Risk Assessment and Reduction

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1 Risk Assessment and Reduction Carol J. Fabian, M.D. Breast Cancer Prevention Program University of Kansas Medical Center Kansas City, KS School of Breast Oncology Atlanta, GA 2013

2 Outline Major and Minor Risk Factors Risk Models and Counseling Biomarkers for Risk Stratification Standard Risk Reduction Strategies Interventions Under Study

3 Risk Factors

4 Major Risk Factors Increase Risk >2 fold Minor Risk Factors Up to 2 Fold Major (>2 fold increase) Minor (>1<2 fold) Mutations associated hereditary cancer 1 st degree < age 60 Chest radiation <30 Pre-cancer (DCIS LCIS, AH) Prior breast or Ovarian Cancer Age >60 Early menarche Nullparity/ Late childbirth No lactation Late menopause 2 nd & 3 rd degree relatives Serum Sex Hormones/SHGB 5 years combined E+ P HRT Obesity Inactivity Serum Insulin/Growth Factors Alcohol

5 Variable Risk with Hormone Replacement

6 Breast Cancer Risk Hormone & Replacement 1. If oophorectomy no excess risk to age After 50 E+P HRT > Risk than E alone 2. E+ Progestins > Risk E+ Natural Progesterone 3. Risk Higher in Lean women 4. Risk Higher if start first 5-10 yrs after Menopause WHI no risk E alone vs inc Million Women 5. Excess risk dissipates within few years of stopping 6. No excess risk vaginal hormones Minimal Excess Risk to Age 60

What about HRT High Risk Women Who Undergo Oophorectomy < Age 45 ERT or combined HRT does not attenuate reduction in breast cancer risk in premenopausal women from

7 What about HRT High Risk Women Who Undergo Oophorectomy < Age 45 ERT or combined HRT does not attenuate reduction in breast cancer risk in premenopausal women from hereditary breast cancer families undergoing oophorectomy. ERT/ HRT reduces risk of premature CVD oophorectomy < 45 Rebbeck JCO 2005; 23:7804 Domchek et al ASCO 2011 Abstract 1501

HRT Reduces Premature CVD Risk from Early

HRT to age 45-50 reduces excess CVD risk Nelson

8 HRT Reduces Premature CVD Risk from Early Surgical Menopause (<45 ) Oophorectomy : 2 X increase CV death 2X Increase Parkinson s CVD risk? higher BRCA1 mutation carriers. HRT to age reduces excess CVD risk Nelson JAMA 2004;291:1610 Rivera 2009, Rocca 2007, Singh J Thoracic, CV Surg 2013

9 Risk Models and Counseling

10 Risk Assessment and Prevention Consultation Estimate long and short term risk of breast cancer Need for genetic testing Suggest surveillance based on risk Discuss benefits and side effects standard prevention approaches Discuss clinical trials

11 Gail Model (II) Considers Current age Age at menarche Age at first live birth Number of 1st degree relatives Number of biopsies Presence of Atypical Hyperplasia Race Good calibration and Validated in Screening Populations, but discriminatory accuracy is suboptimal ( C statistic ~.63) Rockhill JNCI 93:358, 2001 Tice Breast Cancer Res Treat 94:115, 2005 Gail et al. JNCI 81:1879, 1989, Costantino et al JNCI 91: 1541, 1999.

12 Problems with the Gail Model Cannot use to estimate risk women < age 35 Cannot use if woman has LCIS Does not consider 2 nd or 3 rd degree relatives Underestimates risk if + Paternal FH. Does not estimate risk of BRCA1/2 mutation Does not consider age at diagnosis. Does not consider ovarian cancer Does not consider BMI, age at menopause. Does not take into account preventive Rx

13 Tyrer Cuzick Model IBIS Risk Evaluator Tool

14 Tyrer Cuzick (IBIS) Pros and Cons Pros Estimates Risk if < 35 Estimates risk of BRCA1/2 Considers Factors Gail II Does Not. LCIS Height and Weight 2 nd and some 3 rd degree relatives Age of relatives diagnosis HRT use Ovarian Ca & Oophorectomy Age at menopause Cons Overestimates risk if patient has a dx of Atypical hyperplasia or LCIS and a + FH Does not take into account alcohol, physical activity Does not take into account SERM or AI use Tyrer et al Stat Med ; 23 : 1111 Boughey J CO 2010;28: 3591

15 Printout for Patient

16 We Still Have a Way to Go in the Area of Risk Prediction

17 Adding Biomarkers for Better Risk Prediction Breast Density RR=1 RR 4-5X SNPs and Germline Mutations

19 Cumulative Frequency, Percent RPFNA Atypia Increases Relative Risk of Breast Cancer by 5-Fold FNA Atypia (N=102) P< Total High Risk Cohort (N=480) 0 No FNA Atypia (N=378) Time from Entry on Study, months Fabian et al. J Natl Cancer Inst 92:1217, 2000.

20 Risk Reduction: Standard Approaches

21 Type of Prevention Intervention Should Vary With Risk Level 1) Prophylactic Surgery: Very High Risk 2) Anti-Hormones: High Risk 3) Lifestyle: Average to Moderate Risk

22 Surgical Risk Reduction Strategies For Very High Risk Women (BRCA1/2) Oophorectomy < age 45 risk by 50-70% even when women are given add back HRT Mastectomy ( risk by ~90%) Cost effective and likely to provide survival advantage Rebbeck et al. NEJM 346:1616, 2002; JCO 23:7804, 2005 Hartmann et al. NEJM 340:77, Warner et al J Clin Oncol. 2011;29: Grann et al Breast Cancer Res Treat :837

23 Decision Tool For BRCA1 and 2 Carriers Determines risk of development of breast cancer and ovarian cancer and death from those cancers by choice and timing of Breast imaging Mammography Breast MRI Prophylactic Oophorectomy Prophylactic Mastectomy Kurian JCO 2012;30:497

24 Relative Risk Reduction in Randomized Trials in Which Eligibility: 5 yr Gail Risk >1.6 or AH or LCIS Pre-menopausal Women (age 35 and over) Tamoxifen ( 50%) Postmenopausal Women Raloxifene (40%),Tamoxifen (50%),Exemestane (65%) Reduction after: AH 85%, LCIS 66%, DCIS ~ 40% Reduction ER+ but not ER- Cancer No Survival Advantage Fisher J NCI 1998; 90: 1371 Fisher Lancet. 1999;353:1993 Vogel Cancer Prev Res :681 Cuzick Lancet 2003; 361:296 Goss NEJM :2381

25 Meta Analysis SERMs for Prevention Individual patient data meta analysis suggest 38% reduction risk for breast cancer (Tamoxifen 33%) SERMs no effect on CV disease Continued effect 5-10 years Only reduces ER+ Cuzick et al Lancet 2013

26 Side Effects Of Preventive Agents Tamoxifen Hot Flashes, Vaginal Discharge Uterine surgery & cancer DVT, PE, Cataracts Raloxifene Hot Flashes, Vaginal Dryness DVT, PE Fisher J Natl Cancer Inst 90:1371,1998 Cuzick. Lancet 361:296, 2003 Vogel JAMA 295:2727,2006 Exemestane Hot Flashes Vaginal Dryness Joint & Muscle pain Bone Density Loss Fatigue Goss NEJM :2381

Decreases Bone Density Not Used Prevention < age 35 Very Little: Few BRCA

27 What Do We Know About Tamoxifen in Young Women BRCA Mutation Carriers 70% BRCA2 ER+ 30% BRCA1 ER+ Increases Ovarian Cysts Increases Estrogen Levels Decreases Bone Density Not Used Prevention < age 35 Very Little: Few BRCA mutation carriers in Primary Prevention trials Reduces contralateral ca adjuvant

28 Although Tamoxifen > Efficacy Than Raloxifene in the STAR Trial Raloxifene Often Drug of Choice in Postmenopausal Women With A Uterus Because of Fewer Side Effects. Tool Available to Help Define Benefits Freedman et al JCO 2011; 29: 2327

29 Tamoxifen or Raloxifene Contraindicated if Prior Deep Venous Thrombosis Prior Stroke Inherited Clotting Disorder

30 ASCO Guidelines Risk Reduction Counseling Update 2013 Tamoxifen should be discussed with a premenopausal or postmenopausal woman at increased risk for Breast Cancer with a 5 year Gail model or equivalent risk of >1.66 %. Do not monitor with pelvic sonos. Raloxifene or exemestane should be discussed in a postmenopausal woman with a 5 year Gail model or equivalent risk of >1.66 %. < 5% of risk eligible take any of the above Visvanathan et al JCO 2013

31 Hot Flash Free Interventions Under Study Weight Loss Metformin ASA Lignans Omega-3 FA Vitamin D Letrozole for Women on HRT Curcumin Polyphenols

32 How Much Does Weight Loss Does it take to Reduce Breast Cancer Risk? Don t Know NHBL goal 10% general health although 5 % may benefit. Bariatric Surgery 20-30% loss reduces risk Does 5-10 % loss (usual with behavioral wt loss) reduce risk? Observational studies suggest 10% if maintained Sjostrom Lancet Oncol 2009 Teras Cancer Causes Control 2011, Byers Diabetes Obes Metab 2011 Sjostrom Arch Intern Med 1998

33 Phase II Prevention Trials With Tissue Biomarkers as Primary Endpoint Atypia No Atypia Intervention vs Placebo Ki- 67 >2% Ki-67<1%

Obesity Leads to Infiltration with macrophages Less adiponectin, more leptin Insulin Resistance More cytokines and inflammatory cell infiltration : TNF alpha, IL6, PAI1, HGF Activation mtor Survival

34 Obesity Leads to Infiltration with macrophages Less adiponectin, more leptin Insulin Resistance More cytokines and inflammatory cell infiltration : TNF alpha, IL6, PAI1, HGF Activation mtor Survival Path motility, angiogenesis, apoptosis Elevated free hormones via aromatase & SHBG Increased Activation of Estrogen Receptor Crown Structures Khandskar Nat Ca Rev 2011, Subbaramaiah Cancer Prev Res 2011

35 Phase II Weight Loss Pilot Trial Design Supported by NCI R21 High Risk Women BMI >25 Kg/m 2 No HRT N=24 Screen for Serum and Tissue Risk Biomarkers RPFNA 6 Months Intervention Tissue Changes Decrease estrogen signaling ( ps2) Decrease tissue proliferation; Ki-67, Cyclin B1 Decrease mtor signaling (S6K) Increase Adiponectin: leptin ratio Fabian Breast Cancer Res Treat 2013 Median 11% Weight Loss Repeat Biomarkers RPFNA

36 Relative Difference, percent Biomarker Change Greater with >10% Weight Loss Adiponectin: Leptin Ratio * * * <10% BW Loss >10% BW Loss Significant change within group Adiponectin * * Leptin * IGF1:IGFBP3 Leptin Ratio * ** * * * * Insulin CRP HGF PAI-1 SHBG * Free E2 & Test -200

37 Reinforces Goal of 10% Loss for Cancer Risk Reduction Expense of Definitive Phase III Primary Prevention Trial May Prevent Ever Being Done

38 Key Components of Successful Behavioral Weight Loss Interventions Goal 10% Loss over 6 months Portion Control with Calorie Restriction Behavioral Modification Exercise Maintenance Encouragement by Physician

39 Metformin Reduces Insulin Resistance and is Associated with Modest Weight Loss Metformin Reduced Breast Cancer risk type II Diabetes ~ 5 % weight loss in diabetics, insulin resistance Being studied in adjuvant setting. Reduces Insulin and mtor Signaling

40 Biomarker Trial Metformin Only Effective in Women with Insulin Resistance 200 T1 3a Invasive BC Core Needle Biopsy R A N D O M I Z E Metformin 850 mg po daily for 3 and bid X 25 days Placebo daily for 3 and bid X 25 days S U R G E R Y Primary Outcome: Secondary Outcome: Change in Cancer/ADH Ki-67 Change in Ki-67 by HOMA Ki-67 No Change Overall Ki67 Lower HOMA>2.8 Higher HOMA<2.8 DeCensi et al Abstract # 519, Bonanni et al JCO 2012

41 Cohort Studies with ASA Suggest Benefit but not Randomized Trial Aspirin Iowa and Minnesota Cohort ( 26,000) 20-30% reduction regular use WHI observational same in higher risk women if dose >100 mg Randomized WHI 100 mg qod negative Bardia 2011, Harris 2003, Cook 2005

Enterolactone Enterodiol Buffer effects of ER alpha Flaxseed Most

42 Lignans Function as Natural Selective Estrogen Receptor Modulators Plant Lignan Secoisolariciresinol (SDG) Mammalian Lignans SDG Gut Bacteria Enterolactone Enterodiol Buffer effects of ER alpha Flaxseed Most Concentrated Source of SDG (100x other plants) Used in Canada to treat cylic mastalgia

12 Month Pilot Study in Premenopausal Women High Risk Women Low or undetectable baseline lignan levels with 10 fold increase at 6,12 mos Minimal to no side effects.

43 12 Month Pilot Study in Premenopausal Women High Risk Women Low or undetectable baseline lignan levels with 10 fold increase at 6,12 mos Minimal to no side effects. Decrease in Ki-67 over 12 months in majority. Significant decrease in proportion of women with Atypia Placebo Controlled multicenter trial ongoing Pre-Study Change Ki-67 Ki67 p=.0001 P<.0001 Post-Study Fabian et al. Cancer Prevention Res 2010

44 Omega-3 Fatty Acids Replace Pro-inflammatory Omega 6 Fatty Acids in Cell Membranes Being Studied Phase II mg EPA + DHA/day recommended for heart health Animal and correlative studies reduced breast cancer risk but probably at higher doses ( ~3.5 grams) Brasky Ca Epi Biomarkers Prev 2010; 19:1696.

45 Incidence of Atypia, percent 6 Months of DHA + EPA 3.4 g/d Improved Cytomorphology & Proliferation Premenopausal Reduction in % with RPFNA Atypia N=34 77% p= % Reduction in Follicular Phase Ki-67 (%) Ki-67 % N= P=.021 p= Pre-Study Post-Study 0 Pre-omega Pre-Study Post- Post-Study omega Pre-omega Post- omega Favorably modulated proteins associated with MAPK, PI3K, mtor Fabian et al Abstract 1515 ASCO 2013

46 Sun Vitamin D: Important Autocrine Role in Breast Homeostasis Vitamin D Sequestered in FAT Liver Prohormone 25(OH)D Breast 1-α hydroxylase Active hormone 1,25(OH) 2 D Ca++ transport-lactation, Buffers Action Hormones Growth Factors

47 Phase III Studies of Vitamin D for Prevention in Postmenopausal Women Study Type Prevention Menopause Status Vitamin D 3 Dose/day WHI negative Primary Post 400 IU (+ Calcium 1000) Lappe Positive Vital Ongoing Primary Post 1000 IU (+ Calcium 1000) Primary Post > IU + 1gm Omega-3 FA Chlebowski JNCI 2008; 100:1581, Lappe Am J Clin Nutr 2007; 85:1586, Chlebowski JNCI 2008; 100:1581, Lappe Am J Clin Nutr 2007; 85:1586

48 Optimal 25OH D Levels for Breast Health may be Higher than the 32 ng/ml for Bone 50% reduction at 52 ng/ml vs 6ng/ml Quintile Median Values Modified from Garland et al. Steroid Biochem Molec Biol, 2007.

49 Future Prevention: Personalized Medicine Risk and Biology Based Recommendations Biomarkers: Risk, Type of Intervention Likely to Work and Response Increased Emphasis on Healthy behaviors and Natural Products Save Strong Antihormonal agents for Higher Risk

50 END

51 The Million Women Study, Lancet 2003, J NCI 2011, E3N Fournier 2008 Nurses Health Study NEJM 1997, WHI Health Consequences HRT after 50 Large Cohort Studies (50s) Breast Cancer Risk Estrogen Alone; up to 30% relative increase at 10 yrs Estrogen + Progestin; up to 2X relative increase at 10 yrs Higher in lean women and 1 st 5 years after menopause Excess gone after stop 4 years Cardiovascular Risk 20-30% decrease CV deaths ERT starting 40s-50s WHI Randomized Trial (60s) Breast Cancer Risk Estrogen ( CEE) alone no increase /decrease risk 8 years Estrogen + Progestin ~ 25% increase in risk at 5 years Risk higher in women starting within first 10 yrs of menopause Excess gone after stop 2-3 years Cardiovascular Risk Decrease CV ERT starting in 50s. Increased CV events starting oral E or E+P HRT in 60s

Excess Breast Ca Risk with HRT for Woman in her 50s Woman in her 60s WHI: None if ERT or 5yrs E+P HRT and no prior E+P HRT. No increase CV events Million Women: ERT 1.

52 Excess Breast Ca Risk with HRT for Woman in her 50s Woman in her 60s WHI: None if ERT or 5yrs E+P HRT and no prior E+P HRT. No increase CV events Million Women: ERT 1.5 extra breast ca/ extra breast ca /1000 women 5 yrs E+P HRT WHI: None if 8 yrs ERT but increase if 5 yrs E+P Increase CV events Million Women: ERT1.5 extra breast ca/ extra breast ca/1000 women 5 yrs E+P HRT.

53 Low Dose Vaginal Hormones No Increased Risk for Breast Cancer Testosterone 1-2 % + Estriol 2 mg every other day. Estrogen rings, creams or inserts Beral Million Women Study Lancet 2003

54 Breast Cancer and Health Risks in Average Risk Women Starting HRT after 50

55 Transdermal Estradiol less CV risk than Cardiovascular Less risk probable with transdermal formulations because less likely than oral to cause blood clots. Breast Cancer Oral CEE alone no increased risk WHI. Transdermal estradiol ~ 30 % excess 10 yrs continuous use in Million Women study. Oral CEE? Fournier Breast Ca Res & Treat 2008; 107: 103, Beral Million Women Study

Relative Risk Associated with FH (Compared to those without FH) By Age 1 st degree relative @ DX Under 40: tripling of

56 Relative Risk Associated with FH (Compared to those without FH) By Age 1 st degree DX Under 40: tripling of relative risk 40-50: doubling of relative risk 50-65: increase by 1.5 (50%) > 65: little increase Cuzick Breast Cancer 2008; 10 :S13

57 Minor Risk Lifestyle Factors : < 2 Fold Relative Risk but Important For Population Risk Alcohol: Increase relative risk (RR) by 10%/drink/day Estrogen +Progestin Replacement therapy: Increase in RR by 5% per yr of current use (1.25 after five years) Estrogen Alone Replacement Therapy 0-2% increase in RR per year of current use Postmenopausal Obesity:30% increase in RR BMI >30 vs BMI < 25 kg/m 2 Sedentary Lifestyle:25-30% increase in RR no exercise vs 3 hours per week.

58 Major Factors Absolute & Relative Risk Per Year BRCA 1/2 > 30 DCIS Breast XRT<30 LCIS AH + Family HX AH Prior Inv Cancer Age > 60 (vs 30) 2% 2% 2% 1% 1% 0.5% 0.75% 0.33% 20 x 20x 20x 10x 8-10x 4-5x 5-8x 10x

Natural Progesterone with Estradiol (E2) May Be Less Risky than Progestins + E2 Estrogen and Progestins > breast tissue proliferation than estrogen + natural progesterone.

59 Natural Progesterone with Estradiol (E2) May Be Less Risky than Progestins + E2 Estrogen and Progestins > breast tissue proliferation than estrogen + natural progesterone. Baseline Transdermal E2 + MPA French Cohort Study: estradiol + natural progesterone did not increase risk of breast cancer Baseline Transdermal E2 + Progesterone Murkes Fertility and Sterility : Fournier Breast Ca Res & Treat 2008; 107: 103

Ongoing Lignan Randomized Phase II Clinical Trial Integrated with Phase II-III Animal

Breast Tissue/Blood 1. Response: Ki-67, cytomorphology 2.

60 Ongoing Lignan Randomized Phase II Clinical Trial Integrated with Phase II-III Animal Trial Fabian, MD Premenopausal Women SDG 50 mg/d or Placebo 1 yr Biomarkers in Benign Breast Tissue/Blood 1. Response: Ki-67, cytomorphology 2. Mechanism: qrtpcr estrogen response genes, Proteomics: activated MAPK, mtor, Cytokines 3. Follicular reserve Petroff, DVM, PhD Hursting, PhD ER+ Rat/Ovarian SDG or Placebo ER- WNT transgenic mouse Change in Biomarkers 3 mos Cancer Incidence Komen for the Cure Promise Grant KG101039

Less than 5 % of Risk Eligible Women Take Tamoxifen for Primary Prevention Perceived education problem Those with the most counseling least likely

61 Less than 5 % of Risk Eligible Women Take Tamoxifen for Primary Prevention Perceived education problem Those with the most counseling least likely to take. Concerns: QOL/ side effects Since no survival advantage still very much a patient choice. Waters CEBP 2010 ; Ropka JCO 2010; 28: 3090

62 Phase II Prevention Trials To Test for Risk Biomarker Effect Screen for Risk Biomarker to be Primary Endpoint for trial R A N D O M I Z E Placebo* vs Study Agent 6-12 Months * For Pilots Placebo arm is deleted Repeat Biomarkers

63 Change in Proliferation, ER & Activation, Cytomorphology Normal Hyperplasia Atypia In Situ Cancer Ki-67 Ki-67 <1% 2-15% Relative Risk 2X 5X 10X 100 ER

64 Need IU Vitamin D/ Day to Maintain Serum 25OH D in the ng/ml optimal range. Phase II Trials Ongoing 8oz Milk =100IU Salmon= 400 IU Total body sun exposure to minimal erythema = 10,000 IU

Increased Risk of Breast Cancer: Screening and Prevention. Elizabeth Pritchard, MD 4/5/2017

Increased Risk of Breast Cancer: Screening and Prevention Elizabeth Pritchard, MD 4/5/2017 No disclosures Defining Risk Risk Factors Modifiable Lifestyle obesity physical activity alcohol consumption breast