cancer

Question 1

HPV types and associations

Answer 1

6, 11 ➡️ genital warts

16, 18, 31, etc. ➡️ cervical cancer

Question 2

stages of prostate regulation throughout lifetime (4)

Answer 2

1. Development → puberty: paracrine effects; androgens act on stromal AR → growth factor production → epithelial cell proliferation
   Epithelial cells also secrete factors that maintain stromal cells in differentiated state
2. Adult: AR in epithelial cells important at this stage
3. Second growth spurt: due to breakdown of regulation w ↑age

Question 3

investigations for prostate cancer (3)

Answer 3

1. DRE
2. PSA (can have temporary increases e.g. from DRE, also false positives)
3. USS: tumours outside prostate capsule

Question 4

prostate cancer Tx options (4)

Answer 4

Low grade tumour, older patients → active surveillance (periodic PSA tests)
Confined to prostate gland (stage T1, T2) → radical prostatectomy
(nerves nearby control erection & urination ∴ risk of incontinence & impotence)
Confined or local spread (T1 to T3) → radical radiotherapy (external or implants)
Metastatic cancer → hormone therapy

Question 5

possible mechanisms behind castration-resistance prostate cancer (4)

Answer 5

Amplified response to low levels of residual/administered hormones due to:

1. Overexpression/amplification of AR
2. Overexpression/amplification of coactivator genes
3. Reduced expression/deletion of corepressor genes
4. Mutation or alternative splicing of AR (can drive AR target gene expression and growth in absence of ligand)

Question 6

treatment for breast cancer (4)

Answer 6

1. SERMs e.g. tamoxifen, bind competitively to ER
2. ovarian ablation (prevention of oestrogen production by ovaries): surgery/hormone therapy e.g. goserelin (LHRH analogue)
3. SERDs e.g. fulvestrant, bind competitively to ER and induce receptor degradation
4. aromatase inhibitors: prevent conversion of androstenedione to estrone and testosterone to estradiol

Question 7

mechanisms of resistance to hormone therapy in breast cancer

Answer 7

1. de novo endocrine resistance: tumour independent of estrogen, despite being ERα-positive
2. acquired endocrine resistance: growth promotion of initially estrogen-dependent tumours, by other mitogenic pathways
3. transcription coactivators/repressors
4. ER mutations

Question 8

what type of virus is HPV

Answer 8

dsDNA

Question 9

HPV screening

1. methods
2. schedule

Answer 9

1. Smear test: taken from SCJ
   25-50: 3 yearly, 50-65: 5 yearly (1/4 false negatives)
2. HPV DNA test will replace smear test (more sensitive; detected in 99.7%)
3. CIN 2/3 → colposcopy and loop excision
   Remove affected tissue + assess extent of neoplasia

Question 10

presentation of cervical cancer

Answer 10

Early disease asymptomatic
Irregular bleeding: after intercourse, in between periods
Advanced disease → offensive discharge, backache, leg pain/oedema, haematuria, bowel changes, malaise, weight loss, anaemia

Question 11

endometrial cancer: types + mutations

Answer 11

oestrogen dependent: PTEN mutation
more common, younger women, better prognosis
non-oestrogen dependent: p53 mutation

Question 12

mainstay treatment of endometrial cancer

Answer 12

TAH + BSO

radiotherapy (after surgery; pre-op makes surgery more difficult)

Question 13

HPV interaction w host genome

Answer 13

integrates into host genome -> overexpression of E6 and E7 genes -> proteins degrade tumour suppressors e.g. p53, pRb -> aneuploidy, increased cell cycling and survival

Question 14

composition of HPV vaccine

Answer 14

virus like particle: L1 protein of HPV capsid

Question 15

breast cancer biomarkers (3)

Answer 15

ER: nuclear transcription factor
PR: nuclear transcription factor
- ER and PR -> better response to endocrine therapy
Her-2-neu: growth factor receptor
important in deciding on management (also prognostic factors)

Question 16

breast cancer risk factors (3)

Answer 16

1. oestrogen exposure
2. family history
3. genetic syndromes e.g. BRCA1 and 2

Question 17

breast cancer investigations (3)

Answer 17

triple assessment

1. clinical: palpation
2. imaging: mammography / USS (young pts)
3. biopsy: fine needle aspiration / core-cut biopsy

Question 18

breast cancer presentation (7)

Answer 18

Breast lumps/thickening (w or w/o pain)
Nipple discharge, reaction, excoriated rash
Lumps in armpits
Pain in breast/armpits
Change in how breast feels/looks
Rarely, metastasis related symptoms: bone pain, pathological fracture, convulsions, jaundice
Asymptomatic → mammographic abnormalities upon screening

Question 19

endometrial cancer risk factors (6)

Answer 19

Obesity
Diabetes mellitus
Nulliparity 
PCOS 
Oestrogen only HRT 
Prolonged tamoxifen use

Question 20

prostate cancer symptoms

Answer 20

Urinary symptoms: 
Polyuria, nocturia 
Poor urinary stream
Urgent need to urinate 
Hesitancy whilst urinating
Lower back pain 
Blood in the urine (rare) 
Can also be asymptomatic and go undetected

Question 21

hormone therapy for prostate cancer + MOAs (5)

Answer 21

1. GnRH analogues e.g. gosrelin: overstimulate GnRHR → downregulation
   Takes 2 weeks; initial rise in LH and testosterone
2. GnRH antagonists: block GnRHR activation ∴ more rapid effects
3. AR antagonists (anti-androgens) e.g. flutamide
   a. Compete w ligand for AR binding
   b. Sequester AR in cytoplasm
   c. Prevent dimerisation
   d. Prevention formation of active transcription complex
4. 5α-reductase inhibitors: inhibit testosterone → DHT
5. Abiraterone: inhibits CYP17
   Affects synthesis of other steroids; ↑11-deoxycorticosterone + corticosterone (glucocorticoids + mineralocorticoids) → secondary mineralocorticoid syndrome (hypertension etc.)

Question 22

how is blood vessel integrity maintained (3)

Answer 22

1. angiopoietin 1 binds to tie 2 receptor
2. contact w ECM
3. physical contact between endothelial and mesenchymal cellst

Question 23

regulation of ECM remodelling (MMPs and TIMPs)

Answer 23

MMP-TIMP complex requires both dissociation of TIMP and cleavage of MMP N-terminus to expose active site

Question 24

actions of angiopoietins

Answer 24

angiopoietin 1: agonist for tie2
angiopoietin 2: antagonist for tie2 (produced by tumours)
multiple signalling pathways -> endothelial cell assembly and survival, ECM interactions -> blood vessel formation and maintenance

Question 25

process of angiogenesis

Answer 25

1. loss of contact between endothelial cells 2. proliferation, invasion of ECM 3. contact w pre-existing blood vessel 4. formation of new junction between vessels

Question 26

hallmarks of cancer (10)

Answer 26

1. sustained proliferative signalling: 2. evasion of tumour suppressors e.g. pRb, CKIs 3. resisting cell death 4. replicative immortality e.g. uregulation of telomerase 5. induction of angiogenesis e.g. increased HIF, VEGF 6. invasion and metastasis emerging hallmarks: 7. deregulation of cell energetics 8. evasion of immune response enabling hallmarks: 9. DNA instability and mutations 10. inflammation

Question 27

imatinib: 1. moa 2. development of resistance

Answer 27

1. ATP analogue which binds to BCR-ABL (fusion protein found in CML) also targets some receptor tyrosine kinases e.g. PDGF-receptor and c-Kit (gastrointestinal stromal tumours) 2. threonine mutation to larger amino acid -> loss of imatinib binding

Question 28

type 1 vs type 2 kinase inhibitors

Answer 28

type 1 targets active receptor e.g. dasatinib | type 2 targets inactive receptor (juxtamembrane region blocks active site) e.g. imatinib

Question 29

tyrosine kinase inhibitor resistance; mechanisms (5)

Answer 29

1. mutation prevents drug binding 2. upregulation of alternative kinase 3. alternative kinases 4. downregulation of phosphatase 5. downstream mutation in receptor signalling pathway

Question 30

cancers associated w infection (4)

Answer 30

H. pylori → stomach cancer Hep B → liver cancer Pancreatitis → pancreatic cancer HPV → cervical cancer

Question 31

immune responses that can be prognostic in cancer (2)

Answer 31

Tumour infiltrating lymphocytes (TILs) → better prognosis | Tregs → worsened prognosis

Question 32

how do tumours evade the immune response (6)

Answer 32

1. Secrete cytokines e.g. IL10, IGFβ → ↓effector T cell response, ↑Treg 2. ↓MHC class I and II 3. Expression of ligands e.g. CTLA-4/PDL1 that bind to inhibitory receptors on T cells 4. Loss of Fas and other death receptors 5. Upregulation of anti-apoptotis proteins e.g. Bcl2 6. Continuous shedding of tumour associated antigens → tolerance

Question 33

immunotherapy approaches for cancer Tx (4) 2017 essay

Answer 33

1. Cytokines (e.g. Interferons, IL2) 2. Monoclonal Antibodies (mAbs) 3. Cancer vaccines 4. Adoptive immunotherapy e.g. TILs, haematopoetic stem cells, NK cells, T cells

Question 34

immunotherapy: cytokine therapy examples (2) + issues (2) 2017 essay

Answer 34

Examples 1. IL-2 → activation and expansion of CD4 and CD8 T-cells (metastatic melanoma and renal cell carcinoma) 2. IFN → expression of MHC class I, maturation of DCs, activation of CTLs (melanoma) Issues: 1. Non-specific (cytokines have multiple effects) → toxic side effects 2. Redundancy; alternative pathways compensate

Question 35

immunotherapy: monoclonal Abs examples and MOA (4) 2017 essay

Answer 35

1. Herceptin → HER2 (breast cancer) internalisation and degradation 2. Rituximab binds to CD20 (malignant lymphoma) → Fc receptors of NK cells can bind → crosslinking → perforin, granzymes → cell lysis 3. Ipilimumab blocks co-stimulation needed for T cell activation (melanoma) 4. Brentuximab targets CD30 Ag of lymphocytes, delivers chemo drug MMAE (Hodgkin's lymphoma)

Question 36

what is adoptive immunotherapy + one example 2017 essay

Answer 36

transfer of lymphocytes to patient | e.g. TILs (tumour infiltrating lymphocytes): retrieve T cells from pt, select, expand and then transfer back

Question 37

how does obesity and insulin resistance increase endometrial cancer risk 2017 SAQ

Answer 37

1. Adipose tissue aromatase: androgens → oestrogens 2. Fat cells produce adipokines that may stimulate or inhibit cell growth a. Leptin promotes cell proliferation b. Adiponectin may have anti-proliferative effects 3. Fat cells have direct & indirect effects on tumour growth regulators, including mammalian target of rapamycin (mTOR) and AMP-activated protein kinase 4. Obese people often have chronic low-level, or “sub-acute,” inflammation, which has been associated with increased cancer risk

Question 38

side effects of anti-androgens (5) 2015 SAQ

Answer 38

Osteoporosis, muscle loss, ↑fat deposition, gynaecomastia, loss of libido

Question 39

management of cervical cancer (4)

Answer 39

1. CIN (cervical intraepithelial neoplasia)/CIS are resected to avoid progression to cancer 2. Invasive cancer: radical hysterectomy and lymph node dissection OR radical chemoradiation therapy 3. Radical hysterectomy ○ Benefits: ovarian preservation ○ Complications: bowel-bladder dysfunction 4. Radiotherapy: ○ Benefits: Good for frail patients with co-morbidities ○ Complications: menopause, late sequelae on bladder