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Fall 2007 Symposia Series

St. Melville Marriott Long Island Melville, New York December 1, 2007. Fall 2007 Symposia Series. Breast Cancer: Women at Risk and New Strategies for Prevention. Therese B. Bevers, MD Associate Professor Department of Clinical Cancer Prevention Medical Director

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Fall 2007 Symposia Series

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  1. St Melville Marriott Long IslandMelville, New YorkDecember 1, 2007 Fall2007Symposia Series

  2. Breast Cancer: Women at Risk and New Strategies for Prevention Therese B. Bevers, MD Associate Professor Department of Clinical Cancer Prevention Medical Director Clinical Cancer Prevention and Prevention Outreach Programs The University of Texas M. D. Anderson Cancer Center Houston, Texas

  3. 0 For what percentage of your female patients have you done breast cancer risk assessments? • 0%-15% • 16%-39% • 40%-55% • 56%-75% • >75% Use your keypad to vote now!

  4. Faculty Disclosure • Dr Bevers: consultant/grant support: Eli Lilly and Company

  5. Learning Objectives • Evaluate women for breast cancer risk reduction • Advise women on appropriate lifestyle alterations to lower breast cancer risk • Explain the rationale and current clinical trial results of pharmacologic interventions for breast cancer risk reduction

  6. The Good News Trends in Female Breast Cancer Incidence Rates* by Race and Ethnicity, US, 1975-2004 • Fewer women dying of breast cancer • Better treatment • Cancer prevention activities • Fewer women diagnosed with breast cancer • Possibly related to fewer women using hormones? 160 140 120 100 Rate/100,000 80 White African American Hispanic/Latina Asian American/Pacific Islander American Indian/Alaska Native 60 40 20 0 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2004 Year *Rates are age-adjusted to the 2000 US standard population. Data source: Surveillance Epidemiology and End Results (SEER) Program, 1973-2004, Division of Cancer Control and Population Science, National Cancer Institute, 2007. Data for whites and African Americans are from the SEER 9 registries. Data for other races/ethnicities are from the SEER 13 registries. For Hispanics, incidence data do not include cases from the Alaska Native Registry, Hawaii, and Seattle. Incidence data for American Indian/Alaska Natives are based on Contract Health Service Delivery Area (CHDSA) counties. American Cancer Society, Surveillance Research, 2007 ACS Breast Cancer Facts and Figures 2007-2008. Available at: http://www.cancer.org/docroot/stt/stt_0.asp

  7. Breast Cancer Risk Reduction—NCCN Guidelines Assessment of risk Utilization of risk reduction interventions NCCN = National Comprehensive Cancer Network. Available at: www.nccn.org

  8. 0 What percentage of your female patients for whom you have done breast cancer risk assessments may be eligible for more than lifestyle changes? • 0%-15% • 16%-39% • 40%-55% • 56%-75% • >75% Use your keypad to vote now!

  9. Breast Cancer Risk Assessment Step 1 • Identify individuals with an inherited predisposition for breast cancer (eg, BRCA1, BRCA2 gene mutations) Step 2 • Determine risk for noncarriers using population-based risk assessment tools • Calculate breast cancer risk by Gail model BRCA = breast cancer. Gail MH et al. J Natl Cancer Inst. 1989;24:1879-1886.

  10. MDACC Referral Criteria for Genetic Risk Counseling • More than 2 relatives with breast cancer diagnosed before age 50 or ovarian cancer • One relative with breast and ovarian cancer • One relative with bilateral breast cancerbefore age 50 • One male relative with breast cancer • Ashkenazi Jewish descent and breast or ovarian cancer in the family MDACC = Monroe Dunaway Anderson Cancer Center.

  11. Genetic Counseling • Counseling involves • Review of family history • Development of pedigree • Determination of probability of mutation • Discussion of pros and cons of testing • Review of test results, if testing done • Outline of management options CRC, 47 CRC, 42 & 51 CRC, 53 Endo, 46

  12. http://www.cancer.gov/bcrisktool/ or Breastcancerprevention.com

  13. Risk Factors Used in Risk Assessment Tool • Age • Age at menarche • Age at first live birth or never having children • Number of first-degree relatives with a history of breast cancer • Number of breast biopsies • History of atypical hyperplasia • Race Available at: www.cancer.gov/bcrisktool; www.breastcancerprevention.com

  14. NCI Breast Cancer Risk Assessment Tool • Output of tool • Risk of developing breast cancer during next 5 years • Risk of developing breast cancer in lifetime • Comparison • Women of same age, same race, average risk • Definition of elevated risk • 1.7% risk of developing invasive breast cancer in 5 years NCI = National Cancer Institute. Available at: www.cancer.gov/bcrisktool

  15. Limitations of Risk Assessment Tool • Underestimation of risk • Genetic predisposition not considered • No adjustment for age of diagnosis for first-degree relative with breast cancer • Bilateral disease not considered • Race? • Not applicable to women with: • Breast cancer, DCIS, or LCIS • Does not take into consideration: • HRT, previous radiation therapy to the chest for treatment of Hodgkin’s lymphoma, or recent migration from a region with low breast cancer risk (ie, China) DCIS = ductal carcinoma in situ; HRT = hormone replacement therapy; LCIS = lobular carcinoma in situ. More information: http://www.cancer.gov/bcrisktool

  16. Breast Cancer Risk Reduction Assessment of risk Utilization of risk reduction interventions

  17. Risk Reduction Interventions • All women • Healthy lifestyle • Women at increased risk • Chemoprevention • Women at high risk • Prophylactic mastectomy • Prophylactic oophorectomy Available at: www.cancer.gov/cancertopics/types/breast

  18. Risk Reduction:Maintain a Healthy Weight • Maintain BMI <25 kg/m2 • Avoid weight gain, especially postmenopausal BMI = body mass index. Available at: www.cancer.gov/cancertopics/types/breast

  19. Risk Reduction: Diet • Eat a variety of healthful foods, with an emphasis on plant sources • Eat 5 or more servings of vegetables and fruits per day • Choose whole grains instead of processed grains and sugar • Limit consumption of red meat, especially meat high in fat and processed meat Available at: www.cancer.org

  20. Risk Reduction: Exercise • Regular exercise reduces breast cancer risk 10%-25% • At least moderate activity ≥45 minutes ≥5 days a week Available at: www.cancer.org

  21. Risk Reduction: Alcohol in Moderation • Women • Men • 1 drink = • 12 oz regular beer • 5 oz wine • 1.5 oz liquor Available at: www.cancer.gov/cancertopics/types/breast

  22. Risk Reduction: Prophylactic Surgeries • Options for women at high risk of developing breast cancer • Prophylactic mastectomy • Prophylactic oophorectomy

  23. Prophylactic Mastectomy • Highly effective: 90% risk reduction • Alters body form and image • Irreversible • Considered only in cases of significant risk • Gene carriers Hartmann LC et al. N Engl J Med. 1999;2:77-84.

  24. Prophylactic Oophorectomy • 47%-68% breast cancer risk reduction if done by age 35 • Causes premature menopause with systemic effects • Use of postmenopausal HRT after oophorectomy does not appear to increase breast cancer risk • Also reduces risk of ovarian cancer Domchek SM et al. Curr Opin Obstet Gynecol. 2007;19:27-30; NCCN Practical Guidelines in Oncology. Breast Cancer Risk Reduction. Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf

  25. 0 What chemopreventive agents for breast cancer have you prescribed? • Raloxifene • Tamoxifen • Aromatase inhibitors • All • None Use your keypad to vote now!

  26. Risk reduction therapy based on menopausal status Premenopausal: tamoxifen Postmenopausal: tamoxifen; raloxifene Breast Cancer Chemoprevention Information available at: http://www.fda.gov/

  27. NSABP-P1 BCPT-1 Breast Cancer Prevention Trial: Schema Eligible women at high risk (5-year risk ≥1.66%) Randomization n = 13,388 Tamoxifen 5 years (20 mg/d) n = 6681 Placebo 5 years n = 6707 BCPT-1 = Breast Cancer Prevention Trial; NSABP-P1 = National Surgical Adjuvant Breast and Bowel Project 1. Fisher B et al. J Natl Cancer Inst. 1998;90:1371-1388.

  28. NSABP-P1 BCPT-1 Trial Fisher B et al. J Natl Cancer Inst. 1998;90:1371-1388. First clinical trial to demonstrate that incidence of breast cancer can be reduced with chemopreventive therapy >13,000 women at high risk randomized to tamoxifen versus placebo for 5 years

  29. Tamoxifen: Other Benefits • 32% reduction in incidence of bone fractures (RR = 0.68; 95% CI: 0.51-0.92) • No effect on ischemic heart disease Tamoxifen RR = response rate. Fisher B et al. J Natl Cancer Inst. 2005;22:1652-1662.

  30. Tamoxifen: Risks • Uterine cancer (RR = 2.53; 95% CI: 1.35-4.97) • Thromboembolic events • DVT (RR = 1.60; 95% CI: 0.91-2.86) • PE (RR = 3.01; 95% CI: 1.15-9.27) • CVA (RR = 1.59; 95% CI: 0.93-2.77) • Cataracts • Women <50 years of age did not have the same increase in risk as women >50 years of age CVA = cerebrovascular accident; DVT = deep vein thrombosis;PE = pulmonary embolism. Fisher B et al. J Natl Cancer Inst. 2005;22:1652-1662.

  31. Overview of Tamoxifen Breast CancerPrevention Trials: All Breast Cancers 1.5 0.62 1.0 0.5 0.3 Hazard Ratio Royal Marsden NSABP-P1 Italian IBIS-1 All tamoxifen preventive All tamoxifen adjuvant IBIS-1 = International Breast Cancer Intervention Study-1. Cuzick J et al. Lancet. 2003;361:296-300.

  32. Tamoxifen: The Good and the Bad • Tamoxifen was the landmark as the first drug identified to reduce breast cancer risk • Utilization of tamoxifen has been limited • Seen by PCPs as a “cancer drug” • Concern about risks of tamoxifen Tamoxifen PCP = primary care physician. Evans D et al. Lancet. 2001;358:1652-1662; Kinsinger L et al. Presented at AACR Annual Meeting 2006.Abstract CS16-03.

  33. STAR = Study of Tamoxifen and Raloxifene. Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  34. Raloxifene Suggested to Decrease the Risk of Breast Cancer • MORE trial (1999) • A 72% reduction in the incidence of invasive breast cancer was suggested • Raloxifene does not appear to stimulate development of uterine cancer Cumulative Incidence of All Confirmed Breast Cancer Among Study Participants 1.5 Placebo Raloxifene hydrochloride 1.0 % Randomized Patients 0.5 0 0 1 2 3 4 Years Since Randomization MORE = Multiple Outcomes of Raloxifene Evaluation. Adapted from Ettinger B et al. JAMA. 1999;23:2189-2197.

  35. STAR: Schema Postmenopausal women (mean age 58.5 years) at increased risk (5-year risk 1.7% or LCIS) Randomization n = 19,747 Tamoxifen 20 mg/d x 5 years Raloxifene 60 mg/d x 5 years Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  36. STAR: Invasive Breast Cancers Relative risk = 1.02 95% CI: 0.82-1.28 312* P = .96 Average Annual Rate/1000 Person-Years 163 168 *No. of events Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  37. STAR: Noninvasive (In Situ) Breast Cancers Relative risk = 1.40 95% CI: 0.98-2.00 P = .052 80 57* Average Annual Rate/1000 Person-Years *No. of events Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  38. STAR: Uterine Cancers Relative risk = 0.62 95% CI: 0.35-1.08 P = not significant 36* Average Annual Rate/1000 Person-Years 23 *No. of events Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741. http://www.nsabp.pitt.edu/STAR/Index.html

  39. STAR: Hysterectomy at Enrollment Prior Hysterectomy 51.7% (10,153) Half of the women enrolled in STAR had a prior hysterectomy, which limited the study population for this finding Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  40. STAR: Endometrial Hyperplasia (Relative risk = 0.16; 95% CI: 0.09-0.29) *Treatment with raloxifene resulted in 84% fewer cases of endometrial hyperplasia with or without atypia Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  41. STAR: Hysterectomy During Follow-up TamoxifenRaloxifene 244 cases 111 cases (Relative risk = 0.44; 95% CI: 0.35-0.56) 64% more hysterectomies in tamoxifen group thus obscuring the uterine cancer finding Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  42. STAR: DVT and PE Tamoxifen Raloxifene Relative risk = 0.74; 95% CI: 0.53-1.03 87* Relative risk = 0.64; 95% CI: 0.41-1.00 65 54 Average Annual Rate/1000 Person-Years 35 *No. of events Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  43. STAR: Strokes Relative risk = 1.21 95% CI: 0.79-1.88 P = not significant Average Annual Rate/1000 Person-Years 53* 51 *No. of events Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741. http://www.nsabp.pitt.edu/STAR/Index.html

  44. STAR: Cataracts Cataract Surgery Cataracts 80 80 Raloxifene Tamoxifen Raloxifene Tamoxifen 70 70 60 60 50 50 Cumulative Incidence/1000 Person-Years Cumulative Incidence/ 1000 Person-Years 40 40 30 30 20 20 P = .002 P = .03 10 10 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 Time Since Randomization (mo) Time Since Randomization (mo) No. at risk Raloxifene 8329 7638 5727 3632 690 Tamoxifen 8334 7672 5686 3605 657 No. at risk Raloxifene 8329 7594 5662 3567 673 Tamoxifen 8334 7622 5600 3532 638 Tamoxifen (394 cases) Raloxifene (313 cases) Cataracts in the raloxifene group do not appear to be elevated over what would be expected in this population Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  45. Additional Findings • No significant differences between the treatment groups for: • Other invasive cancers • Cardiac events • Osteoporotic fractures • Deaths Adapted from Vogel VG et al. JAMA. 2006;23:2727-2741; http://www.nsabp.pitt.edu/STAR/Index.html

  46. Participant-Reported Side Effects Mild to Moderate Severity • Tamoxifen • Vasomotor symptoms • Vaginal discharge • Vaginal bleeding • Genital itching or irritation • Difficulty with bladder control • Leg cramps • Raloxifene • Vaginal dryness • Pain with intercourse • Weight gain Land SR et al. JAMA. 2006;23:2742-2751; Vogel VG et al. JAMA. 2006;23:2727-2741.

  47. FDA Recently Approved Raloxifene for 2 New Indications • Breast cancer risk reduction for women with osteoporosis • Based on data from MORE and CORE • Breast cancer risk reduction for women at increased risk of developing breast cancer • Based on data from STAR • Raloxifene is NOT a treatment for breast cancer CORE = Continuing Outcomes Relevant to Evista; FDA = Food and Drug Administration. Available at: www.fda.gov/

  48. Significant Outcomes From STAR • Women now have 2 options for breast cancer risk reduction • Tamoxifen • Raloxifene • Raloxifene plays a role in 2 diseases of concern for women • Osteoporosis prevention/treatment • Breast cancer risk reduction

  49. SERMs: An Emerging Treatment Modality for the Management of Breast Cancer • Modeling suggests approximately 2.5 million American women aged 35-70 could benefit from chemopreventive therapy • Represents 25% of women in that age range who are considered at increased risk for breast cancer (ie, 5-year risk ≥1.66%) SERMs = selective estrogen receptor modulators. Freedman AN et al. J Natl Cancer Inst. 2003;95:526-532.

  50. Breast Cancer Risk Reduction in Clinical Practice • Despite proven benefits with use of tamoxifen, use by PCPs remains low • Raloxifene may be used more often than tamoxifen because: • It is a well-established part of primary care practices • Fewer risks • Reduces risk of 2 diseases of concern to women Evans D et al. Lancet. 2001;358:1652-1662; Kinsinger L et al. Presented at AACR Annual Meeting 2006. Abstract CS16-03.

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