1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Breast Cancer

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Worldwide incidence in females* *Incidence per 100,000 population. Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64. 67.4 36.0 28.6 71.7 21.2 25.0 31.5 25.5 86.3 EasternEurope Japan Australia/ New Zealand South Central Asia NorthAfrica SouthAfrica CentralAmerica Western Europe Europe NorthAmerica

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Age-specific incidence (per 100,000) New Horizons in Cancer Management, SRI International, 1990. Incidence Rates 20 2530 3540 4550 55 606570 758085+ 24 2934 3944 4954 59 646974 7984 420 400 300 200 100 0 Age United States England and Wales Italy France Japan

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Cumulative probability of developing breast cancer BREAST CANCER Cumulative probability of developing breast cancer Feuer EJ, et al, JNCI. 1993. % Developing Breast Cancer 3040506070 10 9 8 7 6 5 4 3 2 1 0 4.3 2.0 0.4 1.6 3.9 7.1 2.4 5.7 3.6 7.1 9.0 9.1 7.1 6.5 4.1 In 10 years In 20 years In 30 years Age (years)

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Stage at diagnosis by race Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36. Categories do not total 100% because staging information is not available for all cases. 010203040506070 African American White Localized Regional Distant % of Cases 63 29 6 51 34 9

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER 5-year relative survival rate by ethnicity 020406080100120 African American White All Stages Localized Regional Distant % Surviving 5 Years 86 97 79 71 89 64 15 22 Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Natural history Highly variable course Relatively slow growth rate Generally present several years before time of diagnosis Long preclinical period potentially enables early detection Median survival >2 years in patients receiving conventional treatment for metastatic disease Osteen RT. American Cancer Society Textbook of Clinical Oncology. 3rd ed. 2001;251-268.

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Risk factors BREAST CANCER Risk factors Age Family history of breast cancer Prior personal history of breast cancer Increased estrogen exposure Early menarche Late menopause Hormone replacement therapy/oral contraceptives Nulliparity First pregnancy after age 30 Diet and lifestyle (obesity, excessive alcohol consumption) Radiation exposure before age 40 Prior benign or premalignant breast changes In situ cancer Atypical hyperplasia Radial scar Osteen RT. American Cancer Society Textbook of Clinical Oncology. 3rd ed. 2001;251-268. Winer EP, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1651-1717.

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Breast self-examinationExaminationMammography—the by physicianonly modality shown to decrease mortality Risk factors BREAST CANCER Risk factors

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Screening (high-risk) Annual mammography, beginning 5 yrs before age of youngest affected relative at time of diagnosis Target population: *) High familial risk *) BRCA 1/2-positive Tripathy D, Henderson IC. Current Cancer Therapeutics. 3rd ed. 1999;123-129.

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Breast inspection BREAST CANCER Breast inspection Skin dimpling

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Breast palpation BREAST CANCER Breast palpation

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Regional node assessment BREAST CANCER Regional node assessment

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Screening mammography BREAST CANCER Screening mammography Reduces mortality by approximately: 25-30% in women in their 50s 18% in women in their 40s Supports view that early diagnosis and treatment can prevent metastases ACS recommends annual mammogram starting at age 40 Rimer BK, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;627-640. Smith RA. American Cancer Society Textbook of Clinical Oncology. 3rd ed. 2001:75-121.

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Horizontal mammography BREAST CANCER Horizontal mammography

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Vertical mammography BREAST CANCER Vertical mammography

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Signs and symptoms at presentation BREAST CANCER Signs and symptoms at presentation Mass or pain in the axilla Palpable mass ThickeningPain Nipple discharge Nipple retraction Edema or erythema of the skin

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER

19. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Mammography BREAST CANCER Mammography

20. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Ultrasonography BREAST CANCER Ultrasonography

21. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Liver metastases BREAST CANCER Liver metastases

22. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria MRI scan: Bone metastasis BREAST CANCER MRI scan: Bone metastasis

23. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Diagnostic pathway Evaluation for biopsy Cyst aspiration Biopsy Excisional biopsy Core-cutting needle biopsy Fine-needle aspiration Palpable mass Ductal carcinoma in situ Invasive cancer Lobular carcinoma in situ Benign Insufficient evaluation, rebiopsy If persistent, short-term follow-up with surgeon Continue appropriate screening Cyst Normal Nonpalpable mass Treatment Path Needle localization

24. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Biopsy techniques for palpable and mammographically detected masses BREAST CANCER Biopsy techniques for palpable and mammographically detected masses Excisional biopsy (usually outpatient) Tumor size and histologic diagnosis Core-cutting needle biopsy (in-office) Histological diagnosis Fine-needle aspiration (in-office) Cytological diagnosis Winer E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1651-1717.

25. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Fine-needle aspiration biopsy BREAST CANCER Fine-needle aspiration biopsy In Back and Forth EndSuction Suction Out

26. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Pathology BREAST CANCER Pathology Non-invasive carcinoma in situ Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS) Invasive carcinoma Infiltrating ductal or lobular carcinoma Medullary, mucinous, and tubular carcinomas Uncommon tumors Inflammatory carcinoma Paget’s disease Dollinger M, et al. Everyone’s Guide to Cancer Therapy. 1997;356-384.

27. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Pathology: Non-invasive DCIS & LCIS BREAST CANCER Pathology: Non-invasive DCIS & LCIS DCIS LCIS DCIS LCIS Abnormal mammogramMicroscopic characterization on biopsy Clustered microcalcificationsSolid proliferation of small or non-palpable massescells with uniform round to oval nuclei 30% risk of invasive cancer37% chance of subsequent at 10 years at or nearinvasive cancer original biopsy site DCIS –ductal carcinoma in situ. LCIS –lobular carcinoma in situ. Winer E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1651-1717. Love S, Barsky SH. Cancer Treatment. 4th ed. 1995;337-340.

28. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Incidence of major histologic types BREAST CANCER Incidence of major histologic types Percent of all invasive carcinomas Hendersn IC. American Cancer Society Textbook & Clinical Oncology. 2nd ed. 1995;198-219. 80% 10% 5% Infiltrating Lobular Medullary

29. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Invasive ductal carcinoma BREAST CANCER Invasive ductal carcinoma

30. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria BREAST CANCER Anatomical site

31. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Spread to lymph nodes BREAST CANCER Spread to lymph nodes

32. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Sites of distant metastases BREAST CANCER Sites of distant metastases

33. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TNM stage grouping BREAST CANCER TNM stage grouping Stage 0 Stage 0TisN0M0 Stage I Stage IT1*N0M0 Stage IIA Stage IIAT0N1M0 T1* N1**M0 T2N0M0 Stage IIB Stage IIBT2N1M0 T3N0M0 Stage IIIA Stage IIIAT0, T1,* T2N2M0 T3N1, N2M0 Stage IIIB Stage IIIB T4Any NM0 Any TN3M0 Stage IV Stage IVAny TAny NM1 * Note: T1 includes T1 mic. ** Note: The prognosis of patients with N1a is similar to that of patients with pN0. AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.

34. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Tumor definitions BREAST CANCER Tumor definitions TXPrimary tumor cannot be assessed T0No evidence of primary tumor TisCarcinoma in situ: Intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of the nipple with no tumor T1Tumor 2 cm or less in its greatest diameter T1mic Microinvasion more than 0.1 cm or less in its greatest diameter T1aTumor more than 0.1 cm but not more than 0.5 cm in its greatest diameter T1bTumor more than 0.5 cm but not more than 1 cm in its greatest diameter T1cTumor more than 1 cm but not more than 2 cm in its greatest diameter T2Tumor more than 2 cm but not more than 5 cm in its greatest diameter T3Tumor more than 5 cm in its greatest diameter T4Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4aExtension to chest wall T4bEdema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4cBoth (T4a and T4b) T4dInflammatory carcinoma AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.

35. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage I BREAST CANCER Stage I T1a: T  0.5 cm T1b: 0.5 cm < T  1 cm T1c: 1 cm < T  2 cm T1 N0 M0 T  2 cm T1 N0 = no regional lymph node metastasis M0 = no distant metastasis

36. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage IIA BREAST CANCER Stage IIA

37. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage IIB BREAST CANCER Stage IIB

38. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage IIIA BREAST CANCER Stage IIIA

39. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage IIIB BREAST CANCER Stage IIIB

40. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Stage IV BREAST CANCER Stage IV

41. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Commonly assessed prognostic factors BREAST CANCER Commonly assessed prognostic factors Slamon DJ. Chemotherapy Foundation. 1999;46. Winer E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1651-1717. Nuclear grade Estrogen/progesterone receptors HER2/neu overexpression Number of positive axillary nodes Tumor size Lymphatic and vascular invasion Histologic tumor type Histologic grade

42. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 5-year survival as function of the number of positive axillary lymph nodes BREAST CANCER 5-year survival as function of the number of positive axillary lymph nodes 0% 20% 40% 60% 80% 5-Year Survival 0123456-1011-1516-20>20 Number of Positive Nodes Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.

43. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria HER-2/neu overexpression BREAST CANCER HER-2/neu overexpression HER-2/neu gene is overexpressed in 25% to 30% of breast cancer patients There is a significant decrease of 5-year survival in breast cancer patients whose tumors overexpress HER-2/neu This decrease in 5-year survival is significant for both node-positive and node-negative patients In vitro studies show that HER-2/neu overexpression increases the following cell activities in malignant breast epithelial cells: DNA synthesis Cell growth Anchorage-dependent growth Tumorgencity Metastatic potential Slamon DJ. Chemotherapy Foundation Symposium. 1999;46. Abstract 39. Goldenberg MM. Clinical Therapeutics. 1999;21(2):309-318.