1. Breast cancer: why do people get it and can we prevent it? T. Kuan Yu, M.D., Ph.D. Houston Precision Cancer Center

4. What is Cancer? Our own cells that grows without control –Grow (faster or slower than normal cells) –Die (slower than normal cells) –Proteins and structures that are very similar to normal cell

5. Why do we get cancer? ???

6. Basics of Cells

7. DNA  RNA  Protein

8. DNA is Blueprint for Cells DNA is blue print of cells. Its radius is 1 nm. If you stretch DNA into single strand, it would be 1600 km long. Only 1.5% of DNA are genes (~20,000) that encode proteins

9. Why do we get cancer? Different events can “change” (i.e. mutate) the DNA and change the protein function With the “right” sets of mutations, the cells stop listening to the control of the body  Events that mutate DNA leads to cancer

10. Breast Cancer Statistics 200,000 new cases in 2003 40,200 breast cancer deaths in 2003 Most common female malignancy Second leading cause of female ca mortality SEER data: –Lifetime risk of developing breast ca 13.1% in white American female 9.6% in African-American female

11. Breast Cancer Risk Factors Age Female sex Inherited Factors Family history Benign breast disease Hormones Dietary Factors Environmental factors Non Modifiable Modifiable

12. Largest Risk Factors Age –DNA less stable –Accumulation of previous changes Woman –Hormone –Breast tissue

13. ( Courtesy of Dr. Arun Banu)

15. 1 0 Relative with Breast Cancer RR* of breast cancer Premenopausal3.2 Postmenopausal1.5 Premenopausal, b/l8.8 Postmenopausal, b/l4.0 ( * RR = Relative Risk )

16. Personal history : 0.5-1%/yr Family history : Lifetime risk: 20-30% Mother Sister BRCA 1& BRCA 2: Lifetime risk: 50-80% Family history of breast cancer

17. ( Courtesy of Dr. Arun Banu)

22. Estrogen Exposure Can Drive Breast Cancer Development

23. Estrogen Exposure Early menarche (< 12 yo) Late menopause (> 55 yo) Having no pregnancy Childbirth after 30 yo (RR: 4-5x) Exogenous estrogen use Obesity (post-menopausal)

24. Combined Oral Contraceptive May Increase Risk of Breast Cancer 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies Combined oral contraceptives: –current users  RR 1.24 [1.15-1.33] –1-4 years after stopping  RR 1.16 [1.08-1.23], –5-9 years after stopping  RR 1.07 [1.02-1.13] – 10+ years after stopping use  RR 1.01 [NS] (Lancet. (1996)22;347(9017):1713)

25. Combined Oral Contraceptive May Not Increase Risk of Breast Cancer 4575 women with breast cancer and 4682 controls Combined oral contraceptives: –current users  RR 1.0 [NS] –Former users  RR 0.9 [NS] –No association with family history or use at young age (Lancet. (1996)22;347(9017):1713)

26. Risk from Hormone Replacement after Menopause

27. What Can We Do to Prevent Breast Cancer? Estrogen Exposure Risk: Pregnancy Early Childbirth Breast Feed Limit Exogenous Estrogen

28. Western Lifestyle/Food Increase Breast Cancer Risk in Asian-American >1500 Asian-American immigrants (1983) born in the West  60% higher risk than born in the East. Among those born in the West: women with three or four grandparents born in the West  50% higher risk than those with all grandparents born in the East. Among those born in the East: lived in the West for > 10 years  80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. (JNCI (1993) 85 (22): 1819)

29. Obesity Increases Breast Cancer Risk in Postmenopausal Woman Obesity leads to 11,000 to 18,000 deaths per year from breast cancer in U.S. for women over age 50 Obesity increase the risk of breast cancer by 1.5 fold among postmenopausal women who do not use menopausal hormones Due to increased levels of estrogen in obese post-menopausal women, whose ovary is not functioning

30. What Can We Do to Prevent Breast Cancer? Food Risk: Western diet/lifestyle Weight control (post-menopausal) Soy isoflavones may be protective for prememopausal breast cancer (RR 0.41)

31. Chemicals May Increase Breast Cancer risk Many chemicals led to cancer developments in lab animal No association seen with DDT, DDE, polychlorinated biphenyls and High power line in population studies

32. Woman of the atomic bombings in Japan during World War II; Women with Hodgkin’s disease treated with radiation therapy Girls treated with RT for non-malignant conditions Young women with large numbers of diagnostic x-ray to monitor treatment for TB or severe scoliosis. Radiation Increases Breast Cancer risk

33. Prior RT to breast Mantle RT –Relative risk of breast ca depends on the age at which she received RT 56% for women  19 yrs of age at RT 7% for women b/ 20-29 yrs of age at RT 1% for women  30 yrs of age at RT –Cancer develops 10-15 yrs later –Usually medial portion of the breast

34. What Can We Do to Prevent Breast Cancer? Chemical Risk: Not clear Radiation Risk: Avoid unnecessary exposure of RT such as diagnostic X-ray that are not needed

35. What Can We Do to Prevent Breast Cancer? Early Detection: Self Breast Awareness Annual Mammogram (≥ 40) Clinical breast exam about every 3 years for women in their 20s and 30s and every year for women ≥ 40

36. Screening Mammography HIP (Health Insurance plan of NY) Study –61,000 women, age 0-64 yrs –Randomization: Screening mammo vs. routine medical care –Results: Mortality rate was reduced by 33% in screened women 50-59 yrs of age Survival difference was higher by 7 to 10 yrs after diagnosis in women who had screening mammography

37. The Gail Model Includes: Current ageCurrent age Number of 1 st -degree female relatives with a history of breast cancerNumber of 1 st -degree female relatives with a history of breast cancer Age at first live birth, or nulliparityAge at first live birth, or nulliparity Calculates a woman’s 5-year and lifetime risk of developing breast cancer Number of breast biopsies Number of breast biopsies History of atypical hyperplasia History of atypical hyperplasia Age at menarche Age at menarche Race Race

38. For Woman with BRCA1/2 Mutations ( Courtesy of Dr. Arun Banu)

39. NSABP-P1(BCPT): Schema Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Eligible Women at High Risk (5-yr risk  1.66% or age over 60) Randomization n = 13,388 Tamoxifen 5 Years n = 6681 Placebo 5 Years n = 6707

40. Invasive Breast Cancer Cases by ER Status NegativePositiveUnknown Number of Events 0 50 100 150 Placebo ER Status Adapted from Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. 31 38 130 41 14 10 Tamoxifen

41. Rate of Invasive Breast Cancer Placebo Tamoxifen 0 12354 Placebo 175 43.4 Tamoxifen 89 22.0 Events Rate per 1000 Rate/1000 P < 0.00001 0 10 20 30 40 Years 49% reduction Adapted from Fisher B, Constantion JP, Wickerham DL, et al. J Natl Cancer Inst. 1998;90:1371-1388.

42. Why Not Just Treat All High-Risk Women With Tamoxifen? Less than 5% of high-risk women elect to take tamoxifen when offered. Tamoxifen has some serious side effects (particularly for women ≥ age 50). Type of event Risk Ratio (all ages) Risk Ratio (ages ≥ 50) Endometrial cancer 2.534.01 Stroke1.591.75 Pulmonary embolism 3.013.19 Deep vein thrombosis 1.601.71

43. Breast Cancer Prevention Raloxifene (MORE Trial)* –Post menopausal female with osteoporosis –Breast cancer reduction by 62% –Invasive breast cancer by 72% –Invasive ER+ive breast cancer –No associated with uterine cancer –Side Effects: Increased risk of thromboembolic event 28% hot flashes with raloxifene vs. 21% in placebo 40% reduction in cardiovascular events *Breast Cancer Res Treat 65:125-134, 2001

44. Prophylactic Mastectomy for High risk Woman Removes most but not all breast tissue Total (simple) mastectomy appears more effective than subcutaneous mastectomy Shown to reduce risk of breast cancer by 90% in women with BRCA mutations New Engl J Med 2001;345:159-64 Hartmann LC, Sellars TA, Schaid DJ, et al. J Natl Cancer Inst. 2001;93:1633-37.

45. Oophorectomy for Woman with High Risk for Breast cancer Oophorectomy –Prevents breast ca in BRCA 1 and 2 –RR reduction is 50% in premenopausal pts –RR reductions may be higher if done before the age of 40 yrs and that the duration of protection is approx. 15yrs JCO 23(8):1656-1663; 2005

46. Conclusions Many Non-Modifiable risk factors for breast cancer –Early dectection Many Modifiable risk factors for breast cancer –Reduce estrogen exposure –Adjust diet and weight –Prevent exposure from unnecessary chemical and radiation

47. Thank You Acknowledgement for materials in slides: Dr. Arun Banu Dr. Hemangini Shah