Breast Cancer Prevention for the Population at Large Jack Cuzick Centre for Cancer Prevention Wolfson Institute of Preventive Medicine St Bartholomew s Medical School Queen Mary University of London London, United Kingdom
Lymphoma 15 700 5200 Brain/CNS 11 000 5200 Bladder 10 000 5400 Pancreas 9600 8800 Endometrial 9300 2200 Oesophageal 8900 7800 Leukaemia 9500 4600 Ovary 7400 4100 Stomach 6700 4600 Liver 5600 5100 Major Cancers UK 2014 Incidence Mortality Lung 46 400 36 900 Breast 55 200 11 400 Colorectal 41 300 15 900 Prostate 46 700 11 300
Two approaches to cancer prevention Simple minimally toxic interventions for all Focussed interventions on high risk groups
Relative Risk Whole Population 25% reduction in risk 5 3 1 0.75 0 0 20 40 60 80 100 Population Percentile
Strategies for Breast Cancer Prevention Life style changes Weight control avoiding obesity Increased physical activity Reduced alcohol consumption Identifying those at highest risk Better Risk Assessment Identifying Precursor Lesions & Biomarkers Identifying suitable preventive agents Repurposing Existing Drugs Progressing Evaluation of New Agents
Relative Risks of different cancers by BMI Gallbladder Gastric cardia Pancreas Oesophagus Renal Endometrial 25-29.9 30 + Breast (PM) CRC (women) CRC (men) 0 1 2 3 4 Calle & Kaaks, 2004
Weight loss reduces breast cancer incidence Cohort studies Population Weight loss RR Harvie et al 2005 34,000 postmenopausal women >5% ~3.5 kg 0.61 (0.46 0.80) Eliassen et al 2006 87,000 postmenopausal women >10kg ~ 15% 0.43 (0.25 0.86) Prentice et al, 2006 48,835 postmenopausal women 2 kg ~3% 0.91 (0.83 1.01) Teras et al, 2011 13,055 overweight & obese postmenopausal women >5 kg ~7% 0.78 (0.55 1.10) Bariatric surgery
Aspirin low dose ( 100mg/day) for 10 years between ages 50-70y
Aspirin: Benefit-Harm Analysis Relative Risks Event Incidence Mortality Colorectal cancer 0.65 0.60 Oesophageal cancer 0.70 0.50 Gastric cancer 0.70 0.65 Lung cancer 0.95 0.85 Prostate cancer 0.90 0.85 Breast cancer 0.90 0.95 Myocardial infarction 0.82 0.95 Stroke 0.95 1.21 Major bleeding 1.54 - GI bleeding - 1.60 Peptic Ulcer - 1.60 Cuzick et al Ann Oncology 2015
Estimated Impact of Aspirin on Cancer 7-10% 9-13%
Global Incidence of Breast, Colorectal, Lung and Cervix Cancer 1975-2012 (Female) Globocan 2012
Relative Risk Small Proportion at High Risk 25% reduction in risk 45% 5 3 42% 2 1.75 1 0.5 0 0 20 40 60 80 90 100 Population Percentile
Preventive Therapy Key Ingredients Identification of High-risk women Effective minimally -toxic prophylaxis
Better Risk Assessment
Some Breast Cancer Risk Models Gail (BCRAT) BCSC with BI-RADs density (Tice et al) BOADICEA Tyrer-Cuzick (IBIS) www.ems-trials.org/riskevaluator
Risk factors in TC model V7 Age Height Menarche Age first child Age Menopause BMI HRT Family History BRCA testing Proliferative benign breast disease Atypical Hyperplasia LCIS
New developments V8 Age Lifestyle Height Menarche Age first child Age Menopause BREAST DENSITY BMI HRT Cysts (aspirated) Family History BRCA testing SNPs Proliferative benign breast disease Atypical Hyperplasia LCIS
Tyrer Cuzick Version 8
Displaying the Risks
Approaches to risk assessment Family history/genetics clinics Needs prior referral Risk assessment by GPs Lack of time and knowledge Risk assessment as part of breast screening Done at first screen age 45-50y Identify high women suitable for preventive therapy Determie risk adapted screening intervals
Approaches to Preventive Therapy for Breast Cancer SERMs Tamoxifen Raloxifene Lasofoxifene bbbbarzoxifene
IBIS-I study design High Risk Women (N=7,154) Tamoxifen (N=3579) Placebo (N=3575) Median follow-up 16.0 years 5 years Endpoints: Primary: Breast cancer incidence (incl. DCIS) Secondary: Other cancers, BC mortality, all cause mortality, adverse events
Cumulative incidence (%) 0 2 4 6 8 10 12 14 IBIS-I Cumulative incidence for all breast cancer T vs. P HR (95% CI) All 163 vs 226 0.72 (0.59-0.88) Invasive ER+ 100 vs 145 0.68 (0.53-0.88) Placebo Tamoxifen 6.3% 4.6% NNT = 59 0 2 4 6 8 10 12 14 16 18 20 Number at risk Placebo Tamoxifen Follow-up time (years) 3575 3527 3474 3410 3358 3296 3239 2850 1901 725 165 3579 3542 3495 3446 3385 3344 3293 2890 1918 748 168
Cumulative incidence (%) 0 2 4 6 8 10 12 14 IBIS-I Cumulative incidence for all breast cancer T vs. P HR (95% CI) T vs. P HR (95% CI) All 163 vs 226 0.72 (0.59-0.88) All 88 vs 124 0.70 (0.53-0.91) Invasive ER+ 100 vs 145 0.68 (0.53-0.88) Invasive ER+ 60 vs 93 0.63 (0.45-0.87) Placebo Tamoxifen 6.3% 6.3% 4.6% 3.3% 0 2 4 6 8 10 12 14 16 18 20 Number at risk Placebo Tamoxifen Follow-up time (years) 3575 3527 3474 3410 3358 3296 3239 2850 1901 725 165 3579 3542 3495 3446 3385 3344 3293 2890 1918 748 168
Cumulative incidence (%) 0 2 4 6 8 10 12 14 IBIS-I Cumulative incidence for all breast cancer T vs. P HR (95% CI) All 251 vs 350 0.71 (0.60-0.83) 12.3% Invasive ER+ 160 vs 238 0.66 (0.54-0.81) Placebo Tamoxifen NNT = 22 7.8% 0 2 4 6 8 10 12 14 16 18 20 Number at risk Placebo Tamoxifen Follow-up time (years) 3575 3527 3474 3410 3358 3296 3239 2850 1901 725 165 3579 3542 3495 3446 3385 3344 3293 2890 1918 748 168
ALL INVASIVE BREAST CANCERS, 0-10y SERM vs. placebo Tamoxifen vs. placebo Italian Lasofoxifene vs. placebo PEARL 0.25 mg PEARL 0.50 mg Combined NSABP P1 IBIS-I Marsden Raloxifene vs. placebo MORE/CORE RUTH STAR Arzoxifene vs. placebo.1.2.5 1 2 5 10 Hazard ratio Fixed-effect model: -36.2% [-43.0%;-28.7%], p<0.001
All ER+ Invasive breast cancers, 0-10y Tamoxifen vs. placebo Italian NSABP P1 IBIS-I Marsden Raloxifene vs. placebo MORE/CORE RUTH STAR Lasofoxifene vs. placebo PEARL 0.25 mg PEARL 0.50 mg SERM vs. placebo Arzoxifene vs. placebo Combined.1.2.5 1 2 5 10 Hazard ratio Fixed-effect model: -49.5% [-56.1%;-41.8%], p<0.001
All ER-neg Invasive breast cancers, 0-10y SERM vs. placebo Tamoxifen vs. placebo Italian NSABP P1 IBIS-I Marsden Raloxifene vs. placebo MORE/CORE RUTH STAR Lasofoxifene vs. placebo Arzoxifene vs. placebo Combined.1.2.5 1 2 5 10 Hazard ratio Fixed-effect model: +20.5% [-2.3%;48.6%], p=0.08
Approaches to Preventive Therapy for Breast Cancer Aromatase Inhibitors Anastrozole Letrozole Exemestane
MAP3 - Cumulative Incidence of Invasive Breast Cancer Goss et al NEJM, 2011
IBIS2 - Trial schema Postmenopausal women: Ages 40-70 Increased risk of breast cancer: Family history Atypia / LCIS Breast density No HRT Anastrozole 1 mg/day (N=1920) N=3864 5 years Matching placebo (N=1944) FU Ongoing Baseline 6 M 12 M 24 M 36 M 48 M 60M Clinic visit X X X X X X X Mammogram X X X Blood X X X DXA X
Cumulative incidence (%) IBIS-II Breast Cancer Incidence All breast cancer: HR=0.47 (0.32-0.68), P<0.0001 5 5.6% 2.8% 0 0 1 2 3 4 5 6 7 Number at risk Follow-up time [years] Placebo 1944 1927 1645 1445 1241 975 706 506 Anastrozole 1920 1909 1654 1463 1264 978 720 516 Placebo Anastrozole Cuzick et al Lancet 2014
Conclusions 5 years of tamoxifen produces a very long term 30% reduction of breast cancer Aromatase inhibitors are more effective (>50% reduction) and less toxic ( no endometrial cancer or thromboembolic complications), but only suitable for postmenopausal women Further work needed to explore new preventive treatments for premenopausal women and oestrogen receptor negative disease