Oncology

1. Oncology Basic Science 12/1/09

2. Incidence • 1.44 million new cancer cases were diagnosed in the United States last year. • Also, over one million cases of basal and squamous cell carcinomas of the skin • #2 cause of death in U.S.

4. Hallmarks of Cancer • Hallmarks of Cancer

5. Tumorigenesis • initiation • Initiating events such as gain of function of oncogenes • promotion • loss of function of tumor-suppressor genes may lead a single cell to acquire a distinct growth advantage • progression • disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. • Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers • Mutations in at least four or five genes are required for formation of a malignant tumor, whereas fewer changes suffice for formation of a benign tumor

6. Oncogenes • Designated by three-letter abbreviations, such as myc or ras. • Oncogenes are further designated by the prefix "v-" for virus or "c-" for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. • Oncogenes may be • growth factors - platelet-derived growth factor • growth factor receptors - HER2 • intracellular signal transduction molecules - ras • nuclear transcription factors - c-myc

7. Oncogenes • ras (k-ras) • G Protein defect • Colon cancer, pancreatic cancer • ret – medullary CA of thyroid • erb B • epidermal growth factor receptor • Breast cancer • myc (c-myc, n-myc, l-myc) • Transcription factors • Burkitt’s lymphoma, nasopharyngeal CA • c-kit – CML, Gastric leiomyoma (GIST) • src- tyrosine kinase defect • sis- PDGF receptor

8. Tumor Suppressor Genes

10. Ghetto C3PO

11. Cancer Invasion • in situ cancer vs invasive cancer - tumors that breach the basement membrane • glycoproteins of the ECM bind to tumor cell integrin receptors • Serine, cysteine, and aspartic proteinases and MMPs • MMPs comprise a family of metal-dependent endopeptidases • Active in alsmost every cancer type

12. Metastasis

13. Metastasis • Metastasis is an inefficient process • Must establish vascularization to sustain the new tumor • Only a small subset of cancer cells is able to initiate micrometastases, even smaller - macrometastases.

14. Metastasis • Colon  Liver • Melanoma Skin, Lung, Small bowel • Lung  Brain, Heart • Sarcoma  Lung • Breast  Brain, Adrenal • To Bone  Breast, Prostate, Thyroid • To Skin  Breast, melanoma • To Ovary  Stomach (Krukenberg) • To Small bowel Melanoma

15. Evil Nodes • Supraclavicular node • Stomach (Virchow’s Node) • Neck, breast, lung, pancreas CA • Axillary Node • Lymphoma #1 • breast, melanoma • Periumbilical node • pancreas (Sister Mary Joseph)

16. Selected Genes/Cancers • Hereditary Retinoblastoma (Rb1) • led to the theory that a single mutation is not sufficient for tumorigenesis. • hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations • Knudson's "two-hit" hypothesis. • A "hit" may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene.

17. BRCA1, BRCA2 • Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in  BRCA1 or BRCA2. • Higher in patients such as in the Ashkenazi Jewish population. • Cumulative risks of developing breast cancer and ovarian cancer • BRCA 1– 87% and 44% • BRCA 2- 84% and 27% • Responsible for male breast CA

18. APC Gene and Familial Adenomatous Polyposis • Hundreds to thousands of polyps in the colon and rectum. • Appear in adolescence progress to colorectal cancer. • FAP is associated with benign extracolonic manifestations • congenital hypertrophy • retinal pigment epithelium • epidermoid cysts, and osteomas. • Also at risk for • upper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer), • hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), • thyroid carcinomas, desmoid tumors, and medulloblastomas. • Gardner’s and Turcot’s

19. Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) • Autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. • DNA mismatch repair genes • HNPCC consists of at least two syndromes: • Lynch syndrome 1- colorectal cancer • Lynch syndrome 2- colorectal cancer + carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas. • Amsterdam Criteria

20. Amsterdam Criteria(3-2-1 rule) • At least 3 relatives with an HNPCC-associated cancer: colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis. • At least two successive generations should be affected • At least one tumor should be diagnosed <50 years of age

23. Carcinogens • Coal Tar – larynx, skin, bronchial CA • Beta-naphthylamine – bladder CA • Benzene- leukemia • Asbestos – Mesothelioma • Chinese-style salted fish- Nasopharyngeal carcinoma

24. Carcinogens • Epstein-Barr virus- • Burkitt's lymphoma  • Hodgkin's disease  • Nasopharyngeal carcinoma • Hepatitis B/C virus- Hepatocellular carcinoma • HIV • Kaposi's sarcoma • lymphoma • Human papillomavirus 16 and 18 • Cervical cancer • Anal cancer

25. Screening • http://www.accessmedicine.com/content.aspx?aID=5021361

26. Cancer Diagnosis • Fine-needle aspiration • is easy and relatively safe • disadvantage of not giving information on tissue architecture. Cannot differentiate between an invasive and noninvasive tumor • Core-needle biopsy • is more advantageous when the histologic findings will affect the recommended therapy. • performed either by direct palpation or can be guided by an imaging study • disadvantage of introducing sampling error • Open biopsies • have the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure. • Incisional biopsies are reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy. • Excisional biopsies are performed for lesions for which either core biopsy is not possible or the results are nondiagnostic. Should be performed with curative intent.

27. Staging • TNM staging • For Absite, review: • Breast Cancer • Colon Cancer • Melanoma • Lung cancer

28. Tumor Markers

29. Prostate-Specific Antigen • PSA is the best serum marker available with highest sensitivity • PSA levels may be elevated in benign prostate conditions such as prostatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. • useful in evaluating treatment and monitoring for recurrence after therapy. In monitoring for recurrence, a trend of increasing levels is more significant than a single absolute elevated value. • American Urologic Association and the American Cancer Society both recommend yearly PSA testing for men aged 50 years and older • total serum PSA level of 4 ng/mL should be used as a threshold for performing a prostate biopsy

30. Surgical Management of Primary Tumors • The goal of surgical therapy for cancer is to achieve oncologic cure. • A curative operation presupposes that the tumor is confined to the organ of origin • Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease. • The operability of primary tumors is best determined with imaging studies that can define the extent of local-regional disease. • Primary tumors can be resected for palliative reasons, such as improving the quality of life by alleviating pain, infection, or bleeding.

31. Surgical Management of Lymph Nodes • Unlike most carcinomas, soft tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore lymph node surgery usually is not necessary. • generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancers • On the other hand, there have been opposing opposing views regarding the role of lymphadenectomy in survival of cancer patients.

32. Surgical Management of Lymph Nodes • Relatively new development • Lymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by Cabanas for penile cancer • Lymphatic mapping • isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combination of both techniques to detect sentinel nodes. • ***There is no role for sentinel LN BX for clinically palpable nodes

33. Surgical Management of Distant Metastases • depends on the number and sites of metastases, the cancer type, the rate of tumor growth • such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain. 25% 5 year survival for a single colonic met to liver if successfully resected.

34. Chemotherapy • Classified according to the phase of the cell cycle during which they are effective. • Cell-cycle phase–nonspecific agents have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug. • Cell-cycle phase–specific drugs have a plateau, and cell kill will not increase with further increases in drug dose • Methotrexate and 5-FU are cell cycle specific, all others are non-specific

36. Radiation Therapy • M phase is most vunerable stage of cell cycle for XRT • Most damage to DNA is done by formation of oxygen radicals with H2O2 intermediate • More oxygenated tumor = more damage • Large tumors less responsive • To a lesser extent, ionizing radiation itself can cause direct DNA damage • Most is external beam radiation • Brachytherapy: source of radiation delivered directory into operative bed using catheters. Allows high concentrated radiation with fewer side effects.

37. Radiation Therapy • Fractional Doses • Allows repair of normal cells • Allows reoxygenation of tumor • Allows redistribution of tumor cells in cell cycle • Radiosensitive tumors: • Seminomas, lymphomas • Radioresistant tumors • Epithelial, Sarcomas

38. Side effects

40. THE END