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 promotion progression
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) ret – medullary CA of thyroid erb B
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
Retinoblastoma
(RB1)
Chromo 13
Cell cycle
Osteosarcoma
P53
Chromo 17
Li-Fraumani- sarcoma, breast, leukemia
adrenal, brain
APC
Chromo 5
Cell adhesion
FAP (colon cancer)
DCC
Chromo 18
Colon cancer
bcl
Apoptosis
Breast CA, multiple
BRCA I/II
Chromo
17/13
DNA repair
Breast CA

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 Axillary Node Periumbilical 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

26. Cancer Diagnosis Fine-needle aspiration Core-needle biopsy
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 Marker Cancer Sensitivity Specificity
Prostate-specific antigen (PSA)
Prostate
57–93
55–68
Carcinoembryonic antigen (CEA)
Colorectal
40–47 90
Alpha-fetoprotein (AFP)
Hepatocellular 98 65
Cancer antigen 19-9
Pancreatic
78–90 95
Cancer antigen 125
Ovarian
Beta-HCG
Testicular, Choriocarcinoma
NSE
Small cell lung
Neuroblastoma

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

35. Drug Mech of action Side FX Methotrexate
Inhibits dihydrofolate reductase
inhibiting purine synthesis
Renal toxicity
5-Flourouracil
(5-FU)
Inhibits thymidylate synthesis
Cyclophosphamide
Alkylating agent
Gonad dysfxn, SIADH, hemorrhagic cystitis
Isofosfamide
Bisulfan
Pulmonary fibrosis
Cisplatin
Platinum alkylating agent
Nephro, neuro, ototoxic
Carboplatin
Bone marrow surpression
Vincristine
Microtubule inhibitor
Neurotoxic
Vinblastine
Taxol
Microtubule stabilizer
Etopside
Inhibits topoisomerase
Bleomycin
Antitumor antibiotic
Doxorubicin
(O2 radical formation)
Heart toxicitiy
Levamisole
Antihelminthic drug, stimulates immune system

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 Radiosensitive tumors:
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