MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
12 breast cancer
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
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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
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
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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.
88. >30% Comparison of IHC （ 3+ ） and FISH for Her-2 ×40 ×100 ID ： 177319 Invasive ductal carcinoma grade II. IHC ： +++ FISH ： + ×100
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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
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
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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%
118. It is estimated that optimal chemotherapy would reduce annual odds of recurrence by about 50%-60%
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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
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.
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
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
Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths, by Sex, United States, 2008. *Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates are rounded to the nearest 10. Breast cancer is the most common cancer and the leading cause of cancer-related death for women around the world. Although breast cancer is more frequently diagnosed in affluent countries, the death rate associated with breast cancer is higher in economically disadvantaged countries. The reasons for this disparity are complex but are likely due to both earlier detection programs and improvements in treatments in developed countries. Accurate statistics regarding incidence and mortality rates for breast cancer are not available in many developing regions of the world. Overview of breast health care guidelines for countries with limited resources. Breast J . 2003 May-Jun;9 Suppl 2:S42-50. Global Summit Consensus Conference on International Breast Health Care: guidelines for countries with limited resources. Breast J . 2003 May-Jun;9 Suppl 2:S40-41. Early detection of breast cancer in countries with limited resources. Breast J . 2003 May-Jun;9 Suppl 2:S51-59.
The breast looks like a thickened circular disk of tissue. The mature female breast extends from the level of the second or third rib to the inframammary fold at the sixth or seventh rib. It extends transversely from the lateral border of the sternum to the anterior axillary line. Fibrous bands of connective tissue travel through the breast (suspensory ligaments of Cooper), insert perpendicularly into the dermis, and provide structural support. The deep or posterior surface of the breast rests on the fascia of the pectoralis major, serratus anterior, and external oblique abdominal muscles, and the upper extent of the rectus sheath. The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants. The breast has a protuberant conical form. The base of the cone is roughly circular, measuring 10 to 12 cm in diameter. Considerable variations in the size, contour, and density of the breast are evident between individuals. The nulliparous breast has a hemispheric configuration with distinct flattening above the nipple. With the hormonal stimulation that accompanies pregnancy and lactation, the breast becomes larger and increases in volume and density, while with senescence, it assumes a flattened, flaccid, and more pendulous configuration with decreased volume.
The breast is composed of 15 to 20 lobes (Fig. 16-3), which are each composed of several lobules. Drained by ducts that lead to the nipple. Breast alveoli are grape-like clusters which produce milk.
The breast receives its principal blood supply from (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries; and (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial ( 胸肩峰） artery (Fig. 16-6). The second, third, and fourth anterior intercostal perforators and branches of the internal mammary artery arborize in the breast as the medial mammary arteries. The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and minor, and subscapularis muscles. It also gives rise to lateral mammary branches. The veins of the breast and chest wall follow the course of the arteries with venous drainage being toward the axilla. The three principal groups of veins are (1) perforating branches of the internal thoracic vein; (2) perforating branches of the posterior intercostal veins; and (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. Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the intercostal spaces between slips of the serratus anterior muscle. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm.
The veins of the breast and chest wall follow the course of the arteries with venous drainage being toward the axilla. The three principal groups of veins are (1) perforating branches of the internal thoracic vein; (2) perforating branches of the posterior intercostal veins; and (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.
Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation ( 神经分布） of the breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the intercostal spaces between slips of the serratus anterior ( 前锯肌） muscle. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular （锁骨上） nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial （肋间壁） nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm. 乳腺由 2~6 肋间神经及颈丛 3~4 支支配。 与乳腺癌手术有关的神经： Lateral pectoral nerve 胸外侧神经 ——约在胸小肌内侧缘处跨腋静脉前方下 行进入胸大肌深面。 胸内侧神经 ——约在胸外侧神经 外 1cm 处，不跨腋静脉 进入胸小肌和胸大肌。 胸长神经 ——紧贴胸壁下行，支配前据肌。 胸背神经 ——与肩胛下血管伴行，支配肩胛下肌、大 圆肌。 Resection of the thoracodorsal n. does not result in any important cosmetic or functional defect; nevertheless, it should be preserved when possible.
The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. Several routes of lymphatic drainage of breast. 乳腺的淋巴管主要伴随乳腺的静脉行走外侧及中央部分注入腋窝淋巴结。内侧部分注入内乳淋巴结。两者之间相互吻合。 总的说来，腋窝淋巴结接受乳腺淋巴引流的 75% 左右，而内乳淋巴结仅为 20%~25% 。其次，乳腺皮下淋巴管一般注入乳晕下淋巴管丛。若其回流受阻，则可注入对侧的乳腺、腋窝、腹壁及膈下淋巴管等处。 The 6 axillary lymph node groups recognized by surgeons (Figs. 16-7 and 16-8) are (1) the axillary vein group (lateral) that consists of 4 to 6 lymph nodes, which lie medial or posterior to the vein and receive most of the lymph drainage from the upper extremity; (2) the external mammary group (anterior or pectoral group) that consists of 5 or 6 lymph nodes, which lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels and receive most of the lymph drainage from the lateral aspect of the breast; (3) the scapular group (posterior or subscapular) that consists of 5 to 7 lymph nodes, which lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels and receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder; (4) the central group that consists of 3 or 4 sets of lymph nodes, which are embedded in the fat of the axilla lying immediately posterior to the pectoralis minor muscle and receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes and directly from the breast; (5) the subclavicular group (apical) that consists of 6 to 12 sets of lymph nodes, which lie posterior and superior to the upper border of the pectoralis minor muscle and receive lymph drainage from all of the other groups of axillary lymph nodes; and (6) the interpectoral group (Rotter's) that consists of 1 to 4 lymph nodes, which are interposed between the pectoralis major and pectoralis minor muscles and receive lymph drainage directly from the breast. The lymph fluid that passes through the interpectoral group of lymph nodes passes directly into the central and subclavicular groups.
the lymph node groups are assigned levels according to their relationship to the pectoralis minor muscle. Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which consist of the subclavicular group.
The tumor suppressor genes BRCA1 and BRCA2 are involved in familial breast-ovarian cancer. It is estimated that about 80% of hereditary breast cancer is caused by mutations in BRCA1 or BRCA2 . Women who inherit a BRCA mutation have a 50% to 85% chance of breast cancer developing in their lifetime. Men with BRCA1 and BRCA2 mutations may be at increased risk of breast and prostate cancers. Both women and men with BRCA2 mutations may be at increased risk of breast cancer or other types of cancer. Approximately one in 50 women with Ashkenazi Jewish heritage carry a mutation in BRCA1 or BRCA2 genes that raises their lifetime risk of breast cancer to between 50% and 85%. Ataxia telangiectasia is caused by mutations on chromosome 11 of the ATM gene. An ataxia-telangiectasia mutation raises a woman’s breast cancer risk. Li-Fraumeni syndrome is rare and accounts for less than 1% of all breast cancers. People with Li-Fraumeni syndrome have up to a 90% lifetime risk of cancer. The p53 tumor suppressor gene is associated with the syndrome. The CHEK2 gene may also be responsible for features of Li-Fraumeni syndrome in some families, and mutations in this gene may raise the risk of breast cancer two to five times in women and increase the risk by as much as 10 times in men. Cowden syndrome confers a 25% to 50% lifetime risk of breast cancer and a 65% lifetime risk of benign breast changes. The tumor suppressor gene PTEN is associated with the syndrome. The lifetime risk of breast cancer associated with Peutz-Jeghers syndrome is approximately 50%. Associated with the tumor suppressor gene STK11 .
54–57 Cancer cells are in situ or invasive depending on whether or not they invade through the basement membrane. Broder's original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confinement within natural ductal and alveolar boundaries. As areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopy sections to exclude invasion. In 1941, Foote and Stewart published a landmark description of lobular carcinoma in situ (LCIS), which distinguished it from DCIS. In the late 1960s, Gallagher and Martin published their study of whole breast sections and described a stepwise progression from benign breast tissue to in situ cancer, and subsequently to invasive cancer. They coined the term minimal breast cancer (LCIS, DCIS, and invasive cancers smaller than 0.5 cm in size) and stressed the importance of early detection. It is now recognized that each type of minimal breast cancer has a distinct clinical and biologic behavior. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted less than 6% of all breast cancers, and by a ratio of more than 2:1, LCIS was more frequently diagnosed than DCIS. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and by a ratio of more than 2:1, DCIS was more frequently diagnosed than LCIS. Table 16-9 lists the clinical and pathologic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer, whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer. Multicentricity occurs in 60 to 90% of women with LCIS, while the rate of multicentricity for DCIS is 40 to 80%. LCIS occurs bilaterally in 50 to 70% of cases, while DCIS occurs bilaterally in 10 to 20% of cases.
nvasive breast cancers have been described as lobular or ductal in origin. Early classifications used the term lobular to describe invasive cancers that were associated with lobular carcinoma in situ, while all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. Eighty percent of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classification for invasive breast cancer: Paget's disease of the nipple was described in 1874. It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle, but may progress to an ulcerated, weeping lesion. Paget's disease is usually associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. Biopsy of the nipple will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget's cells) in the rete pegs of the epithelium. Paget's disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on S-100 antigen immunostaining in melanoma and carcinoembryonic antigen (CEA) immunostaining in Paget's disease. Surgical therapy for Paget's disease may involve lumpectomy, mastectomy, or modified radical mastectomy, depending on the extent of involvement and the presence of invasive cancer. Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in 60% of cases. This cancer usually presents in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologies with variable cellular and nuclear grades (Fig. 16-18). Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent phenotype of BRCA-1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physical examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by (1) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (2) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and (3) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation (Fig. 16-19). Approximately 50% of these cancers are associated with DCIS, which is characteristically present at the periphery of the cancer, and fewer than 10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma. Mucinous carcinoma (colloid carcinoma), another special-type breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the elderly population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consistency to the cancer. Approximately 66% of mucinous carcinomas display hormone receptors. Lymph node metastases occur in 33% of cases and 5- and 10-year survival rates are 73 and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopy sections and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma. Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a disproportionate number of nonwhite women. Typically, papillary carcinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. McDivitt and colleagues noted that it showed a low frequency of axillary lymph node metastases and had 5- and 10-year survival rates similar to those for mucinous and tubular carcinoma. Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammography screening and is usually diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases, which are usually confined to the lowest axillary lymph nodes (level I). However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%. Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 16-20). Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive lobular carcinoma varies from clinically inapparent cancers to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammography features, invasive lobular carcinoma may be difficult to detect.
Most women with early stage breast cancer have no symptoms. Pain in the breast is not usually a symptom.
62,63 The surgeon inspects the woman's breast with her arms by her side (Fig. 16-21A), with her arms straight up in the air (Fig. 16-21B), and with her hands on her hips (with and without pectoral muscle contraction). Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d'orange), nipple or skin retraction, and erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.
In the United States, annual screening mammography beginning at age 40 years is recommended by the American Cancer Society, the American College of Surgeons, the National Cancer Institute, and the American College of Radiology because randomized trials have shown a 44% reduction in mortality. Additionally, screening mammography can detect clinically occult cancer in the form of suspicious microcalcification, a mass, or architectural distortion. Disease can thus be detected before the tumor becomes palpable to the patient or the health care providers and diagnosed at an earlier stage. Interpretation of screening mammograms requires radiologists with training and expertise in this area. Screening mammography includes a two-view mammogram (taking two x-rays of the breast). It is important to note that current mammography techniques use low doses of radiation and the odds of inducing breast cancer because of radiation from mammography are extremely remote (more than 3,333,332 to 1). Kopans DB. An overview of the breast screening controversy. J Natl Cancer Inst Monogr . 1997;22:1-3. Kerlikowske K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr . 1997;22:79-86. Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet . 2003;361:1405-4510.
Screening mammography detected a four-millimeter, nonpalpable invasive ductal carcinoma, identified by the white arrow on the left (it is enlarged with a coned view in the small box). On the screening mammogram on the right, obviously malignant calcifications can be seen.
Second only to mammography in frequency of use for breast imaging, ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. On ultrasound examination, breast cysts are well circumscribed, with smooth margins and an echo-free center (Fig. 16-25). 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 (Fig. 16-26), but may have smooth margins with acoustic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization of breast lesions. It is highly reproducible and has a high patient acceptance rate, but does not reliably detect lesions that are 1 cm or less in diameter.
In the process of evaluating MRI as a means of characterizing mammography abnormalities, additional breast lesions have been detected. However, in the circumstance of both a negative mammogram and a negative physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in using MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women with a strong family history of breast cancer or who carry known genetic mutations require screening at an early age, but mammography evaluation is limited because of the increased breast density in younger women. In the second case, a study of MRI of the contralateral breast in women with a known breast cancer showed a contralateral breast cancer in 5.7% of these women.
TNM 'Staging' takes into account the size of the tumour, whether the lymph glands (lymph nodes) are affected and whether the tumour has spread anywhere else. The tests and scans you have when diagnosing your cancer give some information about the stage. The stage is important because it helps your breast cancer specialist to decide on the best treatment for you. Doctors also treat breast cancer according to its grade. A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has modified the TNM system for breast cancer
Primary tumor (T) Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3); if other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1-cm increment Paget's disease associated with a tumor is classified according to the size of the tumor)
T1mic:microinvasion 0.1 cm or less in great dimension. T1a:the tumor is more than 0.1 cm but not more than 0.5 cm across. T1b:the tumor is more than 0.5 cm but not more than 1.0 cm. T1c:the tumor is more than 1.0 cm but not more than 2.0 cm.
T2:the tumor is more than 2.0 cm but not more than 5.0 cm across.
T4 is divided into 4 groups. Inflammatory breast cancer is a cancer in which the overlying skin is red , swollen, and painful to the touch.
The five-year survival rate decreases and the 10-year risk of recurrence rate increases with increasing size of the primary tumor for patients with axillary node-negative disease.
N1. Cancer in nodes in the armpit but nodes not stuck to the structure.
There is a direct correlation between the number of involved axillary lymph nodes and the risk of recurrence and risk of mortality. Gebauer G, Fehm T, Lang N, Jager W. Tumor size, axillary lymph node status and steroid receptor expression in breast cancer: prognostic relevance 5 years after surgery. Breast Cancer Res Treat . 2002;75:167-173.
N1. Cancer in nodes in the armpit but nodes not stuck to the structure. pN2: Met in 4 to 9 axillary LN, or in clinically apparent a internal mammary lymph nodes in the absence of axillary lymph node metastasis p N2a:Metastases in ipsilateral axillary lymph nodes fixed or matted or to other structures, pN2b:Metastasis only in clinically apparent a ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis pN3: Metastasis in 10 axillary LN, or in infraclavicular lymph nodes, or in clinically apparent a ipsilateral internal mammary LN in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes. pN3a; pN3b;pN3c.
M0: No sign of cancer spread. M1: Distant metastasis, Cancer has spread to another part of the body, apart from the breast and LN under the arm.
Staging of breast cancer ， Doctors divide breast cancer into four number stages. 'Staging' takes into account various factors, such as the size of the tumour, whether cancer cells have spread into the nearby lymph glands (lymph nodes), whether the cancer cells have receptors for hormones or other proteins, and whether the tumour has spread to any other part of the body. The word tumour means either a breast lump or the area of cancer cells found on a scan or mammogram. The tests and scans you have when diagnosing your cancer give some information about the stage. The stage is important because it helps your breast cancer specialist to decide on the best treatment for you. Doctors also treat breast cancer according to its grade . They usually make decisions about treatment for breast cancer according to the TNM stage and the grade of the cancer .
Like Stage I, Stage II is considered an early stage of breast cancer. Tumors can range from 2 cm to more than 5 cm. They may or may not have spread to the axillary lymph nodes. Stage II breast cancer This is divided into two groups
Stage III (A-C). This is considered a locally advanced form of breast cancer. It has spread to the axillary lymph nodes, to tissues near the breast (such as the skin or chest wall) or to lymph nodes inside the chest wall. Tumors can range from smaller than 2 inches (5 cm) to larger than 2 inches.
Cancer is staged with the tumor, node, metastasis (TNM) staging system developed by the American Joint Commission on Cancer. This system is consistent with that of the International Union Against Cancer (UICC). The T stages here are associated with early stage disease. Greene FL, Lord DL, Fleming ID, et al. AJCC Cancer Staging Manual , 6th ed. New York, NY: Springer, 2002.
These N and M stages are associated with early stage disease.
In 2003, the American Joint Committee on Cancer (AJCC) revised the staging system for breast cancer. Prior to the revisions, stage II (IIA and IIB) was considered to be early stage disease. Most breast cancer clinicians now consider stage IIB disease to be a form of locally advanced and large primary breast cancer. The new staging system includes information on the number of nodes with metastases. Clinical stage II disease includes the presence of movable ipsilateral axillary metastases. However, if more than four lymph nodes with metastases are found during pathologic evaluation, patients are considered to have stage III breast cancer. This change was made because it was determined that the prognosis is directly proportional to the absolute number of lymph nodes with metastases. The survival rate for women with more than four lymph nodes with metastases is similar to that for women with stage III breast cancer, as defined by the previous staging system. Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on cancer staging system for breast cancer. J Clin Oncol. 2002;20:3576-3577.
Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases were possible after resection and pathologic analysis of 10 or more level I and II axillary lymph nodes. Overall survival for women with breast cancer according to axillary lymph node status. The time periods are years following radical mastectomy. ( Reproduced with permission from Valagussa P et al: Patterns of relapse and survival following radical mastectomy . Cancer 41:1170, 1978 .)
Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see Fig. 16-16B). B . Risk of metastases according to breast cancer volume and diameter ( Reproduced with permission from Koscielny S et al: Breast cancer: Relationship between the size of the primary tumor and the probability of metastatic dissemination . Br J Cancer 49:709, 1984 .)
Candidate prognostic and predictive biomarkers for breast cancer include (1) indices of proliferation such as proliferating cell nuclear antigen (PCNA), BrUdR, and Ki-67; (2) indices of apoptosis such as bcl-2 and the bax:bcl-2 ratio; (3) indices of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (4) growth factors and growth factor receptors such as human epidermal growth receptor (HER)-2/neu and epidermal growth factor receptor (EGFr); and (5) p53.
It is impossible to generalise about breast cancer treatment because there are so many different sets of circumstances. Your doctor will take many different factors into account when deciding how to treat you. 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 tests on your cancer cells Your general health
Risk factors are used to predict the prognosis for a patient and to guide treatment decisions. Relative survival rates decrease as the time after diagnosis increases. In a study reported by Michaelson et al., survival rates were 87% at five years after diagnosis, 77% at 10 years, and 52% at 20 years. Women under age 40 with breast cancer have slightly lower survival rates than older women, which may be due to more aggressive tumors and less responsiveness to hormone therapy. Survival decreases with the increasing size of tumors and five-year survival is lower for patients who have a more advanced stage of disease at the time of diagnosis. The prognosis is better for women with ER-positive or PR-positive tumors than for women with hormone-negative tumors. American Cancer Society . Breast Cancer Facts and Figures 2003-2004. Available at: www.cancer.org/downloads/STT/CAFF2003BrFPWSecured.pdf. Accessed September 25, 2004. Michaelson JS, Silverstein M, Wyatt J, et al. Predicting the survival of patients with breast carcinoma using tumor size. Cancer . 2002;95:713-723.
You may have any of these treatments, or all of them, depending on your situation. It is impossible to generalise about breast cancer treatment because there are so many different sets of circumstances. Your doctor will take many different factors into account when deciding how to treat you. This is also referred to as breast conserving therapy. The surgeon removes the cancerous area and a surrounding margin of normal tissue. 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. After the lumpectomy, a five- to eight-week course of radiation therapy is often used to treat the remaining breast tissue. The majority of women who have small, early-stage breast cancers are excellent candidates for this treatment approach. Women who are not usually eligible for a lumpectomy include those who have already had radiation therapy to the affected breast, have two or more areas of cancer in the same breast that are too far apart to be removed through one incision, or have cancer that was not completely removed during the lumpectomy surgery.
The goals of axillary lymph node dissection are to provide accurate staging information and to remove node disease that may cause later difficulty with regional control of disease. The procedure is controversial among oncologists, but it is likely that the survival advantage conferred by the removal of node disease is small. There is no benefit in removing healthy lymph nodes.
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. The Lymph Node Mapping with Sentinel Node Biopsy procedure - commonly called Sentinel Node Biopsy - helps doctors discover which lymph nodes need to be removed and whether cancer cells have spread to these nodes. Here's how the procedure works. Often, the first step is a visit to Nuclear Medicine where a radioactive tracer is injected around the tumor site. Then during surgery, the surgeon injects a blue dye around the tumor site. The lymph fluid will carry the dye and tracer as it drains to the lymph nodes.
The surgeon then looks for the node with the blue dye or scans with a special gamma probe to find the node with the highest tracer count. This is the sentinel node. Often, the first step is a visit to Nuclear Medicine where a radioactive tracer is injected around the tumor site. Then during surgery, the surgeon injects a blue dye around the tumor site. The lymph fluid will carry the dye and tracer as it drains to the lymph nodes. The surgeon then looks for the node with the blue dye or scans with a special gamma probe to find the node with the highest tracer count. This is the sentinel node. The dye or radioactive tracer creates a &quot;map&quot; of the nodes, showing which nodes to remove. In some cases, only the blue dye may be used to find the sentinel nodes. Once the sentinel lymph nodes have been &quot;mapped,&quot; the surgeon can remove those specific nodes - the Sentinel Node Biopsy. After the biopsy is done, the pathologist can do an in-depth analysis in the lab to see if the nodes contain cancer cells. The blue dye may cause the breast skin to stain blue for several days. It may also cause the urine to look greenish for about 24 hours while it is excreted by the kidneys. In rare cases, the patient may experience an allergic reaction to the dye. Sentinel Node Biopsy may add some time to a patient's surgery, but it will not increase recovery time. Furthermore, there are few serious side effects to Sentinel Node Biopsy. Due to the information from the Sentinel Node Biopsy, some patients may not need to have additional lymph nodes removed. In that case, there is less time in surgery.
Data from the Early Breast Cancer Trialists’ Collaborative Group meta-analysis has shown that tamoxifen reduces the risk of recurrence and improves survival in patients with ER-positive or ER-unknown early stage breast cancer. Cytotoxic chemotherapy has also been demonstrated to confer benefit, but has a greater impact for younger patients compared with older patients. Combined treatment with both endocrine therapy and chemotherapy is additive in terms of reducing the risk of recurrence and improving survival.
Parathyroid hormone related peptide (PTHrP) is a protein produced by tumours which may lead to hypercalcaemia. The measurement of PTHrP can be of assistance in determining the cause of an otherwise unexplained hypercalcaemia.
The findings of the Early Breast Cancer Trialists’ Collaborative Group have clearly demonstrated the benefit of five years of adjuvant treatment with tamoxifen in significantly reducing the risk of recurrence and improving survival for women with hormone receptor-positive early breast cancer. Nevertheless, disease will recur or death will occur in a significant number of patients in the 10 years following the completion of five years of adjuvant tamoxifen therapy. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998;351:1451-1467.
For mortality as well as recurrence, the benefit of adjuvant chemotherapy is greater for patients under the age of 50 who have node-positive disease. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet . 1998 Sep 19;352(9132):930-942.
Adjuvantonline.com is a tool available to anyone with access to the Internet. This tool allows the user to enter the clinical characteristics of a given patient and choose possible adjuvant therapies. The program provides the clinician with a bar diagram depicting the magnitude of benefit that might be derived from different treatments (i.e., how many recurrences or cancer-related deaths would be prevented using one therapy compared with another). The patient benefit described is based on the Early Breast Cancer Trialists’ Collaborative Group meta-analysis. www.adjuvantonline.com
positive predictive value (PPV)
Trastuzumab: 1 target, 4 mechanisms of action: activation of ADCC prevention of the formation of p95 HER2 , a truncated and very active form of HER2 inhibition of cell proliferation by preventing HER2-activated intracellular signalling inhibition of HER2-regulated angiogenesis.
Actually, targeted cancer therapy is now concept. In 2004, Dr. Charles sawyer defined it in a nature paper. Saying, Targeted cancer therapies is using drugs that block the growth and spread of cancer. Targeted cancer therapies include several types of drugs. Some examples are listed below:… .the relatively new one is gene therpay. They interfere with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. Because scientists call these molecules “molecular targets,” these therapies are sometimes called “molecular-targeted drugs,” “molecularly targeted therapies,” or other similar names. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. Most targeted cancer therapies are in preclinical testing (research with animals), but some are in clinical trials (research studies) or have been approved by the U.S. Food and Drug Administration (FDA). Targeted cancer therapies are being studied for use alone, in combination with each other, and in combination with other cancer treatments, such as chemotherapy . Targeted cancer therapies include several types of drugs. Some examples are listed below: “ Small-molecule” drugs block specific enzymes and GFRs involved in cancer cell growth. These drugs are also called signal-transduction inhibitors. Gleevec ® (STI–571 or imatinib mesylate) is a small-molecule drug approved by the FDA to treat gastrointestinal stromal tumor (a rare cancer of the gastrointestinal tract ) and certain kinds of chronic myeloid leukemia (1, 2). Gleevec targets abnormal proteins, or enzymes, that form inside cancer cells and stimulate uncontrolled growth. Iressa® (ZD1839 or gefitinib ) is approved by the FDA to treat advanced non-small cell lung cancer . This drug targets the epidermal growth factor receptor ( EGFR ), which is overproduced by many types of cancer cells. Other small-molecule drugs are being studied in clinical trials in the United States. “ Apoptosis-inducing” drugs cause cancer cells to undergo apoptosis (cell death) by interfering with proteins involved in the process. Velcade® ( bortezomib ) is approved by the FDA to treat multiple myeloma that has not responded to other treatments (3). Velcade causes cancer cells to die by blocking enzymes called proteasomes, which help to regulate cell function and growth. Another apoptosis-inducing drug called Genasense™ ( oblimersen ), which is only available in clinical trials, is being studied to treat leukemia , non-Hodgkin’s lymphoma , and solid tumors . Genasense blocks the production of a protein known as BCL–2, which promotes the survival of tumor cells. By blocking BCL–2, Genasense leaves the cancer cells more vulnerable to anticancer drugs. Monoclonal antibodies, cancer vaccines , angiogenesis inhibitors , and gene therapy are considered by some to be targeted therapies because they interfere with the growth of cancer cells. Information about these treatments can be found in the following National Cancer Institute (NCI) fact sheets, which are available on the Internet or by calling the Cancer Information Service (CIS) (see below): — Biological Therapies for Cancer: Questions and Answers includes information about monoclonal antibodies and cancer vaccines. This fact sheet is available at http:// www.cancer.gov/cancertopics/factsheet/Therapy/biological on the Internet. — Herceptin® (Trastuzumab): Questions and Answers contains information about Herceptin, which is a monoclonal antibody. This fact sheet can be found at http:// www.cancer.gov/cancertopics/factsheet/Therapy/herceptin on the Internet. — Angiogenesis Inhibitors in the Treatment of Cancer is available at http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors on the Internet. — Gene Therapy for Cancer: Questions and Answers can be found at http:// www.cancer.gov/cancertopics/factsheet/Therapy/gene on the Internet. He would have made a good pilot but his drinking habit was his Achilles ’ heel. 他本来会成为一名很好的飞行员，不过他的饮酒习惯却成了他的致命弱点。
As compared to the CMV promoter, the CCKAR promoter is very weak. We hypothesized that TSTA and WPRE could improve the CCKAR promoter activity. Thus, we engineered the CCKAR promoter with TSTA and WPRE, producing a C-VISA system (VP16-Gal4-WPRE integrated systemic amplifier). The C-VISA involves three steps, first , CCKAR promoter drives expression of the GAL4-VP16 fusion protein; second, GAL4-VP16, in turn, drives target gene expression under the control of GAL4 response elements in a minimal promoter; third, WPRE would augment posttranscriptional activity. To augment the transcriptional activity of CCKAR, the two-step transcriptional amplification (TSTA) system [22, 23] should be a good choice. In this system, the first step involves the tissue-specific expression of the GAL4-VP16 fusion protein. In the second step, GAL4-VP16, in turn, drives target gene expression under the control of GAL4 response elements in a minimal promoter. The use of TSTA can lead to amplified levels of transgene expression. Schematic diagram of the TSTA system. The first step involves the tissue-specific (e.g., PSE) expression of the GAL4-VP16 fusion protein. In the second step, GAL4-VP16, in turn, drives target gene expression under the control of GAL4 response elements in a minimal promoter [shown are five GAL4 binding sites (bs)]. Transcription of the reporter gene, either fl or HSV1-sr39 tk , leads to reporter protein, which in turn leads to a detectable signal in the presence of the appropriate reporter probe. The use of the GAL4-VP16 fusion protein can potentially lead to amplified levels of the reporter protein (FL or HSV1-sr39TK) and therefore an increase in imaging signal. The molecular biology of HBV and WHV show that its viroin contains a negative and discontinuous positive strands of DNA. The HBV liver-specific enhancer and WHV and HBV liver-specific enhancer II regulator gene expression. Importantly, the PRE element further regulate the gene expression after transcription. A) The negative and discontinuous positive strands of HBV relaxed DNA are shown in the center circle (bold). The HBV liver-specific enhancer (Enh) I and the WHV and HBV liver-specific enhancer II are shown as rectangles. The four classes of hepadnavirus RNAs are represented by the curved arrows. The RNAs encode core (C), presurface (preS), surface (S), and X proteins. The shaded region within these RNAs indicates the position of the HPRE. (B) Comparison of the PRE and enhancer I regions of HBV and WHV. The darkened regions correspond to the open reading frames of the polymerase (Pol) and X proteins. The regions containing the HPRE and HBVPRE subelements are indicated. Homologous nucleotides (nt) are aligned, and the fragments are drawn to scale. The HBV enhancer (enh) is indicated.
In conclusion. CCKAR promoter is pancreatic cancer-specific. C-VISA is robust and pancreatic cancer-specific in vitro and in vivo. C-VISA-BikDD inhibits tumor growth and prolongs mouse survival in an orthotopic model, more effectively than CMV-BikDD.
Now, we have set VISA offices in Houston, Taiwan and probably in China. we has been developing pr-visa to pancreatic cancer. More VISA to other cancers such as Breast cancer, ovarian cancer and liver cancer are under development. The oil market is enjoying a boom
