1. Risk Assessment and Risk Reduction in Women with non Hereditary BC Risk Fabienne Liebens MD Breast Unit Isala Breast Cancer Prevention Center CHU Saint Pierre – ULB-VUB Brussels

2. FL - BBM2 - 2008 Breast Cancer Prevention WHO definitions Primary prevention: covers all activities designed  to reduce the incidence of an illness in a population risk  to reduce the risk of new cases appearing Secondary prevention: (early screening/diagnosis)  to reduce the prevalence of an illness in a population  to reduce its duration Tertiary prevention:  to reduce the incidence of chronic incapacity or recurrences in a population,  to reduce the functional consequences of an illness  knowledge of independent risk factors of the disease  efficient risk reduction options

3. FL - BBM2 - 2008 Risk Assessment and Risk Reduction Why do we need to address these issues? – Are there effective preventive strategies? How do we assess BC risk? How could we refine risk and predict benefit of interventions? Challenges/Conclusion?

4. FL - BBM2 - 2008 Risk Assessment and Risk Reduction Why do we need to address these issues? – Are there effective preventive strategies? How do we assess BC risk? How could we refine risk and predict benefit of interventions? Challenges/Conclusion?

5. FL - BBM2 - 2008 Breast Cancer Risk Assessment Why ? Burden of BC European BC  2006  430 000 cases  132 000 deaths  Life time risk approaching 1 in 9 women  Demographic increase  Ageing population  Rise in young women  Wide differences in survival (16%) Eurocare 3 Adapted from Dr Nick Perry, Europa Donna Pan-European Conference- Amsterdam 2007

6. FL - BBM2 - 2008 Belgian Cancer Patients’ Needs Study Frequency of difficulties encountered % More than 26 difficulties6,3% From 21 to 25 difficulties 14,0% From 16 to 20 difficulties28,7% From 11 to 15 difficulties23,7% From 6 to 10 difficulties17,9% No difficulty0 % From 1 to 5 difficulties9,4% 2005- Courtesy of Darius Razavi and Isabelle Merckaert Assessment of 38 types of difficulties (psychosocial, physical, marital, sexual…)

7. FL - BBM2 - 2008 Breast Cancer Risk Assessment Why ? Risk Factors Tamoxifen Genetic Factors Life Style EnvironmentHormonalhistory Breast Biopsy BRCA1 BRCA2  Obesity  Lack of physical activity  Alcohol  Irradiations  Diet  Tobacco Early menarcheEarly menarche Late menopauseLate menopause NulliparousNulliparous Age of first pregnancyAge of first pregnancy HRTHRT -ADH -ALH -DCIS -LCIS 5-10% >25% Breast Density

8. FL - BBM2 - 2008 Risk Assessment and Risk Reduction Why do we need to address these issues? – Are there effective prevention strategies? How do we assess BC risk? How could we refine risk and predict benefit of interventions? Conclusion?

9. FL - BBM2 - 2008 Prevention strategies Risk FactorPrevention OptionsRisk reduction Gail risk ≥1.67Tamoxifen/Raloxifen49% BRCA1/2Mastectomy90–95% BSOophorectomyAge <35 ans 61% Age 35–50 ans 51% Age >50 yans 49% Tamoxifen50% AtypiaTamoxifen86% All womenLife style modifications30%–45% Adapted from Ozane EM. The Breast Journal 2006; 12: 103-133.

10. FL - BBM2 - 2008 Breast Cancer Risk Assessment Why ? Preventive strategies  Tamoxifen/raloxifen  Prophylactic surgery  Life style modifications to quantify accurately the net risk/benefit ratio depends on the ability to quantify accurately a woman’s baseline likelihood of developing breast cancer June 2008 Bishop J et al. The Health Economic of chemoprevention for Breast Cancer in Australia. Cancer Institute NSW, June 2008

11. FL - BBM2 - 2008 Risk Assessment and Risk Reduction Why do we need to address these issues? – Are there effective prevention strategies? How do we assess BC risk? How could we refine risk and predict benefit of interventions? Conclusion?

12. FL - BBM2 - 2008 How do we assess BC risk? Models Gail, Claus, Tyrer Cuzick  The most common models used to predict a woman’s risk of breast cancer BRCAPRO, Frank, Cough  Used in a subset of the high-risk population to predict a woman’s probability of having a genetic mutation

13. FL - BBM2 - 2008 Breast Cancer Risk Assessment How ? Models  The Gail risk assessment model  estimates the risk of developing breast cancer in women undergoing annual screening.  Gail et al used data from 284,780 predominately white women in 28 participating centers of the Breast Cancer Detection Demonstration Project (BCDDP) to develop the model.  An unconditional logistic regression model  based on the ratio of risk in a woman with specified risk factors compared with the risk in a woman with no risk factors.

14. FL - BBM2 - 2008 51 12 1 YES NO 0 0 1

15. Breast Cancer Risk Assessment How ? Models: Gail Advantages  Use is widespread, with many forms of access (National Cancer Institute [NCI] Web site, handheld and computer applications).  Applicable to the largest number of women  Has been validated  Has been shown to be well calibrated.Limitations  Does not show great discriminatory power (predicts population risk well, but not individual risk).  58%-65%-73% discriminatory  Not sufficient family history Rockhill et al. J Natl Cancer Inst 93:358, 2001. Tice. Breast Ca Res Treat 88(suppl 1):2004; abstract 13 Cuzick. ASCO Educational Session 2005 Cuzick. ASCO Educational Session 2005.

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17. Breast Cancer Risk Assessment How ? Models It is not sufficient Conclusion: It is not sufficient to use only these mathematical models for the purpose of individual decision making regarding prevention interventions.

18. FL - BBM2 - 2008 Risk Assessment and Risk Reduction Why do we need to address these issues? – Are there effective prevention strategies? How do we assess BC risk? How could we refine risk and predict benefit of interventions?How could we refine risk and predict benefit of interventions? Conclusion?

19. FL - BBM2 - 2008 Breast Cancer Risk Assessment Breast Cancer Risk Assessment Options to Refine Risk and Predict Benefit of InterventionBiomarkers Breast Density Histologic or Cytologic evidence of atypia - To improve individualized risk assessments - To tailor prevention care

20. FL - BBM2 - 2008 Mammographic Density Mammographic Density Options to Refine Risk and Predict Benefit of Intervention Reflective of amount of epithelium, stroma, and fluid relative to fat. Stroma and collagen make up the bulk of density. Strong hereditary component Boyd et al. Lancet Oncol 2005 6(10):798-808. McCormack VA et al. Cancer Epidemiol Biomarkers Prev. 2006 5(6):1159-69. Chen J. et al. J Natl Cancer Inst 2006; 98: 1215-1226. Risk biomarker for both ER + and ER - cancers in pre- and postmenopausal women.

21. FL - BBM2 - 2008 Risk of Breast Cancer According to Breast Density in Premenopausal and Postmenopausal Women RR=3.4 RR=5.3 Santen et al. N Engl J Med 2005;353:275

22. FL - BBM2 - 2008 Agreement between computer-assisted quantitative measurement of mammographic breast density (MBD) and clinicians' assessment. F. Liebens et al. Proceedings of EBCC-6; European Journal of Cancer 2008; 6 (7):63. (abstract 45).

23. FL - BBM2 - 2008 Breast Cancer Risk Assessment Breast Cancer Risk Assessment Options to Refine Risk and Predict Benefit of InterventionBiomarkers Breast Density Histologic or Cytologic evidence of atypia - To improve individualized risk assessments - To tailor prevention care

24. FL - BBM2 - 2008 Proliferative benign breast disease with atypia 19/100 15y Degnim AC et al. JCO 2007 25:2671-2677 Elmore, J. G. et al. N Engl J Med 2005;353:297-299

25. FL - BBM2 - 2008 Multifocal occult hyperplasia (+/- Atypia) is prevalent in young and middle aged high risk women high risk womenBut 80% of women have never had a diagnostic biopsy Hoogerbrugge et al. JCO 2003 21:41 Schnitt. Amer J Surg Pathology 2003 27:836

26. FL - BBM2 - 2008 New methods Nipple aspiration fluidNAF cytology Risk Prediction Ductal LavageDL RPFNA Random peri areolar fine-needle aspiration RPFNA RPFNA  Efficient way to obtain tissue for a prevention trial (Fabian et al Frontiers Prev Res 2005)  Cost effective to determine who gets chemoprevention (Ozanne et al Cancer Epidemiol Bio Prev 2004)  Women with AH more likely to enroll on NSABP Prevention Trial (Vogel et al JNCI 2002) and to take tamoxifen (Goldenberg VK Cancer Epidemiol Bio Prev 2007)

27. FL - BBM2 - 2008 Adapted from Arun, B. et al. Clin Cancer Res 2007;13:4943-4948 Cytologic findings RPFNA Ductal lavage Non proliferative epithelium Atypical hyperplasia

28. FL - BBM2 - 2008 Models for Phase II Chemoprevention Trials for Women at High Risk of BC Study Agent Tissue Based Biomarkers Morphology Proliferation NAF Nipple aspiration fluid DL Ductal lavage RPFNA Random periareolar fine needle aspiration RANDOMIZATIONRANDOMIZATION Placebo Repeat Biomarkers 6-12 months Adapted from Fabian C. Endocrine related Cancer 2005 Imaging-Based Biomarkers Mammographic Breast density

29. FL - BBM2 - 2008  AIM of a consultation about breast cancer risk assessment determine  to determine if risk level is high enough to warrant special surveillance measures or prevention interventions, motivate  if so, motivate those at high risk to partake in surveillance/prevention options eassure  reassure those at low/moderate risk Breast Cancer Risk Assessment Why and How ? Clinical Practice NCNN Breast Cancer risk reduction V2.2007 Kushi LH. CA Cancer J Clinic 2006 Sivell S. Cochrane databases of systematic reviews 2007 Kiluk J. Cancer Control 2007

30. FL - BBM2 - 2008 European Journal of Cancer Prevention 2008 in press

31. FL - BBM2 - 2008 Breast Cancer Risk Assessment Challenges  Improve woman’s awareness/Knowledge?  Best practice in risk communication ?  Cost effectiveness ?  Best biomarker that predicts both risks and benefits from intervention ?  Improve the skills of primary care providers ?

32. FL - BBM2 - 2008 “…Cancer is a multistage disease, not a single event, and doctors should emphasize cancer prevention in addition to cancer treatment and cure …” Peter Greenwald, Division of Cancer Prevention, National Cancer Institute.

34. Life is a sexually transmitted disease and there is a 100% mortality rate “… Life is a sexually transmitted disease and there is a 100% mortality rate. …” Woody Allen