Breast Cancer Prevention and Breast Cancer Survivorship

Transcription

1 Insights into Prevention and Survivorship February 7, 2015 Rowan T. Chlebowski, MD, PhD Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Breast Cancer Prevention and Breast Cancer Survivorship Share Many Clinical Issues 1

2 Tumor Growth Kinetic Model and Breast Cancer Chemoprevention 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] Competing Causes of Death From a Randomized Trial of Extended Adjuvant Endocrine Therapy for Breast Cancer Setting: MA.17 trial, 5170 breast cancer pts (median age 62 years) disease-free after 5 years adjuvant tamoxifen randomized to letrozole or placebo Results: After 3.9 years (median follow-up) Deaths Non-breast cancer deaths Total 256 From breast cancer 102 > 70 years = 72% From other malignancies 50 <70 years = 48% From other causes 100 Chapman et al. J Natl Cancer Inst 2008;100:

3 SERMS in prevention of breast cancer: an updated meta-analysis of individual 83,399 participant data from 9 trials HR 0.62 ( ) Cuzick, et al. Lancet 2013;381(9880):

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

5 Tamoxifen vs. Placebo for Prevention: Smoothed Annual Hazard Rate (HR) Curves for Breast Cancer 251 vs 350, HR 0.71 ( ), P<0.001 Cuzick et al, Lancet Oncology 2015 Jan Vol 16 5

6 Tamoxifen for Prevention (IBIS-1) Subgroups by Follow-up Duration Cuzick et al, Lancet Oncology 2015 Jan Vol 16 Deaths in IBIS-1 by Therapy Group Placebo (N=3575) Tamoxifen (N=3579) N OR (95% CI) Total 166 (4.6%) 187 (5.1) ( ) Breast Cancer (Total) Breast Cancer (10+ years) ( ) ( ) Endometrial cancer Cuzick et al, Lancet Oncology 2015 Jan Vol 16 6

7 IBIS-I Tamoxifen Update: Maturity Brings Questions Uncertainty with respect to breast cancer mortality Play of chance in a small sample Decrease in breast cancer with favorable prognosis (over diagnosis?) Increase in breast cancer with unfavorable prognosis Chlebowski RT, The Lancet Oncology, Published online: December 11, 2014 Contralateral Breast Cancers in Aromatase Inhibitor Adjuvant Trials ATAC Italian MA-17 Exemestane ARNO/ABCSG BIG 1-98 Combined Cuzick J et al: EBCC, Odds ratio (log scale) 7

8 Exemestane: number needed to treat(nnt) is ~ 26 over 5 years Goss, Ingle, Alex-Martinez, Cheung, Chlebowski, et al. N Engl J Med 2011;364:

9 Breast Cancer Prevention using Anastrozole in Postmenopausal Women at High Risk: First results of the International Breast cancer Intervention Study II (IBIS-II) 5.6% vs. 2.8% Incidence thru 7 Years All breast cancer: HR = 0.47 ( ), P< Cuzick et al Lancet 2014;383: Aromatase Inhibitor Side Effects in Placebo Controlled Prevention Trials MAP.3 IBIS II Athiti Arthritis AI Placebo AI Placebo > 2 Joint 7% 4% 7% 5% Stiffness Fractures 7% 6% 9% 8% Discontinuation 2 15% 11% 20% 15% Adverse Events Bisphosphonate Use 25% 24% 17% 15% Goss, Ingle, Ales-Martinez, et al. N Engl J Med 2011;364:2381 Cuzick, Sestak, Forbes, et al. Lancet 2014;383:1041 Maunsell, Chlebowski, Ingle, et al. J Clin Oncol 2014;32:1 9

10 Timing, Severity and Risk Factors for Arthralgia in the IBIS-II Trial Sestak et al. SABCS 2014 Abst PD4-1 Treatment Cessation According to Severity Sestak et al. SABCS 2014 Abst PD4-1 10

11 Summary Sestak et al. SABCS 2014 Abst PD4-1 MAP.3 Serious Adverse Effects by Severity and Treatment Serious toxicities Exemestane Placebo n P-value n(%) (%) Cardiovascular 106 (4.7%) 111 (4.9%) 0.39 disease Clinical skeletal 149 (6.7%) 143 (6.4%) 0.72 fractures Osteoporosis 37 (1.7%) 30 (1.3%) 0.39 Other malignancies Therapy stopped for toxicity 43 (1.9%) 38 (1.7%) (15.4%) 242 (10.8%) <0.01 Goss, Ingle, Alex-Martinez, Cheung, Chlebowski, et al. N Engl J Med 2001 June 2 [Epub] 11

12 Cardiotoxicity in Breast Cancer Survivors Following AI Use Cohort of 13,273 postmenopausal women with localized breast cancer from Kaiser Permanente-Southern California with electronic record DX , follow-up through 2012 Exposure (Pharmacy dispensing): tamoxifen, aromatase inhibitor, and CVD drugs 3711 CVD events in 72,889 person/years follow-up Haque, Schottinger, Shi, Chung, Avila, Amundsen, Chlebowski, et al. SABCS 2014 Abst PD4 2 CVD Outcomes by Thearpy Tamoxifen only AI only Non-user HR HR HR MI, Angina 1.00 ref 0.97 ( ) 1.02 ( ) Stroke 1.00 ref 0.97 ( ) 0.93 ( ) Other CVD 1.00 ref 1.26 ( ) 1.23 ( ) Composite CVD 1.00 ref 1.15 ( ) 1.14 ( ) Other CVD=CHF, dysrhythmia, cardiomyopathy, valvular dysfunction, pericarditis *Adjusted for CVD drugs, race, dx age, HTN, diabetes, chemo Haque, Schottinger, Shi, Chung, Avila, Amundsen, Chlebowski, et al. SABCS 2014 Abst PD4 2 12

13 Summary Risk of ischemic disease (MI or Angina) or stroke was not elevated in those who used AIs only versus TAM only While other CVD events were greater in women who used AIs, the relation to these disparate CVD outcomes (CHF, dysrhythmia, cardiomyopathy, valvular dysfunction, and pericarditis) is unclear Haque, Schottinger, Shi, Chung, Avila, Amundsen, Chlebowski, et al. SABCS 2014 Abst PD4 2 Obesity, Breast Cancer, Endometrial Cancer and Role of Estrogen Obese women (>35 BMI) are at endometrial cancer risk (HR > 6 vs BMI < 25) comparable to their breast cancer risk High endogenous estrogen associated with both breast and endometrial cancer risk Emerging results suggest aromatase inhibitors may be active against early stage endometrial cancer Chlebowski, Anderson, Sarto, et al. JNCI 2015 (in press) Zhao et al. Horm Metab Res 2014 Apr 10 (epub). Thangavelu et al. Gynecol Oncol 2013;131:

14 Endometrial Cancer Risk by Endocrine Adjuvant Therapy in Postmenopausal Women with Breast Cancer Contrast Adjusted HR* 95% CI Pr > Chi sq Tam only vs. No hormones AI only vs. No hormones AI only vs. Tam only Tam AI vs Tam only MPR>80% AI only vs. Tam only Tam AI vs Tam only * Adjusted for Kaiser Permanante Southern California cohort of 17,064 early breast cancer pts ethnicity, age, diabetes, hypertension, chemotherapy Chlebowski, Schottinger, Shi, Chung, Haque. Cancer 2015 (in press) WHI Hormone Therapy (HT)Program Design Postmenopausal women with prior hysterectomy N= 10,739 Postmenopausal women with no prior hysterectomy N= 16,608 Eligibility Age No prior breast cancer Informed consent CEE (Conjugated equine estrogen) mg/d Placebo CEE mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d Placebo Observational Study Postmenopausal women N = 93,676 Rossouw, Anderson, Prentice, et al. JAMA 2002;288: Anderson, Limacher, Assaf, et al and the Women s Health Initiative Steering Committee. JAMA 2004;291:

15 WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Overall Combined Phases) 13 year mean follow-up Manson, Chlebowski, Stefanick et al. JAMA 2013;310: U.S. HT Trends by Routes of Administration National Disease and Therapeutic Index TM (NDTI) Database, , 1800 Physicians Survey 62% 76% 32% 58% Tsai, Stefanick, Stafford. Menopause 2011;4:

16 Hormone Therapy Use, Breast Cancer Incidence in the U.S. and the WHI E+P Trial Breast Cancer Incidence by Year Breast Cancer Incidence by Year in the WHI Estrogen plus Progestin Trial Decrease in breast cancer incidence seems related to the drop in hormone therapy use 1 Increased breast cancer risk declined after E+P was discontinued and was unrelated to changes in mammography 2 Reviews irrespective of varying magnitudes of effect, data support a direct association between decreasing HR use and declining breast cancer incidence 3 Ravdin, Cronin, Houlader, Berg, Chlebowski, et al. N Engl J Med 2007;356: Chlebowski, Kuller, Prentice, et al. N Engl J Med 2009;360: Zbuk, Anand. J Epidemiol Community Health 2012;66:1-7 3 Estrogen Plus Progestin and Estrogen Alone Influence on Breast Cancer in the WHI Trials Estrogen plus Progestin Placebo (in combination arm) HR(95%CI) = 1.25(1.07, 1.46) Estrogen Alone Placebo (in estrogen alone arm) HR(95%CI) = 0.77(0.62, 0.95) Estrogen 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] 16

17 Estrogen Alone Effect on Invasive Breast Cancer Incidence by African Ancestry in Case-Only Analyses African Ancestry HR 95% CI p All 0.47 ( ) 0.04 < 79% 0.62 ( ) 79% 0.32 ( ) Results suggest estrogen alone effect modification on breast cancer risk by African ancestry, interaction p = % reduction in breast cancer incidence with estrogen alone in women with > 79% African ancestry Chlebowski, Anderson, Aragaki, Prentice Proc ASCO 2014, Abstr 1503 San Antonio Breast Cancer Symposium, December 9-13, 2014 Women s Intervention Nutrition Study (WINS) Evaluating Dietary Fat Reduction in Early Stage Breast Cancer Eligibility Criteria: Women years R Dietary intervention: reduced A fat intake Early breast cancer N (n = 975) Primary surgery ± D RTx O Systemic therapy M (ER + : I tamoxifen/chemothe Z Control rapy; ER : E (n = 1462) chemotherapy) Dietary fat intake > 20% of calories (n = 2437) Primary Endpoint: Relapse-free survival Randomization 60:40 within a year from primary surgery Accrual 1994 January, 2001 Intervention ended May 2004 Chlebowski RT, et al. J Natl Cancer Inst 2006;98:1767. This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. 17

18 San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS: Dietary Intervention Goal: Reduce dietary fat intake (target 15% calories from fat), weight loss not an intervention target Diet Group: women given a fat gram goal by centrally trained, registered dieticians i implementing a low fat eating plan 1, 2 Eight bi-weekly individual counseling sessions and subsequent contacts every 3 months Monthly group sessions Self-monitoring of fat gram intake, unannounced telephone calls Control Group: women had dietician contacts every three months 1 Chlebowski, Rose, Buzzard, et al Breast Cancer Res Treat 20:73-84, Winters, Mitchell, Smiciklas-Wright, et al J Am Diet Assoc, 104:551-9, 2004 This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium, December 9-13, 2014 Change in BMI and Weight by Randomization Group Diet Minus Control Group Variable Year 1 Year 3 Year 5 BMI (kg/m 2 ) (-1.3 to -0.3) Weight (LBS) -5.0 (-8.0 to -2.1) All values, P <.005 versus control Reduced weight and BMI in Diet Group (-1.3 to -0.2) -3.9 (-6.9 to -0.5) -1.1 (-1.9 to -0.4) -6.0 (-9.9 to -1.9) BMI = Body Mass Index All values for weight, P =.005, intervention versus control Information on weight and BMI was available for all 975 and 1462 women in the dietary intervention group and the control group, respectively, at baseline; for 854 and 1310 at year 1; 698 and 1044 at year 3; and 386 and 998 at year 5. Chlebowski RT, et al. J Natl Cancer Inst 2006;98:1767. This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. 18

19 PATIENTS (%) Control Diet San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS Previously Reported Clinical Outcomes Relapse-Free Survival* (60 months follow-up) HR % CI * Absolute difference:1% 3% 3% 3% 4% 7% Overall Survival Subgroups (108 months follow-up) Group HR, 95% CI P-value All ER+, PR+ ER-, PR- Follow-Up Time (Years) *p=0.03, from adjusted Cox proportional hazard model 0.82 ( ) 0.90 ( ) 0.36 ( ) NS Funding and intervention ended in May Follow-up through 2013 (death registry), 19.4 year maximum 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 This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium, December 9-13, 2014 Death Rate by Randomization Group Number Deaths Percent Control: % Diet: % Lower death rate in Diet Group Hazard ratios (HRs) are reported from Cox proportional hazards models and depicted in Kaplan Meier plots This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. 19

20 San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS Survival for All by Randomization Groups N = 2437 HR 0.94 ( ) NS Product-Limit Survival Estimates With Number of Subjects at Risk and 95% Hall-Wellner Bands This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS Survival (ER negative) by Group N=748 65% 90% Median Survival 11.7 yrs ( ) vs. 13.6yrs ( ) HR 0.64 ( ) P = Product-Limit Survival Estimates With Number of Subjects at Risk and 95% Hall-Wellner Bands This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. 20

21 San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS Survival (ER and PR negative) by Group N=362 92% 65% Median Survival 11.7 yrs ( ) vs yrs ( ) HR 0.46 ( ) P = Product-Limit Survival Estimates With Number of Subjects at Risk and 95% Hall-Wellner Bands This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium, December 9-13, 2014 Cumulative Hazard Ratio for Death by Randomization Group Through Follow-up Years ER Negative and PR Negative Years HR (95% CI) p-value ( ) ( ) ( ) ( ) ( ) ( ) Per SEER, 73% anticipated to be triple negative Howlader et al. J Natl Cancer Inst 2014 Apr 28;106(5). pii: dju055. doi: /jnci/dju055. This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. 21

22 San Antonio Breast Cancer Symposium, December 9-13, 2014 WINS Conclusions A lifestyle intervention targeting fat intake reduction associated with weight loss did not significantly increase overall survival of women with resected breast cancer receiving conventional cancer management. Exploratory analyses suggest favorable lifestyle influence on survival in hormone receptor negative subgroups and during active intervention. Given emerging evidence, future lifestyle interventions should best target weight loss/maintenance and increased physical activity. This presentation is the intellectual property of the author/presenter. Contact them at rowanchlebowski@gmail.com for permission to reprint and/or distribute. Effect of Obesity on Survival of Women with Breast Cancer: Systematic Review and Meta-Analysis 43 studies, 1963 to 2005 enrollment Both treatment and cohort Median follow-up > 4 years Category HR 95% CI Overall survival 1.33 ( ) Breast cancer specific 1.33 (1.21, 1.47) survival Premenopausal 1.47 ( ) Postmenopausal 1.22 ( ) Only one study adjusted for diabetes Protani, Coory, Martin, et al. Breast Cancer Res Treat 2010;123(3):

23 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/inactiv Increase/activ e (n=1121) Decrease/inactive (n=697) e (n=958) Deaths N=46 N=69 N=53 Ageadjusted HR ( ) 1.01 ( ) Multivariate ( ) 1.06 ( ) -adjusted 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 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 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:

24 TEXT and SOFT Designs Presented By Olivia Pagani at 2014 ASCO Annual Meeting ABCSG-12 Design: AI vs. Tamoxifen Addition to Ovarian Suppression Eligibility Criteria Premenopausal women Stage I or II ER+/PR+ breast cancer Prior primary surgery (N=1803) Goserelin 3.6 mg q28d Primary endpoint: DFS Secondary endpoints: RFS and OS R A N D O M I Z E D Tamoxifen 20 mg qd N=451 Tamoxifen 20 mg qd Zoledronic acid 4 mg q6m N=449 Anastrozole 1 mg qd N=453 Anastrozole 1 mg qd Zoledronic acid 4 mg q6m N=450 DFS=disease-free survival; RFS relapse-free survival. Gnant. N Engl J Med. 2009;360:

25 AI vs. Tamoxifen addition to Ovarian Suppression and Overall Survival in Early Stage, ER+, Breast Cancer HR 95% CI p value Duration Tx n (total) ABCSG yrs 1803 TEXT/SOFT yrs 4690 There is no information available on the long term efficacy of ovarian suppression agents to establish/maintain low estrogen levels Gnant et al. Lancet Oncol 2011;12: Pagani et al. N Engl J Med June 1, online Tibolone in Localized Breast Cancer Patients with Vasomotor Symptoms: a double-blind, randomized trial non-inferiority trial HR 1.40 ( ) P= women with localized breast cancer with vasomotor symptoms randomized to tibolone 2.5 mg/d or placebo Kenemans, et al. Lancet Oncology 2009;10:

26 Hazard Ratio for Breast Cancer Recurrence (Tibolone vs Placebo) Aromatase inhibitor HR (95% CI) None 1.38 ( ) Recent 2.42 ( ) GnRH analogues None, ever 1.40 ( ) Recent 2.29 ( ) Kenemans, et al. Lancet Oncology 2009;10: Meta-Analysis: Metformin and Breast Cancer Incidence 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] 26

27 Summary Estrogen plus progestin increases breast cancer incidence Estrogen alone reduces breast cancer incidence Aromatase inhibitors reduce breast cancer risk, may influence endometrial cancer Lifestyle change (weight loss and increased physical activity) may influence breast cancer risk Metformin emerging as candidates for breast cancer prevention trials Combination regimens can now be proposed with potential for higher impact on breast cancer risk 27