1. Strategies for Breast Cancer Prevention John Park Hannah Connolly Jeff Tice Mary S. Beattie

2. Breast Cancer Prevention!

3. Is breast cancer preventable? 5-fold variation in rates around the world (West >> Asia) Migrants assume rate of new country in 1 or 2 generations 4-fold increase in incidence in Iceland over 80 years* *Tryggvadottir JNCI 2006

4. Change in the US Death Rates* by Cause, 1950 & 2005 * Age-adjusted to 2000 US standard population Heart Diseases Cerebrovascular Diseases Influenza & Pneumonia Cancer 1950 2005 Rate Per 100,000

5. Risk Assessment

6. Why risk assessment? Tamoxifen and raloxifene FDA approved for prevention in high risk women: a 5-year risk >1.66% “American Cancer Society advises MRI for high risk women.” - March 28, 2007 Defined as 20-25% lifetime risk.

7. Factors Considered in The Gail Risk Model Current age Race / Ethnicity Age at menarche Age at first live birth Number of 1° relatives with BC Number of breast biopsies Presence of ADH Gail et al. J Natl Cancer Inst 81:1879; 1989. Based on Caucasian women undergoing regular screening (BCDDP)

8. Gail Model on NCI website 5 year and lifetime estimates by race Validated for populations; but modest discriminatory value for the individual discriminatory value for the individual. Rockhill et al. J Natl Cancer Inst 93:358, 2001. http://www.cancer.gov/bcrisktool/

9. Risk factors not included in Gail model Age of diagnosis for family members 2nd degree relatives Alcohol intake Diabetes Physical activity Use of HRT Lactation history Height Weight IGF-1, IGF-BP3 Hormone level (E2, T, SHBG) Bone mineral density Mammographic density NAF/Lavage SNPs

10. Prevention: Lifestyle

11. DIET

12. No association with breast cancer Dietary fat intake – Hunter 1996 – Pooled prospective studies – 4980 cases in 337,819 women Fruits & vegetables – Smith-Warner, JAMA, 2001 – Pooled prospective studies – 7377 cases in 351,825 women Carotenoids; Vitamins A, C, E Selenium

13. Alcohol and breast cancer risk: Meta-analysis 0102030405060 Total Alcohol Intake g/d Multivariate Relative Risk 2.5 2.0 1.5 1.0 0 Smith-Warner, 1998

14. Exercise

15. Exercise and risk of breast cancer Overall 25-30% decreased risk Greatest in thinner women Lifetime exercise matters Modest amounts: 1-3 hours brisk walking/week WHI Observational Cohort (n=74,171; 1780 cancers) McTiernan, JAMA, 2003.

16. Obesity

17. Effect modification by HT use Quintile BMINo HTHT 11.00 21.520.89 31.400.86 41.700.92 52.520.96 WHI Observational Cohort, n=85 917; 1030 cancers. P interaction < 0.001 Libby, CCC, 2002

18. 2nd Look: Low fat diet RCTs for BC RR (95% CI) WHI: 0.91 (0.86-1.01) – Primary prevention – 25% of total calories WINS:0.76 (0.60-0.98) – Secondary prevention – 20% of total calories WHEL:0.96 (0.80-1.14) Prentice JAMA 2006; Chlebowski JNCI 2006; Pierce JAMA 2007.

19. Reducing the risk of breast cancer 1.Early childbirth, breast feed 2.Exercise 3-7 hours / week 3.Maintain normal body weight 4.Minimize alcohol 5.Avoid long term HT, especially progestins 6.Low fat diet? Estimated 30-80% reduction in risk

20. Continuum of Risk Surgical prevention Surgical prevention 0% 100% LifestyleLifestyle ChemopreventionChemoprevention Increased Surveillance Risk-reducing Surgeries

21. Hormones and Chemoprevention

22. Women’s Health Initiative: Breast Cancer with HRT and ERT ERT JAMA 2002 JAMA 2004 Placebo HRT Placebo

23. Ravdin P et al. N Engl J Med 2007;356:1670-1674 Ravden NEJM 07

24. Breast Cancer Prevention Trial (BCPT) 13,388 women age > 35 – Estimated 5 year risk ≥ 1.66% 20 mg tamoxifen vs. placebo Stopped after average of 4 yrs; median follow-up: 55 months Fisher, JNCI, 1998

25. Tamoxifen reduced risk at all ages Age (years) Placebo Tamoxifen Fisher, et al. JNCI 1998;90:1371 Rate per 1,000 0 2 4 6 8 ≤49 50 - 59 ≥ 60

26. Tamoxifen in very high risk women 13 10.1 9.9 6.8 5.7 1.4 5.1 3.4 051015 LCIS Atypical hyperplasia ≥2 relatives All women Rate per 1,000 Fisher JNCI 1998; 90:1371 Placebo Tamoxifen

28. SERMs Reduce the Risk of Breast Cancer

29. SERMs reduced the risk of ER+ but not ER- cancer

30. Adverse Events From Prevention Trials of Tamoxifen & Raloxifene DVT/PE:1.9 (1.4-2.6) Endometrial cancer2.4 (1.5-4.0)  risk fatal stroke  risk cataracts  risk hot flashes ** Majority of adverse events in women ≥ 50 years Fisher JNCI,1998; Cuzick Lancet, 2003; Barrett-Conner, NEJM, 2006.

31. STAR Trial: Key outcomes per 1000 woman-years 19,747 women randomized, 5 year f/u Postmenopausal, average risk 4.0% OutcomeTam 20 mgRalox 60 mg Invasive BC4.34.4 Uterine Ca2.01.2 *DVT/PE3.72.6 Osteop. Fx2.72.5 CVD event4.44.6 *Cataracts12.39.7 * P < 0.05 Vogel, JAMA, 2006

32. Comparison of 2 SERMs TamoxifenRaloxifene FDA Approvalbreast ca rx & prev. osteoporosis & breast ca prev. Populationpre and postpost-menopause Adverse and Side Effects DVT, hot flashes, cateracts, uterine ca DVT, hot flashes, flu-like syndrome, edema Duration rec5 yrs or lessStudied x 8 yrs

33. Raloxifene vs. Tamoxifen Pro raloxifene – Equivalent reduction in IBC – Less thromboembolism, uterine cancer, and cataracts – Primary care comfort with therapy Con raloxifene – Post-menopausal women only – Generic tamoxifen less $$$

34. Aromatase inhibitors: the future? Block conversion of T to E ATAC: Treatment trial n=9366, 8 years – Anastrazole vs. Tamoxifen – 40% reduction in contralateral cancer – Less endometrial cancer, VTE, stroke – More fractures and musculoskeletal pain Letrozole after tamoxifen –37% reduction in contralateral cancer ATAC, Lancet Onc, 2008; Goss, JNCI, 2005. Ingle Annal Onc 2008.

37. Case : Jennifer 34 year old woman My mother’s fine and I don’t have a sister. But my dad had 4 sisters, 2 of whom developed breast cancer and my paternal grandmother also had breast cancer 5-year Gail risk =.31%

38. The Gail Model Can Underestimate Hereditary Risk of Breast Cancer This woman’s breast cancer risk greatly underestimated by Gail model Breast, 44 Breast, 38 Breast, 29 Ovary, 42 Jennifer, 37

39. ASCO How Much Breast Cancer Is Hereditary? Sporadic Family clusters Hereditary Breast Cancer 5%–10% 15%  20%

40. Features that indicate increased likelihood of BRCA mutations Multiple cases of early onset breast cancer Ovarian cancer Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish heritage Male breast cancer

41. BRCA1/2 Mutations Increase the Risk of Early-Onset Breast Cancer Population Risk Hereditary Risk By age 50 2% 33%-50% By age 70 7% 56%-87% By age 40 10%-20% 10%-20% 0.5%

42. Penetrance = Degree to which individuals possessing a genetic trait express that trait Prevalence = Number of carriers in a population at a specific time Research ongoing Moving Targets: Penetrance, Prevalence Breast Cancer Penetrance by BRCA1 or BRCA2 and Age Prevalence depends on population 98-99.8% of US population is - Breast Cancer Penetrance by BRCA1 or BRCA2 and Age Prevalence depends on population 98-99.8% of US population is -

43. Screening and Chemoprevention in BRCA Carriers Breast cancer –CBE q 6 months, MRI/mammo at 25 y/o –Tamoxifen may be more effective for BRCA2 than BRCA1 (80% of BRCA2 is ER+ and 80% of BRCA1 is ER-) Ovarian cancer –Efficacy of CA125 and U/S unclear-- When to start? How frequently? Whether to? –OCP’s for 3-5 years: 50% ↓ ovarian cancer

44. Surgical options for BRCA carriers Risk-reducing salpingo-oophrectomy (RRSO) –↓ ovarian and tubal cancers by 95% – Fine sectioning detects “occult tumors” in about 10% of tubes/ovaries –If pre-menopausal, 50% ↓ in breast cancer Risk-reducing mastectomy (RRM) –↓ breast cancer by 95% –Many reconstruction options

45. Summary points Lifestyle – Exercise, weight loss or maintenance – Minimize alcohol – Avoid/stop HT – Low fat diet? Consider tamoxifen or raloxifene for high risk women Assess familial risk – Consider prophylactic surgery for BRCA carriers

46. “Grateful patients are few in preventive medicine … where success is marked by a non-event” Geoffrey Rose UK epidemiologist

47. Programs at UCSF Cancer Risk Program – Genetic counseling and testing – 415-885-7779 – 877-RISK4CA (toll-free) Breast Care Center: High Risk Program – 415-353-7070

48. BRCA testing can modify 5-year risk beyond family history AgeNo FHAny FH*BRCA+ 300.11%0.23%3.5% 350.28%0.58%5.7% 400.58%1.10%7.9% 450.97%1.61%8.4% 501.3%1.9%7.3% 551.5%2.3%5.7% *FH = mother, sister, or daughter with breast cancer any age