OncologyOncology

Basic ScienceBasic Science

12/1/0912/1/09

IncidenceIncidence

1.44 million new cancer cases were 1.44 million new cancer cases were diagnosed in the United States last year.diagnosed in the United States last year.

Also, over one million cases of basal and Also, over one million cases of basal and squamous cell carcinomas of the skin squamous cell carcinomas of the skin

#2 cause of death in U.S.#2 cause of death in U.S.

Hallmarks of Cancer Hallmarks of Cancer

Hallmarks of Cancer Hallmarks of Cancer

Tumorigenesis Tumorigenesis

initiation initiation – Initiating events such as gain of function of Initiating events such as gain of function of oncogenesoncogenes

promotion promotion – loss of function of loss of function of tumor-suppressor genestumor-suppressor genes may lead a single cell to may lead a single cell to

acquire a distinct growth advantage acquire a distinct growth advantage progression progression

– disease of clonal progression as tumors arise from a single cell and disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly accumulate mutations that confer on the tumor an increasingly aggressive behavior. aggressive behavior.

– Most tumors go through a progression from benign lesions to in situ Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers tumors to invasive cancers

– Mutations in at least four or five genes are required for formation of Mutations in at least four or five genes are required for formation of a malignant tumor, whereas fewer changes suffice for formation of a malignant tumor, whereas fewer changes suffice for formation of a benign tumor a benign tumor

Oncogenes Oncogenes

Designated by three-letter abbreviations, such as Designated by three-letter abbreviations, such as mycmyc or or ras.ras.

Oncogenes are further designated by the prefix Oncogenes are further designated by the prefix "v-" for virus or "c-" for cell or chromosome, "v-" for virus or "c-" for cell or chromosome, corresponding to the origin of the oncogene when corresponding to the origin of the oncogene when it was first detected. it was first detected.

Oncogenes may be Oncogenes may be – growth factors - platelet-derived growth factorgrowth factors - platelet-derived growth factor– growth factor receptors - HER2growth factor receptors - HER2– intracellular signal transduction molecules - intracellular signal transduction molecules - rasras– nuclear transcription factors - c-nuclear transcription factors - c-mycmyc

OncogenesOncogenes

ras (k-ras)ras (k-ras)– G Protein defectG Protein defect– Colon cancer, pancreatic cancerColon cancer, pancreatic cancer

ret – medullary CA of thyroidret – medullary CA of thyroid erb Berb B

– epidermal growth factor receptorepidermal growth factor receptor– Breast cancerBreast cancer

myc (c-myc, n-myc, l-myc)myc (c-myc, n-myc, l-myc)– Transcription factorsTranscription factors– Burkitt’s lymphoma, nasopharyngeal CABurkitt’s lymphoma, nasopharyngeal CA

c-kit – CML, Gastric leiomyoma (GIST)c-kit – CML, Gastric leiomyoma (GIST) src- tyrosine kinase defectsrc- tyrosine kinase defect sis- PDGF receptorsis- PDGF receptor

Tumor Suppressor GenesTumor Suppressor GenesRetinoblastomaRetinoblastoma

(RB1)(RB1)

Chromo Chromo 1313

Cell cycleCell cycle RetinoblastomaRetinoblastoma

OsteosarcomaOsteosarcoma

P53P53 Chromo Chromo 1717

Cell cycleCell cycle Li-FraumaniLi-Fraumani- sarcoma, - sarcoma, breast, leukemiabreast, leukemia

adrenal, brainadrenal, brain

APCAPC Chromo Chromo 55

Cell adhesionCell adhesion FAPFAP (colon cancer) (colon cancer)

DCCDCC Chromo Chromo 1818

Cell adhesionCell adhesion Colon cancerColon cancer

bcl bcl ApoptosisApoptosis Breast CA, multipleBreast CA, multiple

BRCA I/IIBRCA I/II ChromoChromo

17/1317/13

DNA repairDNA repair Breast CABreast CA

Ghetto C3POGhetto C3PO

Cancer Invasion Cancer Invasion

in situ cancerin situ cancer vs vs invasive cancerinvasive cancer - tumors - tumors that breach the basement membranethat breach the basement membrane– glycoproteins of the ECM bind to tumor cell glycoproteins of the ECM bind to tumor cell

integrin receptors integrin receptors – Serine, cysteine, and aspartic proteinases and Serine, cysteine, and aspartic proteinases and

MMPs MMPs MMPs comprise a family of metal-dependent MMPs comprise a family of metal-dependent

endopeptidases endopeptidases Active in alsmost every cancer typeActive in alsmost every cancer type

Metastasis Metastasis

MetastasisMetastasis

Metastasis is an inefficient process Metastasis is an inefficient process Must establish vascularization to sustain the Must establish vascularization to sustain the

new tumor new tumor Only a small subset of cancer cells is able to Only a small subset of cancer cells is able to

initiate micrometastases, even smaller - initiate micrometastases, even smaller - macrometastases. macrometastases.

Metastasis Metastasis

Colon Colon Liver Liver MelanomaMelanoma Skin, Lung, Small bowel Skin, Lung, Small bowel Lung Lung Brain, Heart Brain, Heart Sarcoma Sarcoma Lung Lung Breast Breast Brain, Adrenal Brain, Adrenal

To Bone To Bone Breast, Prostate, Thyroid Breast, Prostate, Thyroid To Skin To Skin Breast, melanoma Breast, melanoma To Ovary To Ovary Stomach (Krukenberg) Stomach (Krukenberg) To Small bowelTo Small bowel Melanoma Melanoma

Evil NodesEvil Nodes

Supraclavicular node Supraclavicular node – Stomach (Virchow’s Node) Stomach (Virchow’s Node) – Neck, breast, lung, pancreas CANeck, breast, lung, pancreas CA

Axillary Node Axillary Node – Lymphoma #1 Lymphoma #1 – breast, melanomabreast, melanoma

Periumbilical nodePeriumbilical node– pancreas (Sister Mary Joseph)pancreas (Sister Mary Joseph)

Selected Genes/CancersSelected Genes/Cancers

Hereditary Retinoblastoma (Rb1)Hereditary Retinoblastoma (Rb1)– led to the theory that a single mutation is not sufficient led to the theory that a single mutation is not sufficient

for tumorigenesis. for tumorigenesis. – hereditary retinoblastoma involves two mutations, of hereditary retinoblastoma involves two mutations, of

which one is germline and one somatic, whereas which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic nonhereditary retinoblastoma is due to two somatic mutations mutations

– Knudson's "two-hit" hypothesis.Knudson's "two-hit" hypothesis. – A "hit" may be a point mutation, a chromosomal deletion A "hit" may be a point mutation, a chromosomal deletion

referred to as referred to as allelic loss,allelic loss, or a loss of heterozygosity, or or a loss of heterozygosity, or silencing of an existing gene. silencing of an existing gene.

BRCA1, BRCA2BRCA1, BRCA2

Of women with early-onset breast cancer (aged 40 Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline years or younger), nearly 10% have a germline mutation in  mutation in  BRCA1BRCA1 or or BRCA2.BRCA2.

Higher in patients such as in the Ashkenazi Jewish Higher in patients such as in the Ashkenazi Jewish population. population.

Cumulative risks of developing breast cancer and Cumulative risks of developing breast cancer and ovarian cancer ovarian cancer – BRCA 1– 87% and 44%BRCA 1– 87% and 44%– BRCA 2- 84% and 27% BRCA 2- 84% and 27%

Responsible for male breast CAResponsible for male breast CA

APCAPC Gene and Familial Gene and Familial Adenomatous Polyposis Adenomatous Polyposis

Hundreds to thousands of polyps in the colon and rectum. Hundreds to thousands of polyps in the colon and rectum. Appear in adolescence progress to colorectal cancer. Appear in adolescence progress to colorectal cancer. FAP is associated with benign extracolonic manifestationsFAP is associated with benign extracolonic manifestations

– congenital hypertrophy congenital hypertrophy – retinal pigment epitheliumretinal pigment epithelium– epidermoid cysts, and osteomas.epidermoid cysts, and osteomas.

Also at risk forAlso at risk for– upper intestinal neoplasms (upper intestinal neoplasms (gastric and duodenal polyps, duodenal gastric and duodenal polyps, duodenal

and periampullary cancerand periampullary cancer), ), – hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and

cholangiocarcinoma),cholangiocarcinoma),– thyroid carcinomas, desmoid tumors, and medulloblastomas. thyroid carcinomas, desmoid tumors, and medulloblastomas.

Gardner’s and Turcot’sGardner’s and Turcot’s

Mismatch Repair Genes and Hereditary Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer Nonpolyposis Colorectal Cancer

(HNPCC) (HNPCC) Autosomal dominant hereditary cancer syndrome that Autosomal dominant hereditary cancer syndrome that

predisposes to a wide spectrum of cancers, including predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. colorectal cancer without polyposis.

DNA mismatch repair genesDNA mismatch repair genes HNPCC consists of at least two syndromes: HNPCC consists of at least two syndromes:

– Lynch syndrome 1Lynch syndrome 1- colorectal cancer- colorectal cancer– Lynch syndrome 2- Lynch syndrome 2- colorectal cancer + carcinoma of the colorectal cancer + carcinoma of the

endometrium, transitional cell carcinoma of the ureter and renal endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.pancreas.

Amsterdam Criteria Amsterdam Criteria

Amsterdam CriteriaAmsterdam Criteria(3-2-1 rule)(3-2-1 rule)

At least At least 33 relatives with an HNPCC-associated relatives with an HNPCC-associated cancer: colorectal cancer, or cancer of the cancer: colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal endometrium, small intestine, ureter or renal pelvis. pelvis.

At least At least twotwo successive generations should be successive generations should be affected affected

At least At least oneone tumor should be diagnosed <50 tumor should be diagnosed <50 years of age years of age

CarcinogensCarcinogens

Coal Tar – larynx, skin, bronchial CACoal Tar – larynx, skin, bronchial CA Beta-naphthylamine – bladder CABeta-naphthylamine – bladder CA Benzene- leukemiaBenzene- leukemia Asbestos – MesotheliomaAsbestos – Mesothelioma

Chinese-style salted fish- Nasopharyngeal Chinese-style salted fish- Nasopharyngeal carcinomacarcinoma

CarcinogensCarcinogens

Epstein-Barr virus- Epstein-Barr virus- – Burkitt's lymphoma Burkitt's lymphoma – Hodgkin's disease Hodgkin's disease – Nasopharyngeal carcinomaNasopharyngeal carcinoma

Hepatitis B/C virus- Hepatocellular carcinoma Hepatitis B/C virus- Hepatocellular carcinoma HIV HIV

– Kaposi's sarcomaKaposi's sarcoma– lymphoma lymphoma

Human papillomavirus 16 and 18Human papillomavirus 16 and 18– Cervical cancerCervical cancer– Anal cancerAnal cancer

ScreeningScreening

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

Cancer Diagnosis Cancer Diagnosis Fine-needle aspirationFine-needle aspiration

– is easy and relatively safeis easy and relatively safe– disadvantage of not giving information on tissue architecture. Cannot disadvantage of not giving information on tissue architecture. Cannot

differentiate between an invasive and noninvasive tumor differentiate between an invasive and noninvasive tumor Core-needle biopsyCore-needle biopsy

– is more advantageous when the histologic findings will affect the recommended is more advantageous when the histologic findings will affect the recommended therapy. therapy.

– performed either by direct palpation or can be guided by an imaging studyperformed either by direct palpation or can be guided by an imaging study– disadvantage of introducing sampling error disadvantage of introducing sampling error

Open biopsiesOpen biopsies – have the advantage of providing more tissue for histologic evaluation and the have the advantage of providing more tissue for histologic evaluation and the

disadvantage of being an operative procedure. disadvantage of being an operative procedure. Incisional biopsies are reserved for very large lesions in which a definitive diagnosis Incisional biopsies are reserved for very large lesions in which a definitive diagnosis

cannot be made by needle biopsy. cannot be made by needle biopsy. Excisional biopsies are performed for lesions for which either core biopsy is not Excisional biopsies are performed for lesions for which either core biopsy is not

possible or the results are nondiagnostic. possible or the results are nondiagnostic. Should be performed with curative Should be performed with curative intent.intent.

StagingStaging

TNM stagingTNM staging For Absite, review: For Absite, review:

– Breast CancerBreast Cancer– Colon CancerColon Cancer– MelanomaMelanoma– Lung cancerLung cancer

Tumor MarkersTumor MarkersMarker 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 lungNeuroblastoma

Prostate-Specific AntigenProstate-Specific Antigen

PSA is the best serum marker available with highest sensitivityPSA is the best serum marker available with highest sensitivity PSA levels may be elevated in benign prostate conditions such as PSA levels may be elevated in benign prostate conditions such as

prostatitis and benign prostatic hyperplasia, as well as in men with prostatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. prostate cancer.

useful in evaluating treatment and monitoring for recurrence after useful in evaluating treatment and monitoring for recurrence after therapy. In monitoring for recurrence, a trend of increasing levels is therapy. In monitoring for recurrence, a trend of increasing levels is more significant than a single absolute elevated value.more significant than a single absolute elevated value.

American Urologic Association and the American Cancer Society both American Urologic Association and the American Cancer Society both recommend recommend yearly PSA testing for men aged 50 years and older yearly PSA testing for men aged 50 years and older

total serum PSA level of total serum PSA level of 4 ng/mL should be used as a threshold for 4 ng/mL should be used as a threshold for performing a prostate biopsyperforming a prostate biopsy

Surgical Management of Primary Surgical Management of Primary TumorsTumors

The goal of surgical therapy for cancer is to achieve oncologic The goal of surgical therapy for cancer is to achieve oncologic cure. cure.

A curative operation presupposes that the tumor is confined to A curative operation presupposes that the tumor is confined to the organ of originthe organ of origin

Patients in whom the primary tumor is not resectable with Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable negative surgical margins are considered to have inoperable disease.disease.– The operability of primary tumors is best determined with imaging The operability of primary tumors is best determined with imaging

studies that can define the extent of local-regional disease.studies that can define the extent of local-regional disease. Primary tumors can be resected for palliative reasons, such as Primary tumors can be resected for palliative reasons, such as

improving the quality of life by alleviating pain, infection, or improving the quality of life by alleviating pain, infection, or bleeding.bleeding.

Surgical Management of Lymph Surgical Management of Lymph NodesNodes

Unlike most carcinomas, soft tissue sarcomas rarely Unlike most carcinomas, soft tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore metastasize to the lymph nodes (<5%); therefore lymph node surgery usually is not necessary.lymph node surgery usually is not necessary.

generally accepted that a formal lymphadenectomy generally accepted that a formal lymphadenectomy is likely to minimize the risk of is likely to minimize the risk of regional recurrence regional recurrence of most cancersof most cancers

On the other hand, there have been opposing On the other hand, there have been opposing opposing views regarding the role of opposing views regarding the role of lymphadenectomy in lymphadenectomy in survivalsurvival of cancer patients. of cancer patients.

Surgical Management of Lymph Surgical Management of Lymph NodesNodes

Relatively new development Relatively new development Lymphatic mapping and sentinel lymph node biopsy Lymphatic mapping and sentinel lymph node biopsy

were first reported in 1977 by Cabanas for penile were first reported in 1977 by Cabanas for penile cancercancer

Lymphatic mapping Lymphatic mapping – isosulfan blue dye, technetium-labeled sulfur colloid or isosulfan blue dye, technetium-labeled sulfur colloid or

albumin, or a combination of both techniques to detect albumin, or a combination of both techniques to detect sentinel nodes. sentinel nodes.

***There is no role for sentinel LN BX for ***There is no role for sentinel LN BX for clinically palpable nodesclinically palpable nodes

Surgical Management of Distant Surgical Management of Distant MetastasesMetastases

depends on the number and sites of metastases, depends on the number and sites of metastases, the cancer type, the rate of tumor growththe cancer type, the rate of tumor growth

such therapy has resulted in cure in selected such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, cases with isolated metastases to the liver, lung, or brain.or brain.

25% 5 year survival for a single colonic met to 25% 5 year survival for a single colonic met to liver if successfully resected. liver if successfully resected.

ChemotherapyChemotherapy Classified according to the phase of the cell cycle Classified according to the phase of the cell cycle

during which they are effective. during which they are effective. – Cell-cycle phase–nonspecific Cell-cycle phase–nonspecific agents have a linear agents have a linear

dose-response curve, such that the fraction of cells dose-response curve, such that the fraction of cells killed increases with the dose of the drug.killed increases with the dose of the drug.

– Cell-cycle phase–specific Cell-cycle phase–specific drugs have a plateau, and drugs have a plateau, and cell kill will not increase with further increases in drug cell kill will not increase with further increases in drug dosedose

Methotrexate and 5-FU are cell cycle specific, all Methotrexate and 5-FU are cell cycle specific, all others are non-specificothers are non-specific

Drug Mech of action Side FX

Methotrexate Inhibits dihydrofolate reductaseinhibiting purine synthesis

Renal toxicity

5-Flourouracil (5-FU)

Inhibits thymidylate synthesisinhibiting purine synthesis

Cyclophosphamide Alkylating agent Gonad dysfxn, SIADH, hemorrhagic cystitis

Isofosfamide Alkylating agent

Bisulfan Alkylating agent Pulmonary fibrosis

Cisplatin Platinum alkylating agent Nephro, neuro, ototoxic

Carboplatin Platinum alkylating agent Bone marrow surpression

Vincristine Microtubule inhibitor Neurotoxic

Vinblastine Microtubule inhibitor Bone marrow surpression

Taxol Microtubule stabilizer

Etopside Inhibits topoisomerase

Bleomycin Antitumor antibiotic Pulmonary fibrosis

Doxorubicin Antitumor antibiotic(O2 radical formation)

Heart toxicitiy

Levamisole Antihelminthic drug, stimulates immune system

Radiation TherapyRadiation Therapy M phase is most vunerable stage of cell cycle for XRTM phase is most vunerable stage of cell cycle for XRT Most damage to DNA is done by formation of oxygen Most damage to DNA is done by formation of oxygen

radicals with H2O2 intermediateradicals with H2O2 intermediate– More oxygenated tumor = more damageMore oxygenated tumor = more damage– Large tumors less responsiveLarge tumors less responsive

To a lesser extent, ionizing radiation itself can cause To a lesser extent, ionizing radiation itself can cause direct DNA damagedirect DNA damage

Most is external beam radiationMost is external beam radiation BrachytherapyBrachytherapy: source of radiation delivered directory : source of radiation delivered directory

into operative bed using catheters. Allows high into operative bed using catheters. Allows high concentrated radiation with fewer side effects. concentrated radiation with fewer side effects.

Radiation TherapyRadiation Therapy Fractional DosesFractional Doses

– Allows repair of normal cellsAllows repair of normal cells– Allows reoxygenation of tumorAllows reoxygenation of tumor– Allows redistribution of tumor cells in cell cycleAllows redistribution of tumor cells in cell cycle

Radiosensitive tumors: Radiosensitive tumors: – Seminomas, lymphomasSeminomas, lymphomas

Radioresistant tumorsRadioresistant tumors– Epithelial, SarcomasEpithelial, Sarcomas

Side effectsSide effects

THE ENDTHE END