen alone arm) strogen plus progestin and estrogen alone have opposite effects on breast cancer incidence and breast cancer mortality Anderson, Chlebowski, Aragaki, et al. Lancet Oncology 2012 March 6 [Epub ahead of print]

23 The Estrogen-Breast Cancer Paradox in Postmenopausal Women Usually, estrogen simulates breast cellular proliferation and inhibits apoptosis After a period of estrogen deprivation - mammary tumor gene expression profile changes and estrogen then induces apoptosis - estrogen receptor sensitivity increases so even low estrogen levels stimulates tumor growth Complex, time-dependent balance of changes results many breast cancers in postmenopausal women can survive a limited range of estrogen exposure Jordan Cancer Prev Res 2011;4:633 Santen J Steriod Biochem Mol Biol 2005;95:955 Ellis JAMA 2009;302:774

24 Outline Asia vs. Western Incidence Lifestyle Factors Menopausal Hormone Therapy Chemoprevention agents Future

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26 SERMS in prevention of breast cancer: an updated meta-analysis of individual participant data Cuzick, et al. Lancet 2013;381(9880):

27 Events NSABP-P1: Benefits and Risks in Women 50 Years 120 Benefits Risks Tamoxifen Placebo Invasive BC Fractures Risks Approximate Benefits 0 Endometrial Cancer Vascular Events Fisher B et al: J Natl Cancer Inst 90:1371, 1998

28 Benefit/Risk Index for Tamoxifen and Raloxifene in Postmenopausal Women Freedman et al J Clin Oncol 29;2327, 2011 Few postmenopausal women benefit from tamoxifen use for chemoprevention

29 Prevalence of Tamoxifen Use for Breast Cancer Chemoprevention in U.S. Women National Health Interview Surveys 2000 and 2005 Year Tamoxifen use for breast cancer prevention %, 95% CI %, 95% CI In US women age years without breast cancer history, extremely low tamoxifen use for breast cancer prevention Walters et al Cancer Epid Biomarkers Prev 2010;19(2):443

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31 Exemestane: number needed to treat(nnt) is ~ 26 over 5 years Goss, Ingle, Alex-Martinez, Cheung, Chlebowski, et al. N Engl J Med 2001 June 2 [Epub]

32 The Estrogen-Breast Cancer Paradox in Postmenopausal Women Estrogen addition (as conjugated equine estrogen) reduces breast cancer incidence and Estrogen reduction (by aromatase inhibitor use) reduces breast cancer incidence

33 Serious Adverse Effects by Severity and Treatment Arm Serious toxicities Cardiovascular disease Clinical skeletal fractures Exemestane n(%) Placebo n (%) P-value 106 (4.7%) 111 (49%) (6.7%) 143 (6.4%) 0.72 Osteoporosis 37 (1.7%) 30 (1.3%) 0.39 Other malignancies 43 (1.9%) 38 (1.7%) 0.58 Therapy stopped for toxicity 351 (15.4%) 242 (10.8%) <0.01 Goss, Ingle, Alex-Martinez, Cheung, Chlebowski, et al. N Engl J Med 2001 June 2 [Epub]

34 Breast Cancer Incidence and Bisphosphonates in the WHI Cohort of 154,768 Postmenopausal Women Bisphosphonate Use Parameter Invasive breast cancer No (Rate/1000 person years) Yes (Rate/1000 person years) Incidence P Value % <0.01 ER positive % 0.02 ER negative % 0.27 Adjusted for age, ethnicity, smoking, alcohol use, physical activity, BMI, mammogram in the last 2 years, prior hormone use, total calcium, total vitamin D, 5 year hip fracture risk, and Gail 5 year breast cancer risk and stratified on WHI trial randomization arm Invasive breast cancer incidence lower in bisphosphonate users; note ER negative results Chlebowski RT, et al. J Clin Oncol. 2010;22:

35 Meta-Analysis: Metformin and Breast Cancer Incidence (2012) Study Libby Currie Bodner Bosco Rutter Chlebowski von Staa overall MFTable ES (95% CI) % Weight 0.60 ( 0.32, 1.10) ( 0.71, 1.45) ( 0.24, 0.82) ( 0.56, 1.22) ( 0.91, 0.98) ( 0.57, 0.99) ( 0.61, 1.10) Overall Q=12.20, p=0.06, I2=51% 0.83 ( 0.71, 0.97) ES 1 Chlebowski, McTiernan, Wactawski-Wende, Manson, Aragakiet al. J Clin Oncol 2012 (Epub) Col, Ochs, Springmann, Aragaki, Chlebowski. Breast Cancer Res Treat 2012 Jul 31 [Epub ahead of print]

36 Outline New Concepts Lifestyle Factors Menopausal Hormone Therapy Chemoprevention agents Future

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38 5 Models of Breast Cancer Risk Wacholder N Engl J Med 2010;362:11

39 SERM and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention James N Ingle, Mohan Liu, D. Lawrence Wickerham, et al. Cancer Discovery. doi: / cd

40 Body Mass Index and Endometrial Cancer Risk in 16,608 Postmenopausal Women in WHI E+P Trial < > 35 HR (95%) 1.0 (reference) 1.8 ( ) 3.7 ( ) 6.7 ( ) Breast cancer and endometrial cancer risk is higher in women with high endogenous estradiol levels Breast cancer is about 5 times more common than endometrial cancer In adjuvant therapy trials, AI vs. tamoxifen users had lower endometrial cancer risk (HR 0.26, p < 0.001)

41 Summary: Estrogen plus progestin increases breast cancer incidence Estrogen alone reduces breast cancer incidence Exemestane reduces breast cancer risk Lifestyle change (weight loss and increased physical activity) may influence breast cancer risk Bisphosphonate and metformin are emerging as candidates for breast cancer prevention trials Combination regimens can now be proposed with potential for higher impact on breast cancer risk Combined breast cancer and endometrial cancer prevention trial