Oncology Flashcards
PSA screening recommendations
Age - offer PSA testing every 2 yrs from 50-69
FHx
- one first degree relative 2.5-3x risk - from >45yrs
- 3x first degree relatives - from > 40 yrs
Prostate cancer investigations
Indicated if elevated PSA +/- abnormal DRE
MRI prostate
Multifocal core biopsy
Features suspicious of metastatic prostate cancer
PSA > 100ng/dl
Distribution of metastatic disease - sclerotic bone metastases
Prostate management options
Localised
- prostatectomy
- radiotherapy
Advanced disease
- hormonal therapy/bilateral orchiectomy
- chemotherapy
- supportive therapy –> RTx, bisphosphonates, palliative care
MOA of androgen deprivation therapy
ADT –> reduce GnRH –> reduce LH –> reduce testicular testosterone production
Side effects of ADT
Vasomotor symptoms
Reduced libido
Bone density loss
Muscle mass loss
Cardiovascular risk factors
Estrogen deficiency - gynaeocomastia, hot flushes
Testosterone deficiency - erectile dysfunction, diabetes, muscle weakness
Relationship between testosterone and estradiol
Testosterone converts to estrogen via CYP19/aromatase
Chemotherapy for prostate cancer
Taxanes - docetaxel, cabazitaxel
Used in combination with ADT for “high volume” disease, visceral metastases, multiple bone metastases
MOA of taxane chemotherapy
Interferes with microtubule growth, causing cell arrest in G2/M phase
Inactivates bcl-2 –> apoptosis
Side effects of taxane chemotherapy
Hair loss
N+V
Pancytopenia
Mucositis/diarrhoea
Lethargy
Fluid retention
Hypersensitivity reactions
Myalgias and arthralgias
Peripheral neuropathy
Nail changes
Examples of direct androgen receptor antagonist
Enzalutamide
Apalutamide
Darolutamide
Examples of androgen biosynthesis inhibitor (17a-hydroxylase)
Abiraterone
Blocks synthesis of testosterone in adrenal gland via inhibition of 17a-hydroxylase and C17,20-lyase activity
Mechanism of cortisol inhibition of abiraterone
Abiraterone (androgen biosynthesis inhibitor via 17a hydroxylase)
ACTH rises in response to increase in deoxycortisterone (due to decrease in 17OH-progesterone) –> leads to decrease in cortisol (thus should have mandatory concurrent steroids)
Also results in increased shunting, causing excess mineralocorticoid (hyperaldosteronism)
Side effects of direct androgen receptor antagonists
Fatigue
Cognitive impairment
Falls
Seizures
Rash
Side effects of androgen biosynthesis inhibitor
Cardiac toxicity
Hypertension
Concurrent steroids
Bone protection methods for prostate cancer
Calcium and vitamin D supplementation
Weight bearing exercise
DEXA scan monitoring
High risk - denosumab, ZA
Common complications of prostate cancer
Acute urinary retention
Bilateral ureteric obstruction
Spinal cord compression
Pancytopenia from BM infiltration
Bilateral lower limb lymphoedema secondary to pelvic obstruction
Genetic defects in prostate cancer
Aberrations in ~1/3rd of pts
BRCA2 most common alteration seen
Testicular cancer classification
Pure seminoma - AFP not elevated
Non seminoma/mixed germ cell tumour - often elevated
Testicular cancer epidemiology
Most commonly seen in 25-40 yrs
Median age at diagnosis is 33 yrs
Increased risk with cryptorchidism
5 yr relative survival ~98%
Tumour markers for prostate cancer
AFP, beta HCG, LDH
Role of AFP and beta HCG
Useful for surveillance/follow up
Associated with prognosis and used to guide treatment in advanced disease
Treatment of testicular cancer
Localised disease
- Orchiectomy
- Surveillance
Metastatic/advanced disease
- Chemotherapy (Bleomycin, etoposide, platinum)
- Resection of residual masses
Relapsed/refractory disease
- Second line chemotherapy
- High dose chemo and mini-autografts
Toxicities associated with chemotherapy for testicular cancer
Pancytopenia, alopecia, lethargy
Cisplatin
- Hearing impairment
- Tinnitus
- Peripheral neuropathy
- Renal impairment
Bleomycin
- Hypersensitivity
- Pneumonitis/lung toxicity
Risk factors for CRC
Excess body weight
Low levels of physical activity
High consumption of processed meat and EtOH
Low fibre consumption
Cigarette smoking
IBD
- Pancolitis > left sided colitis
- CD
FHx
Familial cancer syndromes
Common heritable syndromes for CRC
HNPCC/Lynch syndrome
FAP
Genetic factors for CRC
High penetrance genes - APC, biallelic MUTYH, BRCA1/2, PALB2, CDKN2A, TP53
Moderate penetrance genes - monoallelic MUTYH, APC allele, p.I1307K, CHEK 2
Characteristics of HNPCC/Lynch syndrome
Autosomal dominant, high penetrance
Mean age - 48 yrs
Defect in DNA mismatch repair (MMR) genes
Phenotype
- 60-70%: R sided/proximal colonic tumours
- 10% synchronous or metachronous tumours
- Polyps may be present, can overlap with AFAP
- Extracolonic tumours - endometrial, ovarian, stomach, SB, hepatobiliary, brain, renal, pelvis/ureter
Pts at risk of HNPCC
Amsterdam criteria
- >/ 3 relatives with Lunch associated Ca (of which one is a 1st degree relative)
- Lynch associated Ca involving at least 2 generations
- >/ 1 diagnosed before 50 yrs
Bethesda criteria
- CRC Dx < 50 yrs
- Synchronous, metachronous or other Lynch associated Ca, regardless of age
- CRC with MSI-like histology (TILs, mucinous/signet ring, poorly differentiated)
- >/ 1st degree relatives with Lynch associated Ca with 1 diagnosed < 50y/o
- CRC diagnosed in >/ 2 1st degree relatives with Lynch associated Ca
BRAFV600E mutation and Lynch syndrome
If BRAFV600E ABSENT - would rule out Lynch syndrome
MMR genes
MLH1, MSH2, MSH6, PMS2
MAPK pathway
EGFR > RAS > BRAF > MEK > ERK > cell growth and differentiation
BRAF mutation positive CRC
Poor prognosis
Poor response to standard chemo
Requires BRAF inhibitor with EGFR inhibitor (due to upregulation of EGFR in pathway)
FAP features
Germline mutation of APC gene on chromosome 5
FAP - Average age of polyposis 16 yrs (100-1000s), CRC by 45 yrs if untreated
–> screening from 10-15 yrs
AFAP - < 100 polyps, CRC 54 yrs
–> screening at 25 yrs
Colonoscopy timing for Lynch syndrome
1-2 yrly colonoscopies from age 25 yrs or 5 years younger than youngest affected case
Colonoscopy timing for APC mutation
Classic FAP
Surveillance from 10-15 yrs
Once adenoma detected, annual colonoscopy until total colectomy and ileorectal anastomosis
Examples and side effects of fluoropyrimidines
5-FU
Capecitabine
S/E:
Hand foot syndrome
Diarrhoea/mucositis
Haematological/myelosuppression
Coronary artery spasm
Acute coronary events
SEs of oxaliplatin
N+V, diarrhoea
Lethargy
Haematological/myelosuppression
Peripheral neuropathy - cumulative
Cold sensitivity/dysaesthesias
Laryngopharyngeal dysaesthesia
Hypersensitivity reaction
Factors to consider for treatment of CRC
L vs R sided primary
RAS/RAF status
MMR status
If metachronous/relapsed
Chemotherapy for metastatic CRC
Single agent:
- Fluoropyrimidines (5FU or capecitabine)
- Irinotecan
- TAS102
Doublet:
- Fluoropyrimidines with addition of oxaliplatin (FOLFOX/CAPOX) or irinotecan (FOLFIRI/CAPIRI)
Triplet: 5FU, oxiliplatin and irinotecan (FOLFOXIRI)
MOA and SE of irinotecan
Topoisomerase inhibitor
Metabolised by UGT1A1*28 genetic polymorphisms
S/E: Diarrhoea, anticholinergic effects, myelosuppression, alopecia
Targeted therapies for mCRC
VEGF inhibitors - bevacizumab (used regardless of RAS/RAF status, location)
EGFR inhibitor - cetuximab/panitumumab (only in RAS WT tumours, left sided primary)
Side effects of VEGF inhibitors
HTN
Delayed wound healing
Intestinal perforation/fistula formation
Proteinuria/nephrotic syndrome
Increased risk of bleeding/haemorrhage
Increased risk of arterial thrombotic events
Mechanisms of resistance for EGFR inhibitors
Downstream mutations of MAPK pathway
- KRAS/NRAS mutations
- BRAF mutations
S/E of EGFR inhibitors
- Cutaneous
- Skin - xerosis (dry skin), paronychia/fissures
- Diarrhoea
- Hypomagnesaemia
- Infusion reactions
Use of pembrolizumab in mCRC
Used in MSI high (or dMMR) mCRC
MSI –> increases presence of neoantigens with increase TILs –> over expression of PD-1 and PDL-1
Oesophageal cancer classification and prognosis
Classified - adenocarcinoma or SCC
Poor prognosis due to aggressive course and metastatic disease
Treatment for oesophageal cancer
Neoadjuvant chemoradiation
Chemotherapy
- 5FU or capecitabine
- Platinum drugs - cisplatin, carboplatin, oxaplatin
- Irinotecan
- Taxanes - paclitaxel
- TAS102
Targeted egents
- HER2 positive - trastuzumab
- Ramicirumab
Immunotherapy
- Nivolumab (for PDL1 positive)
Management of pancreatic cancer
Resection for early stage pancreatic cancer - Whipple’s procedure
Neoadjuvant/Adjuvant therapy with chemotherapy (FOLFIRINOX or gemcitabine based therapy)
+/- chemoradiation or stereotactic therapy
MOA of gemcitabine + adverse effects
Pyrimidine analog chemotherapy
Pneumonitis
- potent radiosensitiser
- synergistically worsens gemcitabine-induced lung toxicity
Clinical features of carcinoid syndrome
Cutaneous flushing
Venous telangiectasia
Secretory diarrhoea
Bronchospasm
Cardiac valvular lesions in right side of heart (inactivation of humoral substances by lungs protects left heart)
Risk factor for breast cancer
Female gender
Increasing age
Older age at first birth
Oestrogen
EtOH
Family history
Genetic factors involved in breast cancer
BRCA 1/2
STK11 (Peutz-Jeghers)
PTEN (PTEN hamartoma tumour syndrome/Cowden)
CDH1 (Hereditary diffuse gastric Ca)
MSH1/ML1/MSH6/PMS2/EPCAM (Lynch)
PALB2
CHEK2
ATM
High risk factors of breast Ca
Multiples relatives with breast or ovarian Ca
> 1 primary Ca
Vertical transmission
FHx of rare malignancies
Epithelial ovarian Ca
Screening of breast Ca
6 monthly breast examination
Annual mammogram from 40 (or 5 yrs younger than relative)
MRI breast (particularly if pre-menopausal)
Investigations of breast cancer
Mammogram +/- US
FNA/Core biopsy
Referral to breast surgeon
Poor prognostic features of breast Ca
Positive axillary lymph nodes
Increasing size
Higher grade
Negative hormone receptors
HER 2+ve
Younger age
Lymphovascular invasion
Treatment of early stage breast Ca
Surgery
- Wide local excision
- Total mastectomy
(Neo)adjuvant chemo
Adjuvant RTx
Adjuvant hormone therapy
Adjuvant trastuzumab
Indications of hormonal therapy for breast cancer
All ER+/PR+ breast cancer
Pre-menopausal: SERM (tamoxifen, toremifene), GnRH agonist
Post-menopausal: Aromatase inhibitors (anastrozole, letrozole, exemestane)
MOA and adverse events of SERMs
Antagonist on oestrogen receptor in breast tissue or cancer
(However agonist effects on some receptors i.e. bones, uterus, liver)
Increases BMD in post-menopausal women
Risk of VTE, uterine Ca
MOA and adverse events of aromatase inhibitors
Blocks DHEA –> reduces oestrogen
Reduces BMD
Arthralgias
No increased risk of VTE, uterine Ca
Indications for and MOA of trastuzumab
HER2+ve tumour
Given with chemotherapy
Mechanism of action: Targets HER2/neu (c-erbB2) tyrosine kinase receptor → ↓ of HER2 initiated cellular signaling and ↑ antibody-dependent cytotoxicity → ↓ tumor growth
Adverse effects of trastuzumab
Cardiomyopathy (usually reversible, however should have TTE prior)
GI side effects
Indications of chemotherapy for breast cancer
- Tumor size > 2 cm
- Triple-negative breast cancer and tumor size ≥ 0.5 cm
- HER-2 positive breast cancer and tumor size > 1 cm
- Positive lymph nodes
- Aggressive tumor histology
Treatment for ER+/HER2- breast Ca
First line - CDK4/6 inhibitor + hormonal therapy
(chemo if rapid response required)
CDK4/6 inhibitor - ribociclib, abemaciclib, palbociclib
Treatment for HER2+ breast Ca
1st line - trastuzumab/pertuzumab/taxane
2nd line -
Trastuzumab emtansine (T-DM1/Kadcyla) - conjugate with antimicrotubule agent
Trastuzumab deruxtecan (T-DXed) - conjugate with topoisomerase inhibitor
3rd line - Lapatinib
MOA of Pertuzumab
Monoclonal Ab, used in combo with trastuzumab
Binds to dimerisation domain of HER2 receptor but also prevents binding with itself or other EGFR
Treatment for BRCA+ve cancer
PARP inhibitor
Repairs DNA damage
Clinical presentation of Pancoast tumour
Superior sulcus tumour
Usually NSCLC
Pain in shoulder/neuropathic arm pain
Horner’s syndrome (though rare)
Wasting hand muscles
Clinical features of lung cancer
Cough
Haemoptysis
Chest pain
Dyspnoea - bronchial obstruction, pleural effusion
Hoarse voice
SVC obstruction
Extrathoracic mets
Hypercalcaemia
SIADH (especially SCLC)
Hypertrophic pulmonary arthropathy
Features of SCLC
Early to metastasise, high mitotic rate
Classically bulky lymphadenopathy
Very chemo and radiosensitive
Almost all cases are smokers
Doesn’t cause clubbing
Paraneoplastic syndromes
Treatment of SCLC
Chemoimmunotherapy
1st line - Atezolizumab (PD-L1) + carboplatin + etoposide
2nd line
- Topotecan/irinotecan
- Lurbinectedin
- Cyclophosphamide/doxorubicin/vincristine
Features of mesothelioma
Asbestos + tobacco related
Long latency (30-40 yrs)
Treatment for mesothelioma
Generally incurable
- Radical treatment - extrapleural pneumonectomy
- Platinum + pemetrexed (folate antimetabolite)
- Dual immunotherapy: nivolumab and ipilimumab
Staging principles
Stage 1: small tumour
Stage 2: large tumour or small tumour with nodal involvement
Stage 3: very large tumour, invasion into mediastinum, ipsilateral lung nodules (3a) or contralateral hilar nodes (3b)
Stage 4: pleural effusion, contralateral lung nodules, distant mets
Driver mutations in lung adenocarcinoma
EGFR
ALK rearrangement
ROS1 fusion
BRAF
ERBB2
MET
RET
NTRK
KRAS
EGFR inhibitor examples
1st gen: Gefitinib, erlotinib
2nd gen: Afatinib
3rd gen: Osimertinib
Adverse effects of EGFR inhibitors
Acne like rash
Diarrhoea
Nausea
Pulmonary fibrosis
Mechanism of action of EGFR inhibitor resistance
Due to T790M resistance mutation
Use of osimertinib highly active against T790M
Targeted therapy for ALK gene rearrangement
ALK phosphorylation inhibitors
1st gen: crizotinib
2nd gen: ceritinib
3rd gen: alectinib (better CNS penetration), lorlatinib, brigitinib
Targeted therapy for ROS-1 fusion
Responsive to ALK inhibitors
- Crizotinib, lorlatinib, entrectinib
Treatment for KRAS +ve lung adenocarcinomas
More common in smokers
Chemo as first line
Sotorasib (KRAS G12C inhibitor) as 2nd line therapyT
Treatment for NSCLC with no driver mutations
PD-L1 score
If < 50% - chemoimmunotherapy
–> platinum doublet + PD-L1 inhibitor
If > 50% –> single agent PD-L1 inhibitor
Tumour markers
CEA - colon cancer
CA125 - ovarian cancer
CA15.3 - breast cancer
CA19.9 - breast cancer
AFP - germ cell tumours/hepatocellular cancer
PSA - prostate cancer
Predictive marker of melanoma
Breslow depth of lesion and presence or absence of ulceration
Clinical signs of melanoma
Asymmetry
Borders (uneven vs even)
Colour
Diameter
Enlargement or evolution
Melanoma subtypes
Radial growth phase
- Superficial spreading
- Lentigo maligna
- Acral lentiginous
Vertical growth phase
- Nodular
Clinical features looked at in early nodular melanoma
Symmetry
Raised
Colour
Firmness
Progressive growth
Major determinants of outcome for stage III melanoma
Number of metastatic lymph nodes
Tumour burden
Presence of absence of ulceration of primary melanoma
Presence or absence of satellite or in-transit metastasis
Pathway activated in melanoma
- MAPK cascade activated in almost all types of melanoma – 80% due to mutations in NRAS or BRAF genes
- BRAF mutations present in 40-60% of metastatic melanomas
- More common in cutaneous melanomas without chronic sun damage (mutations in c-kit more common in CSD)
- With treatments, disease related to BRAF mutations has significantly improved
Management of stage III melanoma
Stage 3A - observation
Stage 3B/3C/3D/resected stage 4 - adjuvant therapies
- BRAF mutant: Dabrafenib and trametinib (BRAF and MEK inhibitor)
- Anti-PD1 for all patients: Nivolumab/Pembolizumab
Treatment of stage IV melanoma
Targeted therapy with immunotherapy (PDL1 inhibitor, BRAF mutant targeted therapy)
Surgical resection of metastasis
BRAF targeted therapy
Dabrafenib
Trametinib
Molecular biology profile of melanoma
Intermittent sun exposure:
- BRAF
- NRAS
- PTEN
- AKT
- p16
Chronic sun exposure:
- KIT
- CDK4
- Cyclin D1
Acral exposure:
- NRAS
- KIT
- CDK4
- Cyclin 4
Mucosal exposure
- CDK4
- KIT
BRAF inhibitors
Vemurafenib (selective V600E mutations)
Dabrafenib (inhibits all V600 mutations)
Encorafenib (inhibits all V600 mutations)
MEK inhibitors
Cobimetinib
Trametinib
Binimetinib
cKIT inhibitors
Imatinib
Management of activating BRAF mutations
BRAF kinase inhibitor (e.g., vemurafenib) is used in metastatic or unresectable melanomas that have the BRAF V600E mutation (substitution of glutamic acid in place of valine at amino acid position 600 caused by activating mutations in the BRAF gene)
BRAF inhibitor adverse events
Cutaneous SCC and keratoacanthoma
Hyperkeratosis
Skin papilloma
Hand foot syndrome
Alopecia
Photosensitivity and sunburn
MOA of CTLA-4
Receptor expressed on activated helper T cells and CTLs
Inhibits T cell activation and proliferation
- Binds to B7 molecule on APCs surface with higher affinity than CD28
- Puts break on T cell proliferation
CTLA4 ligands (CD80 and CD86)
Immune related adverse events with CTLA-4 inhibitors
Rash
Colitis
Arthritis
Hepatitis
Hypo/hyperthyroidism
Pneumonitis
Management of IRAEs
Grade III/IV –> generally reversible and can be treated with standard anti-inflammatory therapies i.e. corticosteroids
Grade IV –> prolonged steroid taper and TNF blockade with infliximab or prolonged bowel rest with TPN
Anti-PD1 MOA
Restores anti-tumour T cell function
Enhances pre-existing T cell response
Increases cytokine production
Anti-CTLA4 MOA
Induces de novo anti-tumour T cell responses
Enables adaptation to evolving tumour
Promotes emergence of memory T cells
Causes compensatory increase in tumour PD-L1
PD-1 protein
T cell coinhibitory receptor structurally similar to CTLA-4 but with distinct biologic function and ligand specificity
Two known ligands, PD-L1 and PD-L2
Selectively expressed on many tumours and on cells within tumour microenvironment in response to inflammatory stimuli
VEGF inhibitor side effects
HTN - predictive marker
Reversible posterior leukoencephalopathy
Proteinuria/renal dysfunction
Haemorrhage
mTOR inhibitors toxicity
Oral ulceration - mouth ulcers, stomatitis
Rash
Fatigue
HTN
Hand and foot syndrome
Diarrhoea
Infections
Pneumonitis
TKIs rash predictive marker
Higher grade rash, higher probability of response
VEGF receptor TKIs
Pazopanib
Sunitinib
Sorafenib
Cabozantinib
Tivozanib
Axitinib
Lenvatinib
mTOR inhibitors
Everolimus
Temsirolimus
Anti-VEGF antibodies
Bevacizumab
RCC paraneoplastic syndrome
- Secondary hypercortisolism: due to ectopic ACTH release
- Secondary polycythemia: due to ectopic erythropoietin (EPO) secretion
- Hypertension: due to the release of renin
- Hypercalcemia: due to the release of PTHrP (parathyroid hormone-related protein)
- Leukemoid reaction: due to bone marrow stimulation
- Limbic encephalitis: Memory loss, Psychosis, Depression
Features of Li Fraumeni syndrome
Mutation of p53 tumour suppression gene
BLAST 53
- Breast cancer/brain tumour
- leukaemia/lymphoma
- adrenocortical carcinoma
- sarcoma
- Tp53
