Dunedin-Oncology Flashcards
Describe some oncogenes
Describe some tumour suppressor genes
What is micro satellite instability (MSI)?
genetic hypermutability that occurs with impaired mismatch repair (MMR)
What does MSH2 and MLH1 bind to?
4 main proteins but 2 main complexes
MSH2 —> attach to MSH6
MLH1 attach to PMS2
MSH6 and PMS2 do not have alternatie binding partners, so id you lose MLH1 and MSH2 then you loose both
What is the inheritance mode of Lynch syndrome?
autosomal dominant
mutations in one of the 5 key MMR genes: MLH1, MSH2, MSH6, PMS2, EPCAM
What is the action of CTLA4?
What is the action of PDI?
CTLA4: Dampens the amplitude of the immune response
PD1: down regulates the activity of T cells (tumour)
What are the mechanisms of metastatic spread?
- Haematogenous spread
- Lymphatic spread
- Transcoelomic spread- direct seeding of peritoneal/pleural cavity
What are some blood tests used for staging of cancer?
- LDH – melanoma
- hCG – gestational trophoblastic tumours
- LDH, hCG, AFP - testis
What is the therapeutic targeting for cancer?
Describe the cell cycle
G1- cellular contents duplicated
S- chromosomes duplicated
G2- double check of chromosomes
Mitosis
cytokinesis
Describe the S-Phase of cell cycle
DNA unraveling from histones (HDAC inhibitors)
Helicase splits DNA double strand
Topoisomerase “release tension” of unwinding helix (topoisomerase poisons)
DNA polyemerase assist matching of base pairs (Purine and pyrimidine analogues)
Ligase joins short fragments and completes replication
Describe Mitosis
Classes of chemotherapies?
Alkylating agents - mustards, platinums
Anti-metabolites- anti-folates, purine analogues, pyrimidine analogues
Alkaloids and topoisomerase poisons
Hormones
What are the types of Alkylating agents?
Mustard and derivatives
Cyclosporin / Cyclophosphamide
* Chlorambucil
* Dacarbazine
* Temozolomide
* Lomustine
* Streptozotocin
Platinum agents
* Cisplatin
* Carboplatin
* Oxaliplatin
What is the MOA of alkylating agents
Work at any point in the cell cycle
Mustard: Addition of ethyl or methyl groups to various positions on DNA bases e.g. cyclophosphamide
Platinum: cause cross linking of DNA preventing helicase separating double strand, preventing replication
What is the MOA of anti-metabolites
Act only in S phase
Work by interfering with T G C A (U) synthesis
Interfere with DNA and RNA production
What are the types of anti-metabolites?
anti-folates: methotrexate
Purine antagonist: Fludarabine, azathioprine, 6-TG
pyrimidine antagonis: fluropyrimidines, gemcitabine
What are examples of alkaloids? and its MOA
Vinca alkaloids- vincristine, vinblastine, binorelbine
Stop microtubule formation
Taxanes- paxlitaxel, docetacel
stops microtubule disassembly
Topoisomerase inhibitor: s-phase specific
What is the MOA of anthracyclines
Non-cell cycle specific
interfere with toposomerase 2
induce histone vision from chromatin
Eg doxorubicin, daunorubicin, epirubicin
Describe some oestrogen signalling axis and inhibitors
LHRH analogues- lucrin, zoladex
Tamoxifen - SERM
Aromatase inhibitors: anastrozole, letrozole
Steroidal aromatase inhibitors - exemestane
Describe some androgen signalling axis and inhibitors
LHRH analogies - lucre, zoladex
peripheral androgen blockage (bicalutamide, flutamide)
Adrenal androgen synthesis (abiraterone)
What are main S/E of chemotherapy?
What pathways are involved in angiogenesis?
VEGF, FGFR, PDGFR
What pathways are involved in epidermal growth factor receptor pathway?
HER2(EGFR2)
* PI3-AKT-mTOR signaling pathway
* RAS-RAF-MEK-ERT signaling pathway
Nomenclature of monoclonal antibodies
What are common side-effects of EGFR pathway?
dermatological toxicity
What are common side effects of VEGF pathway?
hypertension, impaired wound healing, GI perforation (monoclonal antibodies – also proteinuria)
Describe the epidemiology of Colorectal cancer
2nd/3rd most common cancer
2nd most common cause of cancer death
Describe risk factors for colorectal cancer
Risks:
* Personal/Family history
* Ulcerative colitis
* Hyperinsulinism: RR 1.30
* Alcohol:>2pints/d,4glasseswine/d:RR1.41
* Obesity: RR 1.5 if BMI > 25
* Vitamin B6 inversely related to colon cancer
risk: RR 0.51
* Unclear whether supplementation or diet important
* Exercise: RR 0.33-0.60
* Diet – Western Diet
* Red meat > 300g / week -harmful
calcium protective
What are the 3 main molecular subtypes of colorectal cancer?
CIN (APC pathway, classical): Chromosome instability
MSI-H (Lynch/HNPCC or BRAF): Microsatellite instability
CIMP: CpG island methylator phenotype
What is the genetic mode of HNPCC/Lynch syndrome?
autosomal dominant
What is the genetic mode of familial adenomatous polyposis
autosomal dominant
What is the most typical phenotype of HNPCC
right sided, <50, microsatellite instability
What is MUTYH- associated polyposis?
Phenotypically like FAP or attenuated FAP, but no APC mutn.
Homozygous MUTYH mutation. AR.
Estimated 1 in 100 carrier rate.
What is the age range for FOBT screening?
biennial, age 45-70
What microorganism is associated with bowel cancer?
Strep gallolyticus (AKA strep bovis)
Can CEA be falsely elected in smokers?
Yes
What polyp carries the highest likelihood of malignancy?
tubulovillous adenoma with low grade dysplasia
When do you use adjuvant chemo in colorectal cancer?
- stage 3
- high risk stage 2 - t4, obstruction, poor differentiation, extramural venous invasion, adjacent organ invasion, low LN yield
What is the chemotherapy for colorectal cancer
5FU/Capecitabine –> diarrhoea, HFS, coronary vasospasm
oxaliplatin –> cold-induced neuropathy, peripheral neuropathy
irinotecan –> diarrhoea, enter-hepatic recirculation of the active metabolite
What deficiency makes 5FU/Capecitabine dangerous?
Dihydropyrimidine dehydrogenase (DPD)deficiency =
severe tox
Can you give EGFR inhibitors in KRAS Mutation?
No, as its downstream effects will continue.
avoid in BRAF but can consider
What type of patients is cetuximab useful in?
LEFT SIDED CANCER
NO KRAS MUTATION
When do you give immune therapy in colorectal cancer?
MSI-High, dMMR CRC
What is the pathophysiology of gastrointestinal stromal tumour?
“mesenchymal” tumour (mesoderm
derived)
*Connective tissue/ smooth muscle related
What are the genetics of gastrointestinal stromal tumour?
CD117/C-kit positive
(rare: C-kit negative / platelet derived growth factor receptor mutants)
What do gastrointestinal stromal tumour cells look like?
spindle shaped cells
What is the treatment of gastrointestinal stroll tumour?
Localised –> surgery
Advanced disease –> imatinib
if progress –> escalate doses (interesting in other cancers often have to change the drug), sunitinib, regorafenib, ripretinib
What is the epidemiology of HCC?
3rd leading cancer death worldwide.
higher incidence in sub-Saharan Africa and east Asia
How to diagnose HCC?
triple phase CT
hyper vascular liver lesion and AFP >400
How do you monitor cirrhotics for HCC?
USS q6mo; +/- AFP
What is the criteria for liver transplant?
MILAN CRITERIA: (single lesion ≤ 5cm or ≤ 3 lesions of ≤ 3 cm)
Expanded criteria (single lesion ≤ 6cm or ≤ 3 lesions of ≤ 5 cm)
What are advised disease therapies for HCC?
sorafenib
Atezolizumab
Lenvatinib
What is TACE?
Transarterial chemoembolization (TACE) is a specific type of chemoembolization that blocks the hepatic artery to treat liver cancer
often bridge to liver transplant
What is the chemotherapy regimen for oesophagogastric cancer?
FLOT
Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel
Helicobacter pylori reduces the risk of what cancer?
oesophageal adenocarcinoma
PRRT (peptide receptor radionuclide therapy) is a treatment for neuroendocrine cancer like pheochromocytoma. What receptor does the cancer need to express for this treatment to be effective/
somatostatin receptor
What is the biological basis of prostate cancer?
Malignant epithelial malignancy derived from prostatic glandular epithelium
What is the management for castrate-resistant prostate cancer?
docetaxel or cabazitacel
What can you do for organ confined prostate cancer?
radical prostatectomy comparable to radical radiotherapy
Can you give docetaxel to castrate sensitive?
Yes, proven to help
What is a MOA Of abiraterone? S/E
androgen biosynthesis inhibitor
Inhibits CYP17 enzyme complex required for androgen biosynthesis and is expressed in the testes, adrenal glands, and prostate tumour tissue
S/E- HTN, hypokalaemia, fluid retention. GIVE WITH STEROIDS!
List androgen receptor inhibitors
enzalutamide
apalutamide
daroluamide
What can you use in BRCA mutated prostate cancer?
PARP inhibitors eg olaparib
What radiotherapy can you use for prostate cancer?
Radium -223, an alpha emitter good for bone mets
can cause fractures MUST give bisphosphonate with it
What are side effects of ADT?
- Osteoporosis
- Dyslipidemia
- Weight gain
- BMD
- Mood
- Insulin resistance
- CVS morbidity / mortality
Describe the BRAF mutation in melanoma
35-45% have a BRAF Mutation
70% 600E, 20% 600K
What are side effects of V600E inhibitors?
photosensitivity, diarrhoea, KA, SCC
What is immunotherapy for melanoma?
ipilimumab (CTLA-4) + Nivolumab (PD-1)
What is the management for immune related side effects?
- Oral steroids Prednisone 1-2mg/kg
- IV methylprednisolone
- Azathioprine
- Mycophenolate
- Cyclosporin or tacrolimus
- Infliximab (colitis)
- Atgam – anti-thymocyte globulin (hepatitis)
- Tocilizumab (anti IL-6)
How to treat melanoma brain mets?
few brain mets –> stereotactic radiotherapy or surgery
>3 mets: BRAFi or combined ICI
What genes create highest risk of breast cancer?
BRCA1
BRCA2
PALB2
Is there a role for annual screening with pelvic ultrasound and CA125 in BRCA mutations?
NO
How to do surveillance for BRCA1/2?
Breast
* MRI+/-US from age 25-30
* MRI+ MG age 40-60
* Mammogram alone from age 60
Ovary: no evidence of screening
Men with BRCA2: annual PSA from age 40
What are some interventions for BRCA mutations?
Offer bilateral prophylactic mastectomy (best age <40 but individualised)
Risk reducing salpingo-oophorectomy (RRSO) once family complete or > 35-40 (BRCA1),
> 40-45 (BRCA2)
What are some side effects in PARP inhibitors?
Nausea
Diarrhoea
Fatigue
Abdo pain
What is the current breast cancer screening progress?
50-74 for biennial mammogram but also free to those 40-49 and those over 74
What are prognostic biomarkers for breast cancer
ER +ve > HER2+ve > triple negative
Stratification of breast cancer risk
Describe (neo) adjuvant treatments in early breast cancer
What are CYP interactions with tamoxifen?
Blocking of CYP2D6 reduces active tamoxifen.
avoid concurrent fluoxetine or paroxetine
What are examples of aromatase inhibitors
letrozole, anastrozole, exemestane
S/E- menopausal symptoms, arthralgia, accelerated osteoporosis
Describe the adjuvant endocrine treatments for breast cancer
What cell cycle does CDK4/6 act on?
G1
What are the benefits of using CDK4/6 in high risk breast cancer?
Adding adjuvant abemaciclib reduces relapse at 5 years by around 8%
What is a side effect of ribociclib?
prolongs QTc
How trastuzumab deruxtecan work regarding Her 2?
works well even in Her2
Can people with breast cancer have a baby?
Yes, should stop endocrine therapy and have a 3 month wash out
Describe the antibody-drug conjugates in breast cancer
What are side effects of antibody drug conjugates in breast cancer?
Describe the emetigenicity of drugs
What is the chemotherapy options for testicular cancer?
stage 1: seminoma (carboplatin), non-seminoma (1xBEP)
Advanced stage- BEP (bleomycin, etoposide, cisplatin)
Describe the treatment of lung cancer
Describe some toxicities with targeted therapies of lung cancer- alectinib, entrecetinib, lorlatinib, tepotinib
- Alectinib (ALK): Bradycardia, cardiomyopathy, Pneumonitis
- Entrectinib (ROS1): Prolonged QT, neuropathy
- Lorlatinib (ALK)
Hyperlipidemia, neurotoxicity incl confusion - Tepotinib (MET)
Pneumonitis
