Underwriting Breast Cancer Steven E. Zimmerman M.D. Vice President & Chief Medical Director

1. Underwriting Breast CancerSteven E. Zimmerman M.D.Vice President & Chief Medical Director

3. Breast Cancer Statistics – 2008 • The most common cancer in females • 250,230 new cases estimated • 182,460 invasive breast cancers • 67,770 in situ breast cancers • Second only to lung cancer in mortality for females • 40,930 estimated deaths from breast cancer in 2008 • Leading cause of death for American females between ages 40-55 • Lifetime risk is 1 in 7

4. Annual Incidence of Female Breast Cancer (1975-2004) Ravdin P et al. N Engl J Med 2007;356:1670-1674

5. Risk Factors for Breast Cancer • Age • Familial (5 to 10% of all cases; ½ BRCA 1/2) • 1ST degree relative – 1.5 to 3x increased risk • BRCA 1/2 mutation – 26 to 85% lifetime risk • Hormonal factors • Estrogen exposure (HRT, serum estrogen levels) • Reproductive history • Early menarche • Late menopause • Nulliparity

6. Risk Factors for Breast Cancer • Benign breast disease • Atypical hyperplasia • Dietary and lifestyle factors • Alcohol consumption • Dietary fat intake • Environmental factors • Radiation exposure • Greatest when exposure occurs at young age • Risk is greatest in young women treated for Hodgkin’s Lymphoma with mantle radiation

7. Breast Cancer Trends – Incidence by Age

8. Absolute Risk of Breast Cancer and Age

9. Breast Cancer Incidence, Hormone Receptor Status and Hormone Replacement Therapy Ravdin P et al. N Engl J Med 2007;356:1670-1674

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

11. Cancer Arises From DNA Mutations in Cells Normal cell DNA mutations Uncontrolled proliferation Last DNA mutation from: • heredityor • radiation or chemicalsor • spontaneous errorsduring DNA duplication

12. BRCA Mutations • Highest prevalence in Ashkenazi Jewish population • Tumor suppressor genes • BRCA1 • Associated with ~45% of inherited breast cancer & over 80% of inherited breast and ovarian cancer • Location – chromosome 17 • BRCA2 • Associated with male breast cancer, prostate cancer, and GI malignancies as well • Location – chromosome 13

13. Causes of Hereditary Susceptibility Contribution to Hereditary Breast Cancer 20% - 40% 10% - 30% <1% <1% 30% - 70% Gene BRCA1 BRCA2 TP53 PTEN Undiscovered genes

14. Genes Associated with a Hereditary Predisposition to Breast Cancer Robson M and Offit K. N Engl J Med 2007;357:154-162

15. Magnitude of Relative Risk

16. Detecting & Diagnosing Breast Cancer • Breast self examination (BSE) • Physical examination • Mammography • Ultrasonography • Magnetic resonance mammography (MRM)

17. U.S Preventive Services Task Force Nelson, H. D. et. al. Ann Intern Med 2005;143:362-379

18. Mammography • Detection of calcifications • Microcalcifications • Common sign of cancer, e.g. DCIS • Macrocalcifications • More typical of benign disease • Mass – with or without calcification • Issues with: • Dense breasts • Implants

19. Mammographic Findings

20. Mammographic Findings

21. Breast Ultrasonography • Not used for screening • Used to evaluate suspicious lesions – palpated and/or seen on mammography • Differentiates cystic from solid lesions • Distinguish tumor from lymph nodes

22. Breast Ultrasonography

23. Breast Ultrasonography

24. Breast MRI • More sensitive than mammography • Advantages • Dense breasts • Implants • Young women • Hereditary risks • Prior lumpectomy • Disadvantages • Less specific – more false positives • More expensive

25. Breast MRI Fibroadenoma – before contrast Invasive Lobular Ca – before contrast

26. Breast MRI Fibroadenoma – 5 minutes after contrast Invasive Lobular Ca – 5 minutes after contrast

27. Breast MRI Fibroadenoma – subtracted image Invasive Lobular Ca – subtracted image

28. Impact of Screening Age-standardized incidence of and mortality from female breast cancer, England and Wales, Rate per 100,000

29. Anatomy of the Breast

30. Normal Breast Tissue

31. Benign Breast Disease • Fibroadenoma • Fibrocystic disease • Atypical hyperplasia • Other

32. Benign Breast Disease - Fibroadenoma • Usually in women under age 30 • Rounded, easily movable mass • About 10% will disappear per year • Small long term risk for developing cancer

33. Benign Breast Disease – Fibrocystic disease • Gross cyst • Usually in 40’s • Needle aspiration or ultrasound for diagnosis • Non-bloody fluid obtained, then lump disappears

34. Benign Breast Disease – Fibrocystic disease • Fibroadenosis & Micro cysts • Found in 30’s & 40’s • Disappears after menopause • Usually diffuse and ill-defined • Usually cyclic with menses • Painful and prominent before; resolves after

35. Benign Breast Disease – Atypical hyperplasia • Marked proliferation and atypia of epithelium • Found in 3% of benign breast biopsies • Associated with 13% subsequent development of breast cancer – 4x risk factor • Diagnosed by same criteria as DCIS, but doesn’t have all the characteristics • Some may be under-diagnosed DCIS

36. Benign Breast Disease – Other • Phylloides tumor • Unpredictable behavior • About 10% metastasize from either malignant or benign phylloides tumors • Mammary duct ectasia • Breast inflammation and abscess formation • Presents as periareolar inflammation • When chronic, most frequent cause of nipple discharge in premenopausal women

37. Benign Breast Disease – Other • Papillomas • Small (< 1cm) intraductal growths • Frequently have nipple discharge • May be solitary or multiple • Frequently develop more papillomas or cancer • Single without atypia – 3-fold risk • With atypical hyperplasia – 4-fold risk • Multiple often associated with carcinoma

38. Presenting Symptoms of Breast Cancer • Painless breast mass 66% • Painful breast mass 11% • Nipple discharge 9%

39. Breast Cancer • Lobules and Ducts are structures within the breast • Cancer seen only in the ducts = ductal • Cancer seen only in the lobules = lobular • Tumor confined to the ducts or lobules = in situ • Cancer extending beyond the ducts or lobules to adjacent tissue = invasive or infiltrating

40. Breast Cancer – Non-infiltrating (in situ) • Lobular carcinoma in situ – “not a cancer?” • Usually an incidental finding • Low risk of developing invasive breast cancer • More common in premenopausal women • Treatment is usually observation • Breast examination every 6-12 months • Mammogram every 1-2 years • Ductal carcinoma in situ (DCIS) • Diagnosed with increased frequency due to mammography • Subtypes • solid, cribiform, papillary, comedo • High grade and comedo type (usually) can travel extensively but undetected throughout the breast

41. A – Normal cells B – Lobular cancer cells C – Basement membrane Lobular Carcinoma in situ

42. A – Normal cells B – Ductal cancer cells C – Basement membrane Ductal Carcinoma in situ

43. Papillary Solid Cribiform Comedo DCIS - Subtypes

44. Normal Breast Tissue

45. Pathology – DCIS

46. Breast Cancer - Infiltrating • Infiltrating ductal carcinoma • Most common form – 70-80% • Invades breast structures and may spread to lymph nodes and to other organs • Same subtypes as DCIS • Infiltrating lobular carcinoma • Less common – 10-15% • Most common in 45-55 year age group • Sometimes bilateral; often without a lump

47. Breast Cancer - Infiltrating • Paget’s disease of the breast • Uncommon – 1-2% • Red, scaly rash involving the nipple • Nipple may be inverted • May be a discharge • About 50% with underlying lump • If no lump, 60% will be in situ cancers

48. A – Normal cells B – Invading ductal cancer cells C – Basement membrane Infiltrating Ductal Carcinoma

49. A – Normal cells B – Invading lobular cancer cells C – Basement membrane Infiltrating Lobular Carcinoma

50. Vascular and Lymphatic Invasion Lymphatic channel Blood vessels