March 30, 2011Xinni Song MD FRCPCUniversity of Ottawa

Back to BasicsOncology

OutlineClinical epidemiology of Cancer - How Big is

the Problem?

Neoplasia – What is it?

Risk Factors and Screening

Diagnosis and Staging

Treatments

Quiz

Cancer Epidemiology Canadian Cancer Stats

An estimated 173,800 new cases of cancers in Canada in 2010

~ 76,200 cancer deaths in 2010

More men than women are diagnosed with cancer 51.7% vs 48.3%

Over ¼ (27%) of all cancer death due to lung cancer

Between 1995-2005, overall cancer mortality has declined

Increasing incidence of cancer are mainly due to aging population

Incidence

Women

Men

Mortality

Women

Men

Cells and MoleculesNeoplasm:

Characterized by growth and division of cells outside the control of normal regulatory mechanisms

Cells have undergone permanent DNA damageCharacterized as benign or malignant by their

capacity for invasion and metastasisBenign tumours usually designated by the suffix -

omaMalignant tumours are divided most broadly into

carcinomas and sarcomas, and blastomas in children

Exceptions to the rule: Hepatoma, Melanoma, Leukemia,lymphoma, Glioblastoma

Genetic ChangesCancers arise due to changes in a cell’s genetic

machineryOncogenesTumour suppressor genes

Oncogenes eg. bcr-abl in CMLGenes have dominant transforming properties: one

abnormal copy is sufficient Mutation or overexpression leads to unregulated

cell divisionTumour Suppressor Genes eg. BRCA1/2, RB

Genes which are normally involved in the negative regulation of cell cycling

Genes have recessive transforming properties: both copies must be abnormal

loss of these genes function allows cells to proliferate unregulated, or with reduced restraints

CRC Adenoma-Carcinoma Sequence:CRC Adenoma-Carcinoma Sequence:Vogelstein’s modelVogelstein’s model

Mutations can be inherited, or occur through exposures to a carcinogens

CarcinomasCarcinomas

Arise from epitheliumCommonest are adenocarcinoma and squamous

carcinomaMany others, including germ cell tumours,

transitional cell carcinomas, large cell carcinoma, neuroendocrine carcinoma

Adenocarcinoma BreastLungProstateMost GI, including colonEndocrine malignancies

CarcinomasSquamous carcinoma

Head and neck cancersLungSkinCervixEsophagusanus

Germ Cell TumoursMost commonly testicular cancersOvarian Primary mediastinalHistologic subtypes include teratomas,

embryonal carcinomas, yolk sac tumours

SarcomasMuch rarer than carcinomasArise from mesenchymal tissueAbout 800 soft-tissue sarcomas per year in Canada, and

fewer bone sarcomasNamed for the tissue they arise from, when knownKnown tissues of origin

Liposarcoma FatRhabdomyosarcoma Striated muscleLeiomyosarcoma Smooth muscleOsteosarcoma BoneChondrosarcoma Cartilage

Unknown tissue of originMalignant fibrous histiocytoma, Ewing’s Sarcoma, alveolar soft

parts tumour

SummaryHistologic characteristics of cancer

Excessive cellularityDisrupted architectureFrequent mitosesUnusual cell appearance

Large, hyperchromatic nucleiVarying degrees of differentiationInvasion into surrounding tissue

Cancer management

Screening

Diagnosis

Staging

Treatment

ScreeningScreening is the routine testing of

asymptomatic individuals for the presence of cancer

Good screening strategy:Test is acceptable to the target populationRisk is minimal and cost is reasonableTest is accurate: high sensitivity and specificityTest detects the disease in an asymptomatic

(pre-clinical) phaseEvidence exists that treatment in the

asymptomatic phase improves outcomes

Screening test Sn-n-out/Sp-p-in

ScreeningCommonly screened cancers in adults are:

Breast (mammography)Cervix (Pap smears)Colon (FOBT/colonoscopy/sigmoidoscopy)Prostate (PSA)

Evidence behind screening is surprisingly controversial, in part because of the difficulty of designing studies to avoid bias

ScreeningLead-time Bias

Time

Cancer starts

Symptoms

Diagnosis and treatment Death

Diagnosis by screening

Treatment

Cancer becomes incurable

Why Not Screen for All Cancers?

Cancer-related factors

Preclinical interval too short

Cancer incurable, even if screen detected

Cancer Starts Symptoms Death

Cancer Starts Symptoms DeathIncurable

Incurable

Why Not Screen for All Cancers?Test-related factors

Test not sensitive/specific enoughTest can’t be applied to whole population

Too expensiveInsufficient infrastructure/personnelUnacceptable to majority of population

Tumour not common enough

Risk factorsCausal inference:

•Temporality- exposure to precede disease

•Strength of association – stronger association between an exposure and cancer risk is more likely to be causal than a weaker association

•Consistency - association between exposure and outcome demonstrated from other studies

•Gradient of effect – increasing levels of exposure are accompanied by increasing in risk

•Biological plausibility – if the causal model agrees with present knowledge about biology of the target cells and tissues and the biological effects of the exposure

•Specificity – if an association is present between a single exposure and a single disease

Risk Factors for cancer

Factor Type Attributable Risk

Environmental 5%

Lifestyle 45%

Occupational 4%

Pharmacologic 2%

Biologic 4%

Risk Factors for lung cancer90% of all lung cancers are attributable to

smoking Including 2nd hand smoking

10% occur in non-smokers (younger, female, Asian)

Risk increases with # packs smoked, age at onset

Tobacco smoke has > 40 identified different carcinogens

Women are more susceptible to carcinogenic effects

Other risks include some occupational exposuresAsbestos, radon, sillica, chromium, arsenic

Risk factors for breast cancer

Hormonal and reproductive riskEarly

menarcheFirst birth at

older ageAbsence of

breast feedingNulliparityLate

menopauseHRT

Age and gender – older and female

Race/ethnicity – whites>blacks>hispanic/indians/asians

Diet/LifestylePost-menopausal obesityAlcohol

Medical historyIonizing radiationIncreased breast densityBenign breast lesions

Environmental

Risk factors for breast cancer

Family history and genetic risksBreast cancer susceptibility gene 5-6% of all

BCBRCA1/2, p53, ATM, PTEN

BRCA mutationsBRCA1

75 % lifetime risk of breast cancer50 % lifetime risk of ovarian cancer

BRCA275 % lifetime risk of breast cancer25 % lifetime risk of ovarian cancerMelanoma, laryngeal, colon, prostate, pancreas,

lymphoma, leukemia

Colorectal Cancer : Risk Factors

Dietary – most important!fat, fibre, high EtOH, low selenium, low calcium

Underlying ConditionsIBD, prior CRC or polyps, post-radiation

Hereditary – 5%FAP (familial adenomatous polyposis) – 1/200, APC gene

Gardener’sTurcot’s

HNPCC (hereditary non-polyposis colorectal ca) 2-4%Genetics: “microsatellite instability = MSI”, MSH2, MLH1,..

Peutz-JeghersFamily Hx – 10% have

Risk factor for colon cancer

Family History General population 6% lifetime risk

One 1st degree relative: 12%

Two 1st degree relatives: 18%

1st degree relative <45 yrs old: 30-42%

DiagnosisEarly detection of cancer is the key Recommend screening test if availableSystematically think about symptoms of

cancerLocal symptoms of tumourSymptoms from regional (nodal) spreadSymptoms from metastatic spreadSymptoms from paraneoplastic phenomena

DiagnosisLocal Symptoms

Lung Cough, hemoptysis, SOB, chest wall pain

ProstateUrinary obstruction, hematuria

BreastBreast mass, skin changes, bleeding from nipple

Colon Blood in stool, iron deficient anemia, change in

bowel habitsHematological

Symptoms of marrow replacement, cytopenias

DiagnosisSymptoms from

regional (nodal) spreadLung (mediastinal

nodes)SVCO, esophageal

obstruction, hoarse voice, etc

Breast (axillary nodes)Lump under arm

Symptoms from Metastatic SpreadLiver

Jaundice, abnormal LFT, pain

BrainFocal neurologic

symptoms, seizuresLung

Cough, SOB, hemoptysisBone

Pain, pathologic fracture, elevated Alk Phos

DiagnosisParaneoplastic Syndromes

Common, non-specificPoor appetite, weight loss, DVT

Hormonal syndromesSIADH, Cushing’s, hypercalcemia, carcinoid

Neurologic syndromesLambert-Eaton Syndrome, demyelination syndromes

Diagnosis and StagingDefinitive diagnosis – tissue neededPurposes of staging

Group similar patients togetherDetermine intent of treatmentPrognostic purposes

Most cancers are staged with a TNM staging system, which leads to overall stage I-IVTumourNodalMetastases

TreatmentIntent of Treatment

Radical vs. PalliativePrimaryAdjuvantNeoadjuvant

Modalities of TreatmentSurgeryRadiotherapySystemic therapy

Treatment: SurgeryIndications for Surgery

Obtain tissue for diagnosis/stagingDefinitive treatment of primary tumourPalliation of obstructive/mass effect symptomsCancer prophylaxis in high-risk cases

Esophageal dysplasia/BRCA/FAP/ulcerative colitisSupport other procedures

Central venous accessRehabilitation/reconstruction

Treatment: RadiationIonizing radiation delivered to tumour

and surrounding tissueExternal BeamBrachytherapy Systemically administered agents

Radiation treatment intentCurative as primary treatment Adjuvant for local regional disease controlPalliative symptom management

External Beam Radiotherapy

Treatment: Systemic TherapyChemotherapyHormonal TherapyImmunotherapySmall molecules/monoclonal antibodies

Treatment: ChemotherapyMechanisms of action

Bind to DNAAlkylating agents, platinum agents

Antimetabolites5-FU, methotrexate

Bind to microtubulesVinka alkylaoids, taxanes

Interfere with topoisomeraseAnthracyclines

Treatment: ChemotherapyAcute toxicities

Mucositis/diarrheaNauseaHair lossHypersensitivity

reactionsPainThromoboembolic

eventsMyelosuppression

Risk of febrile neutropenia

Fatigue

Chronic ToxicitiesInfertility

Particularly alkylating agents

LeukemogenesisAnthracyclines,

alkylating agentsNeurotoxicity

Cisplatin, taxanes, vinca alkyloids

NephrotoxicityCisplatin

Cardiotoxicityanthracyclines

Treatment: Hormonal TherapyHormone sensitive cancers

BreastProstateEndometrialOvarian

Tumours retain some characteristics of the original tissue

Treatment: Monoclonal Antibodies

Antibody Target Tumour

Trastuzumab (Herceptin) HER-2 BreastRituximab (Rituxan) CD-20 LymphomaCetuximab (Erbitux) EGFR ColonBevacizumab (Avastin) VEGF Colon, LungTositumomab (Bexxar) CD-20 + I131 LymphomaIbritumomab (Zevalin) CD20 + Y Lymphoma

Treatment: Small MoleculesMolecules developed to inhibit specific

proteins/enzymes responsible for malignant behaviorImatinib (Glieevec) CML, GISTGefitinib (Iressa) Lung cancerErlotinib (Tarceva) Lung cancerLapatinib (Tykerb) Breast cancer

Treatment – OtherPalliative care

Pain and symptom managementEnd of life care

Cancer SurvivorshipA rapidly expanding field, arising from the

recognition that people who have completed curative cancer therapy have ongoing complex medical, social, psychologic issues

Lung Cancer - pathology

Lung Cancer: NSCLCStage I-II disease

Limited to lung and ipsilateral hilar nodesSurgery gives ~50% long-term survival rateImproved to ~60-65% with adjuvant chemotherapy

Stage III DiseaseLung and ipsilateral or contralateral mediastinal lymph

nodesSeldom amenable to surgeryRadiation alone can cure 7-12%Adding chemotherapy increases rate to ~18-25%

Stage IV - Metastatic diseaseIncurable, with median untreated survivals of 4 monthsWith chemotherapy, median survival increases to 10 months50% of patients have improved symptoms or QoL on chemo

Lung Cancer: Small CellStaged as either Limited or Extensive

LimitedConfined to one hemithoraxTreated with chemo and radiation, with a long-term

survival rate of ~25%Median survival untreated: 4 months treated: 12

monthsExtensive

Beyond one hemithoraxTreated palliatively with chemotherapyMedian untreated survival 6 weeksMedian treated survival 9 months

Breast Cancer - pathologyInvasive ductal carcinoma - 76%Invasive lobular carcinoma – 8% Ductal/lobular – 7%Mucinous(colloid) – 2.4% Tubular carcinoma -1.5%Medullar carcinoma – 1.2%Papillary carcinoma -1.0% Other (micropapillar and metaplastic) – <5%

Breast Cancer Staging and Prognostic Markers

TNM stagingT - tumor extentN- nodal statusM- metatstatic disease

ER/PR receptor statusHistological grade, lymphvascular invasionHer2 status (epidermal growth factor

receptor)Gene profiling

Breast cancer treatmentStage I-II

Primary therapy – surgery for the breast lesion + regional LN

Systemic therapy – chemotherapy/hormone/targeted therapy

Radiation therapy to breast/chestwall/LNStage III

Neoadjuvant systemic therapySurgery Radiation therapy

Stage IV – metastatic Systemic therapySurgery/radiation as symptom management tools

EstrogenbiosynthesisEstrogenbiosynthesis

Tumour cell

Tumour cell

Nucleus

Adjuvant Endocrine TherapyInhibition of Estrogen-dependent Growth

EstrogenbiosynthesisEstrogenbiosynthesis

TamoxifenTamoxifenTamoxifenTamoxifen

AromataseAromataseInhibitorsInhibitors

AromataseAromataseInhibitorsInhibitors

Inhibition of growthInhibition of growth

Bhatnagar AS, et al. J Steroid Biochem Mol Biol. 2001;77:199-202.

Estrogen

Estrogen Receptor

EBCTCG overview – tamoxifen vs. not

Aromatase vs. Tamoxifen

M. Dowsett, et al; JCO Jan, 2010

Polychemotherapy significantly reduces the risk of recurrence and death

Absolute benefit is bigger in patients Under age 50With ER- tumorsWith Node(+) disease

Polychemotherapy regimens longer than 6 months do not appear to improve survival

1Early Breast Cancer Trialists’ Collaborative Group. The Lancet 352:930-942

Benefits of Chemotherapy

Breast Cancer Molecular Classification

ER(-) ER(+)

Solie et al. PNAS 2001; 98:10869-10874

Metastatic diseasebone > lung > liver > brainMost commonly detected in first 5 years after

definitive treatmentMedian overall survival from time of

diagnosis: 18-24 months5y survival: 5-10%10y survival: 2-5%Age, disease free interval, # and location of

mets, ER status, her2 status

Factors Determining choice of Treatment in Advanced Breast Cancer

Colon CancerStage I-III

Typically treated by surgery, with long-term control rates of 40-85%, depending on stage

Adjuvant chemotherapy decreases relative risk of recurrence by 30%, usually offered to pt with stage III or high risk stage II

Adjuvant chemo and radiation often used together in rectal, rather than colon cancers

Stage IVPalliated by chemotherapy, radiation as indicatedUntreated survival ~4-6 monthsOptimally treated survival ~24 months

Prostate CancerEarly stages maybe treated with surgery or

radiationMore advanced disease is treated with

some combination of radiation and hormone therapy (androgen deprivation)

Chemotherapy has a limited role, usually just for metastatic disease after hormones fail

EGFR EXPRESSION IN HUMAN TUMOURS

• NSCLC 40-80%

• Prostate 40-80%

• Gastric 33-74%

• Breast 14-91%

• Colorectal 25-77%

• Pancreatic 30-50%

• Ovarian 35-70%

• Invasion

• Metastasis

• Late-stage disease

• Chemotherapy resistance

• Radiotherapy resistance

• Hormonal therapy resistance

• Poor outcome

Tumours showing high EGFR expression

High expression generallyassociated with

The HER Family

Courtesy of Kenneth Bloom.

The epidermal growth factor family of receptors comprises 4 transmembrane proteins, eachwith different properties but all involved inthe regulation of cell proliferation

Extracellular

Intracellular

• No natural ligand for HER-2

• Activation of HER-2 occurs by homodimerization

• Activation can occur by heterodimerization with HER-3 or HER-4 after binding with Heregulin

• Activation leads to tyrosine phosphorylation of HER-2 kinase with downstream activation of signal transduction

• Overexpression/gene amp. is anti-apoptotic

6464

TrastuzumabHumanized murine MoAb

2 antigen-specific sitesBind extracellular

domain of ErbB2 receptor

Remainder of antibody is human IgG with a conserved Fc portion

Movie: “Living Proof”

Hudis C. N Engl J Med 2007;357:39

IgG = Immunoglobulin G

Antigen binding

HumanFc

Q: A unilateral vocal cord paralysis is common in the setting of a mediastinal mass and lung cancer, which vocal cord is more commonly involved?

Left vocal cord is more commonly - compression of the left recurrent laryngeal nerve

Q: What are the five most common tumors to metastasize to skin ?

breast, lung, ovary, colon, kidney

Q: What is the most common location of metastasis for renal cell carcinoma?

Lung

Q: Neutropenic fever is found in 30-40% of patients what is the most common etiology?

Gram positive bacteria

Q: What syndrome causes diarrhea, flushing, bronchospasm and right sided heart failure?

Carcinoid syndrome

Q: EKG findings in cardiac tamponade

sinus tachycardia, electric alternans, low QRS voltage

Q: What is the term used for tumor at the apex of the lung or superior sulcus which may involve brachial plexus, sympathetic ganglion, vertebral bodies, leading to pain, upper extremity weakness and horner’s syndrome?

Pancoast tumor

Q:What is the most common paraneoplastic syndrome associated with renal cell carcinoma?

hypercalcemia (20%)

Q: What is the most common pulmonary malignancy associated with hypercalcemia

squamous cell carcinoma of the lung

Q: Multiple endocrine neoplasia

MENI - pancreatic tumors, pituitary adenoma, parathyroid hyperplasia

MEN II – parathyroid hyperplasia, medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromata

Q: Which malignancy is seen at increased frequency in people working in the ruber industry?

Bladder cancer - related to exposure to aromatic amines

Q: What cancer is asscociated with Barrett’s esophagus?

Adenocarcinoma of the esophagus

Q: what is the most common solid malignancy in males aged 15-35?

Testicular cancer

Q: Tumor markers

Breast cancer CA15-3, CA27-29m and CEAOvarian cancer CEA, CA-125Testicular cancer b-HCG, AFPHepatocellular carcinoma AFP

Q: What is Li-Fraumeni Syndrome?

High familial incidence of tumors of soft tissue, breast, brain, bone, leuemia, and adrenal cortex

Q: What chromosomal abnormality is associated with young men with malignant mediastinal germ cell tumors

Kleinfelter’s syndrome

Q: Paraneoplastic syndrome commonly assoicated with small cell lung cancer

SIADHHypercalcemiaEctopic ACTHEaton-Lambert Syndrome