Cancer Flashcards
What are the patterns of multisystem disease presentation?
Single organ involvement moving to multi organ involvement
Multi organ involvement from initial presentation
Multisystem diseases can remain focal in individual patients e.g. patients with sarcoidosis may have just lung involvement or can have lung, skin and gastrointestinal involvement
What common processes underlie multisystem diseases?
Genetic defects (disorders of metabolism and processing) Autoimmune diseases Intracellular accumulations Infections Neoplasia Environmental and nutritional diseases
What can be single gene causes of multi system disease?
Enzyme defects and their consequences: accumulation of a substrate e.g. Galactosaemia, Metabolic block with reduced amount of end product, Failure to inactivate a tissue damaging substrate e.g. alpha-1-antitrypsin
Defects in membrane receptors and transport systems: failure of transport and tissue damage e.g. cystic fibrosis
Alterations in the structure, function or quality of non-enzymic proteins e.g. collagen or proteins that regulate cell growth
What chromosomal defects can cause multi system disease?
Structural abnormalities of chromosomes can underlie multisystem disease
Cytogenetic abnormalities can underlie multisystem disease e.g. Down’s Syndrome
What complex multi genetic disorders can cause multi system disease?
Combinations of multiple polymorphisms and external exposures: multiple diseases of the same type e.g. HLA in autoimmune diseases
Can be disease specific e.g. chronic idiopathic inflammatory bowel disease
How can autoimmune diseases lead to multi system disease?
Antibody formation: mimic or block exogenous ligand causing abnormalities in function of tissue e.g. Grave’s Disease
Immune complex mediated damage: Antibodies reacting within tissues to form complexes e.g. antibodies to normal structural tissue components e.g. the basement membrane in Goodpasture’s Disease
Deposition of circulating antigen-antibody complexes
CD4+ T cell mediated damage e.g. Rheumatoid Arthritis
Describe the Mechanisms underlying abnormal intracellular accumulations
Inadequate removal of a normal substance due to defect in intracellular handling of substance e.g. steatosis (fatty change)
Abnormal endogenous substance builds up e.g. alpha-1-antitrypsin.
Abnormality caused by a problem with: Folding, Packaging, Transport, Secretion
Failure to degrade a metabolite due to an inherited enzyme deficiency e.g.storage diseases
Deposition and accumulation of an abnormal exogenous substance due to lack of necessary machinery
What substances can accumulate in cells?
Lipids e.g. steatosis
Proteins e.g. reabsorption droplets in the kidneys
Glycogen e.g. in macrophages in glycogen storage disease
Pigments e.g. haemosiderosis with iron overload
Pathological calcifications e.g. Dystrophic calcification at sites of cell injury and necrosis, Metastatic calcification of normal tissues due to hypercalcaemia
How can infection cause multi system disease?
infection being present at multiple sites
Infection causing a systemic inflammatory response with potential malfunction of multiple organ systems
How can neoplasia lead to multi system disease?
Secretion of hormones: both indigenous and ectopic
Secretion of inflammatory mediators e.g. TNF leading to cachexia -> Evidence of systemic inflammation, Elevated basal metabolic rate, Equal loss of both fat and lean muscle
Paraneoplastic syndromes: Ectopic hormone production, Production of other humoral factors e.g. parathyroid hormone-related protein causing hypercalcaemia
Metastasis to multiple organs with: Destruction of tissue mass and loss of function, Blockage of drainage of material
How can environmental diseases cause multi system problems?
poisons are: absorbed into system via skin, blood, gut etc
accumulate in the body or are excreted
effect cellular molecules e.g. receptors or enzymes and cause toxicity and dysfunction
Which vitamin deficiency will lead to impaired wound healing?
Vitamin C
What is multi system disease?
disease that affects a number of tissues or the body as a whole
No dominant system affected in every patient
three or more systems involved: GI, MSK, Mucous membrane, Renal, Hepatic, Hematologic, CNS
What is carcinogenesis?
origin or production of a cancer/malignant neoplasm
Carcinogen is an environmental agent participating in the causation
Carcinogenesis results from the accumulation of multiple, sub-lethal genetic mutations in a step wise fashion over time
What steps are involved in the process of carcinogenesis?
Initiating mutation: carcinogen caused, cell is primed with stem cell like properties
Mutation affecting genomic integrity/stability: precursor with mutator phenotype
Acquisition of cancer hallmarks: additional driver mutations, becomes founder cancer cell
Further genetic evolution: additional mutations, emergence of subclones, genetically heterogenous cancer
What abnormalities underlie Carcinogenesis?
Initial mutation may be caused by environmental exposure, inherited or spontaneous
Cancer will form from clonal expansion of single cell which has incurred a mutation. All daughter cells have same mutations
Four classes of normal regulatory genes are principle targets of
cancer-causing mutation: Proto-oncogenes, Tumour suppressor genes, Regulation of apoptosis, DNA repair genes
What is a passenger mutation?
Mutation with no phenotypic consequence
What accounts for tumour progression, acquisition of a more aggressive phenotype with time and changes in response to treatment with time?
Subclone formation
What is a mutator phenotype?
cells have mutations in genes that normally function in maintenance of genetic stability, typically loss of function
What do driver mutations do?
contribute to malignant phenotype e.g. initiating mutation
What are the hallmarks of cancer?
Sustaining proliferative signalling Evading growth suppression Avoiding immune destruction Enabling replicative immortality Tumour promoting inflammation Activating invasion and metastasis Genome instability and mutation Resisting cell death Deregulating cellular energetics
What is a proto oncogene?
normal (non-mutated) counterparts, physiological regulators of cell proliferation
What is an oncogene? Give examples
Positive, accelerators
promote autonomous cell growth In absence of normal growth signals
Products are oncoproteins
Signals from outside the cell (e.g. GF), Receptors – EGFR/Her2, Coupling molecules - ras, Phosphorylation Reactions, Cyclin Dependent Kinases/Cyclin Complexes
What are tumour suppressor genes?
Negative, brakes
Signals from outside the cell (e.g. GI)
Cyclin Kinase Inhibitors
Checkpoints
What is p53?
Acts at G1/S checkpoint
Surveillance in cell cycle, normally stops cell cycle progression of damaged cells or causes apoptosis in non-repairable DNA damage
Induces transcription of genes which repair DNA
Mutated in a large number of cancers (>50%), associated with invasion
Guardian of the genome
What genes other than oncogenes and tumour suppressor genes are involved in carcinogenesis?
DNA Repair: Excision repair, mismatch repair (XP,HNPCC)
Evasion of Apoptosis: p53, bcl family
Limitless replication (telomerase)
Angiogenesis
Genes involved in invasion and metastasis
What is RAS?
Oncogene
Mutation is most common abnormality of dominant oncogenes – 15-20% of tumours
Normally inactivated by hydrolysis of GTP
Blocked when mutated
What is c-Myc?
Oncogene
Transcriptional activator
Targets include cyclin D2
Translocation t(8,14) in Burkitt lymphoma, but also breast, colon & lung cancer
What is HER2?
Cell membrane receptor
Amplified in 25-30% of breast cancers
Trastuzumab (Herceptin) is a specifically targeted therapy for HER2 positive breast cancer
What are BRCA1+2?
tumour suppressor genes
Autosomal Dominant inheritance usual
Increased risk of early onset cancer of the breast, ovary (
What is FAP?
Familial adenomatous polyposis
Mutation in APC gene (Tumour Suppressor Gene)
Predominantly Autosomal Dominant
100s – 1000s of polyps present
100% chance of colorectal carcinoma by age 30 so prophylactic colectomy performed
What is Hereditary Non-Polyposis Coli?
Associated with numerous polyps in colon
DNA mismatch repair gene defect e.g. MSH 1 or 2
Increases risk colon carcinoma (HNPCC)
What is neurofibromatosis?
NF-1 codes for a protein involved in RAS signalling (Tumour suppressor gene)
NF1 product neurofibromin normally switches off RAS, if mutated does not > increased growth promoting signals
Autosomal dominant
Increased risk of malignant peripheral nervesheath tumours (sarcomas)
What is retinoblastoma?
RB is a tumour suppressor gene
Autosomal dominant pattern of inheritance of mutation usual
2 hit hypothesis: Inherit one defective copy of RB gene, 2nd hit = spontaneous mutation > retinoblastoma (& osteosarcomas)
RB protein normally binds E2F, When E2F released cell can enter cycle (at G1 phase)
Tumour of retina in children. 40% of cases familial, 60% sporadic
Familial cases occur younger (1yr age) and can be bilateral
What is Xeroderma pigmentosum?
Autosomal Recessive
Deficiency of DNA repair enzymes
Young children develop skin atrophy & cancers, normally seen in elderly
people
Death often due to metastatic squamous cellcarcinoma or melanoma
Fewer than 40% survive beyond 20 years
What is Ataxia Telangiectasia?
Autosomal Recessive
Deficiency of DNA repair enzymes (ATM)
1 in 40,000 to 100,000
Progressive cerebellar ataxia beginning between ages one and four years
Increased risk of leukaemia and lymphoma
Unusually sensitive to ionizing radiation
What are the stages of carcinogenesis?
Initiation results from exposure to a carcinogen and means it is potentially capable of neoplasia formation
Permanent DNA damage means that there is ‘memory’ of agent, irrespective of when promoter is applied
Promoters induce tumours in initiated cells but are not capable of
tumour genesis in non-initiated cells, Have to be applied AFTER initiation: Not affecting DNA, Not permanent
What substances can act as carcinogens?
Radiation
Chemical Carcinogens including: Exogenous hormones, Occupational exposures
Microbes especially viruses
Except carcinogens, what can increase risk of mutations forming?
Reparative proliferation e.g. chronic inflammation or tissue injury and by immunodeficient states
How does UV radiation act as a carcinogen?
Forms pyrimidine dimers in DNA, which overwhelm normal DNA repair mechanisms
Skin cancers more common on sun exposed areas of fair skinned individuals
Melanoma (superficial spreading type) & Basal cell carcinomas associated episodes of sunburn
How does ionising radiation act as a carcinogen?
Causes DNA damage: chromosome breakage, translocations and point mutations
Increases risk of the following: myeloid leukaemias, thyroid (only in young), breast, lungs and salivary gland
What types of chemical carcinogen are there?
Direct Acting: require no metabolic conversion to be carcinogenic e.g. Alkylating agents
Indirect Acting: require metabolic conversion to become carcinogenic e.g.polycyclic and aromatic hydrocarbons, aromatic amines and dyes
How do chemicals act as carcinogens?
Act on DNA and are mutagenic
highly reactive electrophile groups that directly damage DNA
How do promoters work?
stimulating cellular proliferation e.g.chronic inflammation and increased risk of neoplasia
When are you at risk of exposure to polycyclic aromatic hydrocarbons? And what do they cause?
Smoking
Chimney sweeps
Skin exposure to tar
Squamous cell carcinoma
When are you at risk from nitrosamines? And what do they cause?
Rubber workers
Mouth, oropharynx and oesophageal cancers
What does asbestos exposure cause?
Lung cancer
Mesothelioma
When are you at risk of Aromatic amines exposure and what do they cause?
Rubber and dye workers
Transitional cell carcinoma - bladder
What cancer can androgens and anabolic steroids cause?
Hepatocellular carcinoma
Give some examples of microbiological carcinogens
Hepatitis B (&C): chronic inflammation and repair
HPV (human papilloma virus) 16 and 18 most active/high risk serotypes: inactivate p53 and RB
EBV (Epstein Barr virus): Promote B cell growth and transformation
Helicobacter pylori: chronic inflammation and repair
Aflatoxins (produced by Aspergillus flavus (fungus)): p53 mutations
Schistosoma haematobium: chronic inflammation and repair
What host factors can determine the risk of a tumour developing?
Race / environmental factors Diet Age Constitutional factors: Gender, Inherited risks (e.g. Xeroderma pigmentosum) Premalignant lesions & conditions Transplacental exposure
Describe geographical variation in tumour incidence
High incidence of Burkitt Lymphoma in sub-Saharan Africa -
EBVirus/malaria/other
High incidence of skin cancers in Australia - UV radiation
Thyroid cancer in Russia – Chernobyl: radiation
Hepatocellular Carcinoma in Asia and Africa. Aflatoxins and HBV
Oesophageal Carcinoma in China - diet
What symptom sets may cancer present with?
Local symptoms
Due to metastasis
Catastrophic symptoms
Para neoplastic syndromes
How can asymptomatic cancers present?
Screening
Incidental findings
What local symptoms may present from cancer?
Lump Pain Mark / ‘lesion’ on skin Bleeding Cough Dysphagia Discharge
What symptoms may present from metastasis?
Lump Pain Headache Confusion Fit Cough
What catastrophic symptoms may result from cancer?
Cord compression SVCO Fit / stroke Fracture Bleed
What endocrine para neoplastic syndromes are there?
Low sodium (hyponatraemia) High calcium (hypercalcaemia) Low sugar Cushings Hyperaldosteronism
What neurological para neoplastic syndromes are there?
Eaton-Lambert myasthenia: autoimmune reaction to presynaptic voltage gated sodium channels
Encephalomyelitis
Cerebellar degeneration
Polymyositis: muscle inflammation
What mucocutaneous para neoplastic syndromes are there?
Acanthosis nigricans: darkened, thickened patches of skin develop in armpit and around groin and neck
Dermatomyositis: polymyositis with skin involvement
What haematological para neoplastic syndromes are there?
Polycythemia: high conc of Hb
Trousseau sign: spontaneous venous thrombosis, suggestive of visceral carcinoma esp lung and GI tract
What are the two types of cancer treatment intent?
Radical
Palliative
What types of cancer treatment sequencing are there?
Neo adjuvant: before surgery
Adjuvant: after
What factors are involved in decision making with regards to treatment options for cancer?
Multidisciplinary team meeting Staging (clinical / histopathological) Pathology Patient co-morbidity and performance status Patient preference
56 female, Fit and well, 1,2cm right breast mass detected on national screening mammogram, History – no significant PMH. No FH of cancer. No medications NKDA, Examination NAD lump not palpable. Biopsy confirms Grade 1 lobular breast carcinoma
Oestrogen receptor positive, Progesterone receptor positive
HER2 IHC negative for amplification
Axillary USS no nodal disease
What do you do now?
Wire guided wide local excision and sentinel lymph node biopsy
Adjuvant Radiotherapy to breast
Adjuvant Tamoxifen hormone therapy for 5 years (oestrogen receptor antagonist in breast tissue)
Frail, Performance status 2, Presents with painful 10cm breast mass, History –two years know worsening mass. PMH T2DM on
insulin, Ex-smoker, IHD. Polypharmacy penicillin allergy
Examination Large mass obviously palpable with axillary nodes.
Biopsy confirms Grade 2 lobular breast carcinoma
Oestrogen receptor positive, Progesterone receptor positive
HER2 IHC negative for amplification
Axillary disease evident on imaging, Staging CT no distant mets
What now?
Patient too frail for surgery
Primary palliative radiotherapy
Palliative Hormone therapy Letrozole (aromatase inhibitor – inhibits peripheral conversion of androgens to oestrogen)
What is Letrozole?
Aromatase inhibitor – inhibits peripheral conversion of androgens to oestrogen
Used in post menopause breast cancer treatment
34 year old Female, 3 cm breast mass rapid onset, No PMH No meds NKDA. FH of breast and ovarian cancer. Non smoker. On examination obviously palpable mass in right breast no axillary nodes. Imaging shows 3.3cm mass in right breast. No axillary disease, Biopsy shows ductal breast carcinoma Grade 3. ER PR and HER2 negative
What now?
Patient has Neo-adjuvant Chemotherapy FEC-T (fluorouracil, epirubicin, cyclophosphamide, docetaxel
Marker guided WLE (wide local excision) and SLNB (sentinel lymph node biopsy)
Adjuvant radiotherapy to breast
What is cisplatin?
Chemo drug
Bind and cause cross linking of DNA which triggers apoptosis
What is R CHOP?
Rituximab CD20 antibody on B cells Cyclophosphamide Doxorubicin Vincristine Prednisolone
What is the RECIST criteria?
Response Evaluation Criteria in Solid Tumours
define when tumours in cancer patients improve (respond), stay the same (stabilise), or worsen (progress) during treatment
In what cancers is a BRAF mutation significant?
Proto oncogene
Non Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung
How can chemotherapy be delivered?
Induction: treatment for advanced disease
Adjuvant: Systemic treatment after primary has been controlled by alternative method e.g. surgery/ radiotherapy, reduce risk of recurrence after local treatment alone
Neo Adjuvant/ Primary: initial rx of localised tumour
Direct/ Regional: into sanctuaries or by site directed perfusion of specific regions most affected by cancer
What is an advantage to intrathecal chemotherapy? And what is used to deliver it?
Higher concentrations of drug to localised tumour
OMMAYA RESERVOIR
What are advantages of intraperitoneal chemotherapy? When might this be used?
Peritoneal cavity can be exposed to much higher concentrations of cytotoxics than with systemic delivery
Main indication: ovarian cancer
How do anti metabolite drugs work?
Analogues of natural components of normal metabolic pathways
Disrupt synthetic phase of cell cycle
Inhibit key synthetic enzymes by mimicking a natural substrate or co-factor
Become incorporated into natural molecules such as DNA &
RNA and disrupt function
Toxicity reflects effects on proliferating cells e.g. bone marrow and GI mucosa
Give examples of pyramidine anti metabolite drugs
5-Fluorouracil
Capecitabine
Cytosine arabinoside
Gemcitabine
Give examples of purine anti metabolite drugs
6-mercaptopurine Thioguanine Cladribine Fludarabine Pentostatin
Give examples of anti folate drugs
Methotrexate
Raltitrexed
Pemetrexed
How do tubular binding agents work as anti cancer drugs? And give some types
Inhibit polymerisation of tubulin
Inhibit microtubular disassembly, prevents normal growth and breakdown of tubules required for cell growth
Taxanes (Paclitaxel, Docetaxel) and vinca alkaloids (Vincristine, Vinblastine, Vinorelbine)
How do anthracyclines work as anti cancer drugs?
DNA binding: Planar ring intercalates with DNA, H bonds created between side chain and bases, Sugar moiety binds to minor groove
Topoisomerase II inhibition
Formation of free radicals: Damage to nuclear and mitochondrial DNA, Lipid membrane damage through peroxidation
Name some anthracycline drugs
Doxorubicin
Epirubicin
Caelyx/ Myocet
What are some toxic side effects of anthracyclines?
Myelosuppression Alopecia mucositis Radiosensitizer Radiation recall phenomen Nausea and vomiting Extravasation soft tissue necrosis CARDIOTOXICITY
What is PEG LD?
Pegylated liposomal doxorubicin
Anthracycline Encapsulation in liposomes alters pk of the drug
Different toxicity profile to unencapsulated doxorubicin
Less Myelosuppression & Cardiotoxicity
How do the platins work as anti cancer drugs?
Platin complexes form covalent bonds with electrophilic atoms
DNA -platin adducts: Cross Strand links to adjacent complementary guanines, adjacent guanine and adenine bases
Causing ssDNA and dsDNA breaks and stopping separation of strands for transcription and replication
Name some toxic side effects of cisplatin
Myelosuppression Highly emetic, Mucositis Alopecia Azospermia Nephrotoxicity – K and Mg wasting, acute tubular necrosis, renal failure, worsened by other nephrotoxics Neurotoxicity –Ototoxicity (high frequency loss), peripheral neuropathy Raynauds phenomen, Allergic reactions
What benefit is there of using carboplatin over cisplatin?
Less nephrotoxic
Name some toxic side effects of carboplatin
Myelosuppression – thrombocytopaenia
Nausea and vomiting (less than cisplatin)
Renal impairment
Anaphylaxis, Especially on second rechallenge to drug, Desensitisation can be tried in certain circumstances
How do alkylating agents work?
Form covalent bonds with DNA bases
Causes DNA breaks: ss DNA breaks/ ds DNA breaks
Cross linking of DNA prevents separation of complementary strands for transcription or for synthesis
Name some toxic side effects of alkylating agents
Myelosuppression Alopecia Nausea and vomiting Mutagenesis & Carcinogenesis (AML, bladder Ca) Veno-occlusive disease Infertility Pulmonary fibrosis
What is Extravasation in chemotherapy terms?
Infiltration of a vesicant drug from an I.V. line into surrounding tissue
What might be some signs and symptoms that Extravasation of a drug has occurred?
Oedema,swelling, blanching, and coolness
Patient may complain of pain/feeling of tightness around the site
What could be consequences of drug Extravasation?
Necrotic ulcers, infection, disfigurement, reflex sympathetic dystrophy syndrome, and loss of function
What do you do if a drug has extravasated?
Elevate affected arm
For most extravasations, apply ice for 20 minutes at least four times a day for 24 to 48 hours
Treat extravasations from Vinca alkaloids and epipodophyllotoxins with heat
Photograph site, if possible
Topical hydrocortisone cream- mild reaction
If severe reaction, contact plastics
Define chronic disease
Persistent, long-standing, long-term, constantly recurring; incurable
Intrinsically indolent natural history, but ultimately incurable
Amenable to treatment that may afford control, rather than cure, & impacts on the natural history of disease, transform acute to chronic and prolongs survival
What is a cure?
Die of something completely different, having survived progression-free until that point
What is DCIS?
Ductal carcinoma in situ
What is an IHC ER Q-score?
Immunohistochemistry oestrogen receptor measure
What does FISH negative mean?
Fluorescence in situ hybridisation: done in breast cancer to look for HER2
What is an adnexal mass?
Mass in uterine appendages: ovaries and Fallopian tubes
What is Letrozole?
Aromatase inhibitor used as endocrine therapy in post menopausal women with breast cancer
What is a GIST?
Gastrointestinal stromal tumour
Soft tissue sarcoma
What is imatinib? and give 2 uses
Tyrosine kinase inhibitor
Chronic myelogenous leukemia: Philadelphia chromosome +
Gastrointestinal stromal tumor: after surgical removal of cKIT-positive tumors to help prevent recurrence and unresectable cKIT-positive GISTs
What is Trastuzumab?
herceptin: monoclonal antibody with specificity for extracellular epitope of HER2, and trans-membrane ligand-less member of the EGFR family
What are implications of chronic disease?
Shorten survival
Compromise performance status
Curtail economic activity and impoverish
Degrade quality of life
Impact on friends and family
Require care and carers
Cause depression, anxiety, frustration & anger
Constitute an increasing financial burden to society
What ways should patients be educated on self management of chronic disease?
Information: knowledge as power, expert patient, autonomy, consumer groups
Guiding principle: expectation guiding
Physical: timing of therapeutic interventions
Psychological: relaxation, mindfulness
What is the Gompertzian Growth Curve?
Mathematical model for a time series, where growth is slowest at the end of a time period
Slow initial growth, Rapid subclinical growth, threshold for clinical detection, slower clinical growth, death of patient
What is the self seeding concept of cancer growth?
Primary tumor cells released to enter the circulation to:
Self-seed back to primary
Metastasise to a distant secondary site such as lung, brain, bone
From which they return to primary tumor mass
What factors attract circulating tumour cells?
Tumour-derived inflammatory cytokines IL-6 and IL-8 attract
CTCs, promote accelerated growth, angiogenesis, and recruitment of myeloid cells into the stroma
What are protective factors against ovarian cancer?
Increasing parity, oral contraceptive use, and oophorectomy
What are treatment options for ovarian cancer?
Adjuvant radical chemotherapy curative intent for early stage
Palliative but survival-prolonging intent for advanced stage, before or after surgery
What factors may contribute to survival of ovarian cancer?
Tumour’s platinum sensitivity
Stage
Operability
Which chemo drug is often used in ovarian cancer?
Cisplatin
When is second line therapy appropriate in cancer treatment?
Second-line therapy is never curative, therefore palliative
Palliation means symptom control
Chemotherapy has nasty side effects
Second-line therapy in absence of disease-related symptoms is therefore a nonsense
Good practice therefore means defer Rx until their advent
Longer platinum-free interval, since first-line treatment, higher the response rate
What do prognosis and treatment related toxicity in patients with advanced solid tumours depend on?
Tumour burden & performance status
