The document provides information about breast cancer including: 1. Breast cancer is the most common cancer and second leading cause of cancer death for women in the USA. 2. Survival rates for breast cancer have been increasing due to factors like adjuvant chemotherapy and hormone therapy as well as screening. 3. Risk factors for breast cancer include age, family history, genetic factors, lifestyle factors like alcohol consumption and obesity.

1. Breast Cancer Xiaoming Xie, M.D. and Ph.D. Department of Breast Oncology Sun Yat-Sen University Cancer Center 谢小明 中山大学肿瘤防治中心 乳腺科 Email:xxie1234@yahoo.com Tel: 61639540 (O) ， 13826109540 (Cell)

2. Breast cancer is the most common cancer and the second leading cause of cancer-related death for women in USA Jemal ， A., et al. CA Cancer J Clin 2008; 58:71-96

3. Breast cancer is more frequently diagnosed in affluent countries and the death rate is higher in developing countries

4. Recent Decrease in UK and USA Breast Cancer Mortality at Ages 50­69 Years Modified from Peto et al. Lancet 355:1822, 2000 Adj CTX Adj HT Screening

5. USA: Survival with breast cancer Survival rates are increasing 1 1 Ries, et al. SEER Cancer Statistics Review, 1975–2001. Available at: http://seer.cancer.gov/csr/1975_2001; 2004

6. Five Year Relative Survival Rates for Breast Cancer: 1973 - 2005 Cancer survivors increased from 3 M to 9 M in the same period CA, Jan 1973 and Jan 2005

7. Functional Anatomy

9. Blood Supply (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries(3,4,5); (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery

10. The veins of the breast and chest wall The three principal groups of veins (1) perforating branches of the internal thoracic vein; (2) perforating branches of the posterior intercostal veins; (3) tributaries of the axillary vein. The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lymph vessels generally parallel the course of blood vessels.

11. Neural anatomy of the breast Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation Lateral pectoral n. Medial pectoral n. Long Thoracic n.: supply the serratus anterior muscle . “winging of the scapula and loss of shoulder power” Thoracodorsal n. （ approach subscapular artery ） : supply latissimus dorsi muscle.

12. The lymphatic drainage of the breast 75% 20-25%

13. The lymph node groups 1. level I LN(14-19). located lateral to or below the lower border of the pectoralis minor muscle: the axillary vein （ 4-6): external mammary （ 5-6), scapular groups （ 5-7 ） 2. Level II LN (5-8): located superficial or deep to the pectoralis minor muscle the central(3-4), interpectoral groups (Rotter’s ） (1-4) 3. Level III LN : located medial to or above the upper border of the pectoralis minor muscle: the subclavicular group （ 6-12)

14. Risk factors - unchangeable 1. Being a woman 2. Age 3. Genetic factors - mutations in BRCA1 or BRCA2; 50-60% of women inheriting a BRCA1 mutation from either parent will have breast cancer by age 70 4. Family history of breast cancer (not related to BRCA mutations) 5. Personal history of hyperplastic breast disease

16. Risk factors - unchangeable 1. Being a woman 2. Age 3. Genetic factors - mutations in BRCA1 or BRCA2; 50-60% of women inheriting a BRCA1 mutation from either parent will have breast cancer by age 70 4. Family history of breast cancer (not related to BRCA mutations) 5. Personal history of hyperplastic breast disease

17. Risk factors - unchangeable/contd. 6. Personal history of breast cancer 7. Race: incidence is higher in Caucasian compared with African-American, Hispanic or Asian women. 8. Radiation treatment: chest irradiation as a child/young woman can significantly increase risk of developing breast cancer. 9. Dense breast tissue. 10. Menstrual history: early menarche (<12 yr) or late menopause (>50yr) has some association with increased risk. Also nulliparous, or first childbirth at >30 yrs.

18. Risk factors associated with lifestyle 1. Oral contraceptives - remains controversial Hormone replacement therapy - >5 years of therapy with combined estrogen and progesterone may increase risk Not breast feeding 4. Obesity, lack of physical activity 5. Alcohol - 2-5 drinks/day can increase risk x 1.5 over non-drinkers.

19. Factors with uncertain, controversial or unproven effects on risk of developing breast cancer High fat diet Induced abortions Breast implants Environmental chemical exposure (e.g. pesticides) Tobacco smoke Night shift work Human mammary tumor virus ?

20. Hereditary Breast Cancer Hereditary breast-ovarian cancer (HBOC) syndrome ： Mutation in BRCA1 , BRCA2 genes Ataxia telangiectasia (A-T) : Mutation in ATM gene Li-Fraumeni syndrome: Mutation in p53 gene (? CHEK2 gene). Cowden syndrome: Mutation in PTEN gene Peutz-Jeghers syndrome: Mutation in STK11 gene

21. Breast cancer risk assessment tool (BCRAT) BCRAT- based on Gail model , using woman’s personal medical history (previous breast biopsies, ATH), reproductive history, whether first degree relatives had breast cancer, to estimate risk of invasive breast cancer over specific periods of time (www.cancer.gov/bcrisktool) CARE model gives more accurate estimates of breast cancer risk for African-American women. Gail et al, JNCI 99: 1782-1792, 2007.

22. Histopathology of Breast Cancer

23. Carcinoma In Situ

24. Ductal carcinoma in situ (DCIS) ,cribriform type

25. Ductal carcinoma in situ (DCIS) , cemedo type

26. Lobular carcinoma in situ (LCIS )

27. Invasive Breast Carcinoma Paget's disease of the nipple Invasive ductal carcinoma. A. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80% B. Medullary carcinoma 4% C. Mucinous (colloid) carcinoma 2% D. Papillary carcinoma 2% E. Tubular carcinoma (and ICC) 2% 3 ） Invasive lobular carcinoma 10% 4 ） Rare cancers (adenoid cystic, squamous cell, apocrine)

28. Invasive ductal carcinoma

29. Infiltrating lobular carcinoma

30. Blood vessel invasion

31. Lymphatic invasion

32. Microinvasive breast cancer The extension of cancer cells beyond the basement membrane into the adjacent tissues with no focus greater than 0.1 cm in its greatest dimension. Stage: T1mic. Can be seen in association with DCIS and LCIS First stage in the development of invasion.

33. Diagnosing breast cancer

34. Triple assessment Clinical Imaging Pathology Age Examination Ultrasound Mammography MRI Fine needle aspiration cytology Core-cut biopsy

35. Clinical Presentation New lumps or a thickening in the breast or under the arm Nipple tenderness, discharge, or physical changes Skin irritation or changes (puckers, dimples, scaliness, or new creases)

36. Symptoms that may indicate breast cancer Lumps in the breast: single, hard and painless, irregular in shape Lumps in the armpit Breast pain: seldom (most the menstrual cycle, cyclic mastalgia) Bleeding or discharge from the nipple (5%) Involution or inversion of the nipple Swelling of the arm (lymphedema) Dimpling, ulceration of skin Changes in size or shape of the breast Symptoms of secondary tumors

37. A breast lump is most often the clinical problem that causes women to seek treatment and remain the most common presentation of breast carcinoma. 65% of breast cancer cases. Other less frequent presenting signs and symptoms of breast cancer include (1) breast enlargement or asymmetry; (2) nipple changes, retraction, or discharge; (3) ulceration or erythema of the skin of the breast; (4) an axillary mass; and (5) musculoskeletal discomfort. However, some of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease. Lump

38. Dimpling: skin retraction, tumors deep within the substance of the breast that involves the Cooper’s ligaments) Peau d’orange: edema of the breast. Usually obstruction of the dermal lymphatics with tumor, extensive axillary LN involvement related met tumor, primary disease of the axillary nodes, axillary dissection. (also after irradiation of the breast). Changes in the skin of the breast (DPUSE)

39. Ulceration: in advanced case, the tumor may involve the skin, leading to it. Satellite change: tumor cells enter the lymphatic vessels and form masses around the primary site.

40. Erythema ： inflammatory breast cancer, usually involves the entire breast and is distinguished from the inflammation due to infection by the absence of breast tenderness and fever.

41. Nipple retraction ： tumor involves the tissue beneath the nipple. Bleeding: Eczematous change: Paget's Changes in the character of the skin. The nipple change

42. Lymph nodes

43. Breast self-examination Encourage Adverse effect: a lifetime of uncertainty and anxiety for the patient (of proven harm!) Controversy

45. Mammography Annual screening mammography beginning at age 40 years is recommended in the United States Mammography is shown to reduce mortality from breast cancer by as much as 44% American Cancer Society (ACS) 1997 Aged > 40 Annual mammogram

47. Screening Mammography (cont.) Invasive cancer (4 mm) Malignant microcalcifications

48. Ultrasonography Ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. Breast cysts are well circumscribed, with smooth margins and an echo-free center Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior margins Breast cancer characteristically has irregular walls

50. ．

52. 乳腺癌沿 Cooper’s 韧带浸润》 50% ， C3 级

53. 肿瘤穿破浅筋膜浅层和韧带已达皮下， C4 级 。

54. MRI High sensitivity (94 – 100%) Low specificity (37 – 97%) Better “screening” tool than mammography in high-risk populations Expensive, invasive and more time consuming

55. Breast Biopsy 1. Fine-needle aspiration (FNA) biopsy Sensitivity: 65 ～ 98% Specificity: 34 ～ 100% False-positive Rate: 0.17% 2. Core-needle biopsy Automated biopsy gun (14-guage, 5 core samples for mass and 5-10 for microcalcification) Directional vacuum-assisted biopsy ( Mammotome , EnCore) Stereotactic Core Biopsy Nonpalpable Lesion Sensitivity: 92 ～ 100% Nonpalpable Lesion Imaging-guide Needle Localization 3. Incisional or Excisional Biopsy

56. Biomarkers and Circulatory tumor cells Carcinoembryonic antigen (CEA): positive rate 20%-70%. The MUC -1 gene product (CA15-3: positive 33-60%; CA27.29).(Ch 1q21-24). The HER-2/neuextrocellular domain (Ch 17q11-12). 20-30% overexpression. New serum tumor markers (uPA ， urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1). Circulatory tumor cells (CTC), 5 or more CTC cells in the blood of patients with MBC.

57. Comparative frequency of fibrocystic changes, fibroadenomas, and carcinomas by age groups

58. Staging TNM Histologic type (DCIS. LDIS, IBC) Hormone receptors (ER,PR) Oncogenes (Her-2) Staging procedures

59. TNM staging TNM 'Staging' takes into account the size of the tumour (T); whether the lymph nodes (N) are affected and; whether the tumor has matastasized (M) anywhere else. The TNM system for staging is a frequently used staging system used all over the world. More likely to use this staging system because it describes stage more accurately than others. Treat breast cancer according to the staging and grade.

60. The T0 and Tis Stage Tx: primary tumor cannot be assessed T0 ： No evidence of primary tumor Tis : Carcinoma in situ Tis (DCIS), Ductal carcinoma in situ Tis (LCIS), lobular carcinoma in situ Tis (Paget’s), paget’s disease of the nipple with no tumor. Modified from American Joint Committee on Cancer: AJCC Cancer Staging Manual , 6th ed. New York: Springer, 2002, pp 227–228.

61. T1 Stage T1mic: <0.1 cm T1a:>0.1- ≤ 0.5 cm T1b: >0.5- ≤ 1.0 cm T1c: >1.0- ≤ 2.0 cm

62. T2 Stage T2:>2.0-≤0.5

63. T3 Stage T3: >5.0 cm

64. T4 Stage Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4a: The tumor is fixed to the chest wall T4b: The tumor is fixed to the skin T4c: T4a+T4b T4d: inflammatory carcinoma (red, swollen,and painful to the touch)

65. Risk of Recurrence and Survival by Tumor Size for Patients with Node-Negative Disease 82 55 > 4.0 86 40 3.1-4.0 90 25 2.1-3.0 92 15 1.1-2.0 98 10 ≤ 1.0 5-Yr. Survival Rate (%) 10-Yr. Recurrence Rate (%) Tumor Size (cm)

66. The N stage (clinical regional LN ） Nx ： Regional lymph nodes cannot be assessed (e.g., previously removed) . N0: No cancer cells found in any LN . N1: Metastasis to movable ipsilateral axillary LN . N2: N2a:Met in ipsilateral axillary LN fixed or matted or to other structures, N2b:Met only in clinically apparent a ipsilateral internal mammary LN and in the absence of clinically evident axillary LN met. N3: N3a:Met in ipsilateral infraclavicular LN. N3b: Met in ipsilateral internal mammary LN and axillary LN. N3c: Metastasis in ipsilateral supraclavicular LN.

67. 0 12 24 36 48 60 72 84 96 108 120 Months 1.0 0.8 0.6 0.4 0.2 0.0 Proportion Relapse Free Nodal Status 0 1-3 4-9 10+ Chang JC, Hilsenbeck SG in Dis of the Br 3 rd Ed , p 673-696, 2004 Relapse Free Survival and Number of Involved Lymph Nodes

68. Lymph Node Metastasis and Survival Overall Survival Disease-Free Survival

70. The N stage (pathologic regional LN ） pNx ： Regional LN cannot be assessed (e.g., previously removed) pN0: No regional LN met histologically. pN0(i-),IHC; pN0(i+), IHC ， no IHC cluster greater than 0.2 mm. pN0(mol-),RT-PCR; pN0(mol+), RT-PCR. pN1: Met in 1 to 3 axillary LN , and/or in internal mammary LN with microscopic disease detected by SLN dissection, not clinically apparent. pN1mi: Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm) pNia: met in 1-3 axillary LN. pN1b: met in internal mammary LN with microscopic disease detected by SLN dissection pN1c: pNia+pN1b. pN2: Met in 4 to 9 axillary LN , or in clinically apparent a internal mammary LN in the absence of axillary lymph node metastasis pN2a: Met in ipsilateral axillary LN fixed or matted to other structures, pN2b:Met only in clinically apparent a ipsilateral internal mammary LN and in the absence of clinically evident axillary LN met. pN3: Met in 10 or more axillary LN (pN3a), or in infraclavicular LN (pN3a), or in clinically apparent a ipsilateral internal mammary LN in the presence of 1 or more positive axillary LN; or in more than 3 axillary LN with clinically negative microscopic met in internal mammary LN (pN3b); or in ipsilateral supraclavicular LN (pN3c).

71. The M stage (distant metastasis) Mx: Distant metastasis cannot be assessed M0: No distant metastasis M1 ： Distant metastasis.

72. Stage and Grade The stage of breast cancer means how far it has grown and whether it has spread. The grade means what the cancer cells look like under the microscope. Breast cancers can be grade 1 (Low grade or slow growing) grade 2 ( Intermediate grade ) grade 3 (High grade or fast growing)

73. What the number staging system Stage 0. Tis, N0, M0. Stage I. T1 ， N0, M0. When the cancer has spread beyond a milk duct or lobe, but not outside the breast. The tumor size for this stage is equal to or less than 2 cm. The tumour is no more than 2 cm across (T1) The LN in the armpit are not affected The cancer has not spread

74. Stage II This is divided into two groups Stage IIA : T0,N1,M0; T1,N1,M0; T2,N0,M0 ; T1,N1,M0 : The tumour is less than 2 cm , the LN under the arm contain cancer but are not stuck to each other and the cancer has not spread. T2,N0,M0 : The tumour is less than 5 cm , there are no cancer cells in LN in the armpit and the cancer has not spread. T0,N1,M0: Although no tumour is seen in the breast, the LN under the arm contain cancer cells but are not stuck together, and there is no sign of spread to other parts of the body. Stage IIB: T2,N1,M0; T3,N0,M0 T2,N1,M0 : The tumour is less than 5 cm and the LN under the arm contain cancer cells but are not stuck to each other, and the cancer has not spread or T3,N0,M0 : The tumour is bigger than 5 cm across , there are no cancer cells in the lymph nodes in the armpit and the cancer has not spread

75. Stage III Stage IIIA: T0,N2,M0; T1,N2,M0; T2,N2,M0;T3,N1,M0;T3,N2,M0. Although no tumour is seen in the breast, the lymph nodes under the arm contain cancer cells and are stuck together, but there is no sign of cancer spread or The tumour is 5 cm or less, the lymph nodes in the armpit contain cancer cells and are stuck to each other, but the cancer has not spread elsewhereor The tumour is more than 5 cm, the lymph nodes in the armpit contain cancer cells and may be stuck together, but there is no further spread. Stage IIIB: T4,N0,M0; T4,N1,M0; T4,N2,M0. The tumour is fixed to the skin or chest wall, the lymph nodes may or may not contain cancer cells, but there is no further spread. Stage IIIC: Ant T, N3, M0 . The tumour can be any size and has spread to lymph nodes in the armpit and under the breast bone, or to nodes above or below the collarbone, but there is no further spread.

76. Stage IV Stage IV. Ant T, any N, M1. Metastatic cancer, which is cancer that has spread to other more distant organs of the body. Frequent metastatic sites for breast cancer are the bones, lungs, liver or brain. Stage IV is also the classification given to inflammatory breast cancer or breast cancer that has spread to the lymph nodes in the neck near the collarbone. The tumour can be any size The lymph nodes may or may not contain cancer cells The cancer has spread or metastasised to other parts of the body such as the lungs, liver or bones

77. Survival rate and prognosis factors Stage Survival rate at 8 year(%) StageⅠ 90 StageⅡ 70 StageⅢ 40 StageⅣ 10

78. Early Breast Cancer TNM Staging System T0 No evidence of primary tumor Tis Ductal carcinoma in situ or lobular carcinoma in situ T1 Tumor ≤2 cm T2 Tumor >2 cm but ≤5 cm Greene FL, et al. AJCC Cancer Staging Manual , 6th ed., 2002.

79. Early Breast Cancer TNM Staging System (cont.) NX Regional lymph nodes cannot be assessed N0 No involvement of regional lymph nodes N1 Involvement of one to three axillary lymph nodes MX Distant metastases cannot be assessed M0 No distant metastases

80. Stage Classifications for Early Stage Disease Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIA T0 N1 M0 T1 N1 M0 T2 N0 M0 Stage IIB T2 N1 M0 Singletary SE, et al. J Clin Oncol . 2002;20:3576-3577.

81. Locally Advanced Breast Cancer （ LABC ） This means the cancer has not spread to another part of the body but may be: Bigger than 5 cm across Growing into the skin or muscle of the chest Present in the lymph nodes in the armpit, and these lymph nodes are either stuck to each other, or other structures

82. NCCN 2010 Breast Cancer

84. Overall survival for women with breast cancer according to axillary lymph node status.

85. Risk of metastases according to breast cancer volume and diameter

86. Biomarkers of Breast cancer

87. Biomarkers and Circulatory tumor cells Carcinoembryonic antigen (CEA): positive rate 20%-70%. The MUC -1 gene product (CA15-3: positive 33-60%; CA27.29).(Ch 1q21-24). The HER-2/neuextrocellular domain (Ch 17q11-12). 20-30% overexpression. New serum tumor markers (uPA ， urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1). Circulatory tumor cells (CTC), 5 or more CTC cells in the blood of patients with MBC.

88. >30% Comparison of IHC （ 3+ ） and FISH for Her-2 ×40 ×100 ID ： 177319 Invasive ductal carcinoma grade II. IHC ： +++ FISH ： + ×100

90. Candidate prognostic and predictive biomarkers indices of proliferation: proliferating cell nuclear antigen (PCNA), BrUdR, and Ki-67; indices of apoptosis:bcl-2 and the bax:bcl-2 ratio; indices of angiogenesis: vascular endothelial growth factor (VEGF) and the angiogenesis index; growth factors and growth factor receptors: human epidermal growth receptor (HER)-2/neu and epidermal growth factor receptor (EGFR); p53.

91. Prognostic factors under investigation-1 Cyclin E as a prognostic factor for breast cancer Cyclin E as predictor of response to neoadjuvant chemotherapy and hormonal therapy Validation of circulating tumor cells as prognostic and predictive markers Assays for circulating tumor cells ER reporter genes to predict antiestrogen response Markers of distant metastases in breast cancer

92. Prognostic factors under investigation-2 Screening of breast cancer for expression of 14-3 Zeta Markers predictive of local recurrence after BCS Prospective collection and characterization of nipple aspirate fluid in breast cancer

93. Breast Cancer Therapy It is now recognized that breast cancer is a systemic disease at the time of clinical diagnosis in most cases. Therapies (radiotherapy and surgery) are used to achieve local control. Systemic treatments( chemtherapy, hormone therapy, biological therapy) are used to alter the systemic milieu and attack distant metastases. Some of the factors to be considered are Whether you have had your menopause The type of breast cancer you have The size of your breast tumour The stage of your breast cancer The grade of your cancer cells The results of test on cancer cells (hormone receptors or biological therapy receptors) Patient’s general health

94. Prognostic Factors that Influence Survival Younger age at diagnosis Tumor size at diagnosis Number of nodes with metastasis Histologic grade of primary tumor Hormone and HER2 receptor status American Cancer Society . Breast Cancer Facts and Figures 2003-2004.

95. Surgical options in breast cancer Breast-Conserving Surgery (BCS): an operation to remove the cancer but not the breast itself. some of the lymph nodes that may be removed. and radiation therapy is usually given after surgery for six to eight weeks. Lumpectomy : to remove a tumor (lump) and a small amount of normal tissue around it. A second incision may be made in order to remove the lymph nodes. This treatment aims to maintain a normal breast appearance when the surgery is over. Segmental mastectomy : also called a partial mastectomy or quadrantectomy . to remove more breast tissue than with a lumpectomy. The cancerous area and a surrounding margin of normal tissue are removed.

96. Surgical options in breast cancer (cont.) Total mastectomy: also called a simple mastectomy. to remove the whole breast that has cancer . Modified radical mastectomy: to remove the whole breast that has cancer, many of the lymph nodes under the arm, the lining over the chest muscles, and sometimes, part of the chest muscles. Auchincloss (left the pectoral muscle behind) and Patey (1848) (remove the pectoralis minor muscles). Radical mastectomy (rarely done): Halsted and Meyer reported (1894) . to remove the breast that has cancer, chest wall muscles under the breast, and complete dissection of axillary LD levels I to III, the long thoracic n. and the thoracodosal neurovascular bundle.

97. Surgical options in breast cancer (cont.) Prophylactic mastectomy : is preventive removal of the breast to lower the risk of breast cancer in high-risk people. Prophylactic ovary removal . is a preventive surgery that lowers the amount of estrogen in the body, making it harder for estrogen to stimulate the development of breast cancer. Breast reconstruction . is the rebuilding of the breast after mastectomy and sometimes lumpectomy. Reconstruction can take place at the same time as cancer-removing surgery, or months to years later. Some women decide not to have reconstruction and opt for a prosthesis instead.

98. Axillary Lymph Node Dissection Goals Accurate staging Regional control Survival advantage? No benefit in removing healthy lymph nodes Is complete node dissection necessary for staging?

99. Sentinel node The sentinel nodes are the first nodes through which lymphatic fluid flows from a tumor. In other words, the sentinel nodes are like the gatekeepers to the rest of the lymph nodes.

100. Sentinel Lymph Node Biopsy as a Substitute for Axillary Lymph Node Dissection Standard practice in U.S.A. and Europe Proven accurate method for detection of clinically occult node metastases Can be used to detect lymph node metastases in patients with a clinically negative axilla Technique requires multidisciplinary participation and validation

101. Sentinel Node Biopsy 0.5 mCi of 0.2-micron technetium-99 sulfur colloid in a volume of 0.2 to 0.5 mL is injected isosulfan blue dye (Lymphazurin) is injected in a similar fashion

102. Breast cancers suitable for conservation surgery Single clinical and mammographic lesion Tumor ≤ 4 cm No local advancement (T1, T2 < 4 cm), extensive nodal involvement (No, N1), or metastases (M0) Tumor > 4 cm in a large breast

103. Radiation Therapy is mandatory following breast-conserving surgery. Whole-breast radiation following breast-conserving surgery reduces chance of local recurrence by about two-thirds. Is considered appropriate for patients at high risk of recurrence after mastectomy such as (T ≥ 5 cm, N(+) ≥ 4, involvement of the pectoralis muscle) Treatment is normally given in 3-5-weekly sessions for up to 6 weeks. Accelerated partial breast radiation as an alternative to whole-breast radiation is currently being evaluated in randomized trials Intraoperative radiotherapy following local excision of early breast cancer is a recently developed technique that is current under study.

104. Systemic Adjuvant Therapy Aim to prevent or delay distant metastases. Is based on two principles: Fisrt ， there is a burst of mitotic activity in met sites after a primary tumor is removed; secondly, breast cancer is a systemic disease characterized by widespread early occult met, which usually antedates diagnosis. Tamoxifen is beneficial for ER-positive breast cancer. Cytotoxic chemotherapy improves outcome . Benefit decreases with increasing age . The benefit of tamoxifen and chemotherapy is additive, but must be given sequentially

105. Critical Markers to Select Adjuvant Systemic Therapy Estrogen receptor (ER) Progesterone receptor (PR) HER-2 amplification/overexpression (Her-2)

106. Treatment by Molecular Class ± chemotherapy ± hormonetherapy Bisphosphonates, PTHrP Abs, RANK inhibitors PThRP overexpressors Platinum compounds (?) EGFR-inhibitors (?) Basaloid ± bevacizumab ± chemotherapy ± chemotherapy Additional Therapies Chemotherapy Triple-negative (ER, PR, HER2) trastuzumab HER2-amplified Aromatase inhibitors SERMs ER and/or PR-expressors Treatment Class

107. Tamoxifen Approved by FDA in 1977. SERM, estrogenic or antiestrogenic effects, depending on the tissue. Works in the adjuvant and the metastatic setting. Useful in chemoprevention. 20 mg/day, half-life 7-14 day, reach steady in 4 weeks Binds to ER and mask ER (ER-alfa and ER-beta ） Induced apoptosis, decrease secretion of stimulatory factors(TGF-a, IGF-I,IGF-II, PDGF), increase secretion of inhibitory growth factor (TFG-b) Inhibits the MDR gene at very high dose.

108. Adjuvant Treatment with Tamoxifen Time (yrs.) 85 76 68 73 62 54 68% 54% 0 20 40 60 80 100 0 5 10 15 Recurrence Mortality 0 20 40 60 80 100 0 5 10 15 73% 64% 91 80 73 87 73 64 Time (yrs.) Tamoxifen Control Tamoxifen Control 15% 17% 9% 18% Percent Early Breast Cancer Trialists’ Collaborative Group. Lancet . 1998:351:1451-1467 .

109. Development of Aromatase Inhibitors First generation Second generation Third generation Toxicity Specificity Potency Aminoglutethimide Fadrozole 4-OHA Anastrozol e Exemestane Letrozole Rash, etc. No adrenal Insufficiency, etc. 1,000 to 10,000 100 1

111. Comparative Efficacy of Adjuvant Hormonal Therapies Death Recurrence 12-24 P =0.16 27-64 P =0.00005 Tam (2-3 yr)  AI (2-3 yr) vs. Tam (5 yr) 24 P =0.25 43 P =0.00008 Tam  AI (10 yr) vs. Tam (5 yr) 4-14 P >0.05 19-22 P <0.007 AI vs. TAM (5 years) 33 P <0.00001 50 P <0.00001 Tam vs. no Tam (5 years) % Reduction in Annual Odds of Therapies

112. It is estimated that optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70%

113. Comparative Efficacy of Adjuvant Chemotherapies Therapies % Reduction in Annual Odds of Recurrence Death CT vs. no CT 23.5 17 (CMF vs. Nil) P <0.00001 P <0.00001 Doxorubicin vs. 12.4 (30?) 11 (35?) no Doxorubicin P =0.006 P =0.02 Paclitaxel vs. 17-30 6-18 no Paclitaxel P =0.09-0.0022 P> 0.10-0.0064 Docetaxel vs. 28 30 no docetaxel P =0.001 P =0.008

116. Adjuvant Polychemotherapy and Mortality

117. Clinical Tools: Adjuvantonline.com Adjuvant therapy with 4 cycles of AC: Mortality

118. It is estimated that optimal chemotherapy would reduce annual odds of recurrence by about 50%-60%

119. Effects of Optimal Therapy on Breast Cancer Mortality Treatment modality Reduction in odds of Death Local therapy 10% Tamoxifen 30% Anthracycline-based chemotherapy 20% Overall: approx. 50% The addition of aromatase inhibitors, taxanes and dose-dense therapy probably improved that figure to 60-65% . Trastuzumab improves it further in HER2+ group. EBCTCG 2000 and recent trial results

120. Can we predict benefit for individual patients? ER and HER2 have high NPV but low PPV Gene expression profiles have been proposed to predict pCR Oncotype Dx was reported to predict benefit from tamoxifen and chemotherapy ER status was reported to predict lower or no benefit from chemotherapy

121. Validations in Progress Predictive value of p53 alteration for efficacy of vinca alkaloids, anthracyclines, taxanes Topo II amplification as predictor of anthracycline efficacy MAP-tau expression level to predict activity of taxanes C-MYC amplification to predict activity of trastuzumab Oncotype Dx (Genomic Health) and Amsterdam 70-gene profile currently tested in large clinical trials

122. Biological Targets Steroid hormone receptor pathway HER-family IGF-family PI3K, AKT, mTOR Protein farnesylation Src TGF- β HSP90 Angiogenesis (VEGF, VEGFR) MAPK Integrins PDGF, c-KIT (?) Proteasome Apoptosis modulators Cyclins – cdks COX-2 PPAR-gamma RANK, RANK-L PTHrP Methylation, deacetylation

123. Multiple Growth factors Receptors may be Overexpressed in Numerous Tumors EGFR VEGF-R C-Met Her2 Cetuxamib XL-174 (Phase I group) Tumor Progression ? Multiple agents Herceptn ， Lapatinib

124. erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 No specific ligands - often acts as a dimer partner Heregulins NRG2 NRG3 Heregulins β-cellulin EGF, TGF    Cellulin Amphiregulin, HB-EGF Human Epidermal Growth Factor Receptor Family Adopted from Paul Shapiro TK TK TK

125. Anti-HER2/Neu antibody (Trastuzumab, Herceptin) therapy : Reduction in Risk of Deaths in Five Studies ASCO 2005; SABCS 2005 0.07 7% 59% FinHER NS NA 33% BCIRG 006 0.27 ~4% 15% N9831 sequential 0.26 1% (2-Y) 24% HERA 0.015 P value 3-Year Absolute Reduction Relative Reduction Study 2% 33% B-31/N9831

126. Anti-HER2/Neu antibody (Trastuzumab, Herceptin) therapy ： One target, four mechanisms Inhibit formation of p95 HER2 Inhibit cell proliferation activate ADCC Inhibit HER2-induced angiogenesis

127. Targeted Cancer Therapy 1. Use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis and tumor growth. 2. Types of targeted cancer therapy A. “Small-molecule” drugs Gleevec® (imatinib mesylate),---Target bcr/abl to treat CML Iressa® (gefitinib) -- targets EGFR to treat advanced NSCLC. B. “Apoptosis-inducing” drugs Velcade® (bortezomib), ---block proteasomes to treat multiple myeloma C. Monoclonal antibodies D. Cancer vaccines E. Angiogenesis inhibitors F. Gene therapy

128. Copyright ©2004 AlphaMed Press Osborne, C. et al. Oncologist 2004;9:361-377 Multiple signaling pathways involved in cancer and action of targeted therapeutics

129. Novel therapies for breast cancer: what is new from ASCO 2008 (Chu and Lu, J Hematol Oncol, 1:16) Targets Therapeutics HER2 HKI-272, Trastuzumab-DM, Pertuzumab EGFR Cetuximab, Gefitinib EGFR/HER2 Lapatinib VEGF-R,PDGF-R, c-Kit Pazopanib, Sunitinib, Axitinib VEGF Bevacizumab (Avastin) mTOR RAD001 Microtubules novel taxanes, epothilone (Ixabepilone)

130. VISA-BikDD nanoparticle therapy for breast cancer

131. Claudin-4 and FASN (fatty acid synthase) promoters are more active in breast cancer than in normal cells

132. Claudin-4 and FASN promoters were much weaker than CMV promoter

133. Notes: TSTA (two-step transcriptional amplification system), M. Iyer, et al. PNAS,2001. WPRE (posttranscriptional regulatory element of WHV), J.E. Donello, et al. J. Virol 1998 Clauind4-VISA Cl-VISA-Luc (C laudin4- Vp16-Gal4-WPRE-integrated systemic amplifier-Luc ) Claudin-4-TSTA-Luc Claudin-4-Luc-WPRE p(A) WPRE Luc G5E4T Claudin4 Gal4VP2 p(A) CCKAR Luc WPRE p(A) p(A) Luc G5E4T Claudin4 Gal4VP2 p(A)

134. Claudin-4-VISA and FASN-VISA are robust in breast cancer cells, but remain very low in normal cells

135. Cl-VISA nanoparticle targets Breast Cancer 1. Establish tumor model (4T1) 2. Treat with iv.injection of nanoparticle 3. Monitor gene expression pattern 4. quantitate the signal and plot.

136. Claudin-4-VISA-BikDD nanoparticles effectively represses tumor growth of breast cancer in vivo (in EZC model)

137. Claudin4-VISA-BikDD nanoparticles are systemically less toxic

138. CI-VISA Nanoparticles are profoundly robust, breast cancer-specific and prolongs duration of expression. CI-VISA transcriptionally targets transgene expression to breast cancer CI-VISA-BikDD nanoparticles exhibit significant antitumor effects on breast cancers, and prolongs survival in EZC mouse models. Systemic administration of CI-VISA-BikDD nanopartic is less toxic than CMV-BikDD nanoparticles in C57BL/6 mice. Summary of CI-VISA Nanoparticles

139. Xiaoming’s VISA Offices VISAs ( V p16-gal4-wpre I ntegrated S ystemic A mplifier) Pa-VISA: PaCa (C-VISA) Pr-VISA: PrCa (AT-VISA) B-VISA: BrCa (Claudin4-VISA) O-VISA: OvCa (T-VISA) H-VISA: HCC (AFP-VISA)

140. Xiaoming Xie, Chair of Dept. of Breast Oncology and Dr. Mien-Chie Hung, VP of University of Texas M.D. Anderson Cancer Center

141. << 中国医学论坛报 >>

142. US Science News

143. 美国ＡＢＣ电视台的报道 US ABC News

144. World Health Bulletin News

145. What our VISA ongoing now? Translating “VISA” Nanoparticles from Animals to Humans at UT M.D. Anderson, USA, and at Sun Yat-Sen University Cancer Center

146. Summary Physical examination of the breast and breast cancer Optimal care of patients with early stage breast cancer requires a multimodality approach Screening mammography identifies breast cancer earlier and is associated with improved survival Biomarkers and CTC of breast cancer Breast-conserving therapy is the preferred treatment option for women with early stage breast cancer

147. Summary (cont.) Sentinel lymph node biopsy is associated with lower morbidity and has become the standard practice of care in many countries Adjuvant systemic therapy has been shown to reduce the risk of disease recurrence and improve survival Magnitude of benefit derived from adjuvant therapy can be estimated and is dependent on risk of recurrence and death

148. Summary (cont.) Characteristics important for estimating the impact of adjuvant therapy include tumor size, node status, HER2 and expression of steroid hormone receptors (ER and PR) Critical Markers to select adjuvant systemic therapy.

149. Questions Factors influencing the risk breast cancer? The pathologic characteristics and classification of breast cancer? Changes in the skin of breast? Staging systems? Local control of primary tumor? TNM, Histologic typy and Hormone receptors, Oncogenes? Sequential strategy of locotherapy (surgery and radiotherapy) and systemic adjuvant and neoadjuvent therapy and biotherapy of breast cancer for treating? Recommendations for adjuvant therapy must be individualized?

150. Thank You Very Much!!! Mucho Gracias!!! 非常感谢 !!!