prostate cancer SD Flashcards
3 zones of the prostate
peripheral
transition
central
What zone of the prostate does cancer mostly form in?
peripheral zone 70%
diseases of the prostate
prostatitis
benign porstatic hyperplasia
prostatic carcinoma
age of incidence of prostate diseases
most commonly over 60 years
What do prostatic diseases do to the prostate?
cause enlargement of the prostate
What does an enlarged prostate cause?
- compression of the intraprostatic portion of the urethra
- impaired urine flow
- increased risk of urinary infections
RF for prostate cancer
age
genetics - FHx, 2-3x risk if first degree relative was diagnosed with PC U50yrs
race - 3x risk African/Caribbean
diet - red meat = inc risk, soya = protective
How to diagnose prostate cancer?
DRE - digital rectal examination
PSA blood test
What is DRE?
digital rectal examination
- feel for any prostate enlargement, irregular nodes, rigidity, masses
- normal prostate = smooth
drawbacks of DRE
- males get embarassed
- mass already reached certain size to be detected by touch
diagnosis by PSA
PSA is a serine protease produced by prostatic ductal epithelium
abnormal prostate - inc AR -> inc PSA
normal PSA upper limit = 3-4 ng/ml
What can affect PSA levels?
prostate biopsy
DRE
ejaculation
BPH
proatatitis
intense exercise
limitations of PSA diagnosis
- 20% of PC missed by having normal PSA
- 2/3 with high PSA don’t have PC
- BPH, prostatitis, urinary infections can lead to rased PSA
- some tumours grow very slowly and never progress, some rapidly and lethal
- no PSA screening in UK
TRUS - trans rectal ultra sonography
follow up from +ve DRE and PSA test
ultrasound allows imaging of prostate
can take biopsy if want
highly invasive
What grading system is used for stratifying prostate cancer?
Gleason Grade
How is Gleason grade determined?
adding the 2 most typical grades of the cells in the tissue sample
prostatic bone metastases
often present as
- localised bone pain
- back pain from vertebral metastases
osteosclerotic with areas of new bone formation
types of Tx for PC
- watchful waiting
- surgery - radical prostatectomy
- treatment - androgen deprivation therapy
watchful waiting
some PCs don’t progress or spread
if pt has no Sx, can get no Tx and are monitored for any changes
no s/e of surgery/drugs
if situation changes, Tx can begin
surgery
radical prostatectomy
major operation - blood loss, nerves surounding prostate
- keyhole surgery by hand
- robot assisted surgery - Da Vinci robot
advantages of using robot assisted surgery
less infection, blood loss
faster healing time
less time in hospital
Orchiectomy
surgical castration
What is used for chemical castration?
LHRH agonists
How to LHRH agonists work?
lower the amount of testosterone made by the testicles
continuous agonist presence leads to decreased levels of LHRH receptor levels on pituitary gland
** doesn’t interact with AR
** LOWERS TESTOSTERONE/DHT LEVELS
example of LHRH agonist
Zoladex (goserelin)
How does Zoldex/Goserelin work?
The continuous agonist presence leads to DECREASED levels of LHRH R levels on pituitary gland
drug to inhibit AR
Casodex (Bicalutamide)
MOA Casodex (Bicalutamide)
– Binds to AR directly
– AR STILL ENTERS THE NUCLEUS
– Casodex prevents gene transcription
- Alter dose depending upon response – PSA test
- outcompetes DHT
resistance to Casodex (Bicalutamide)
- Drug Tx slows down cancer growth
- after 2-3 years the pathway can modify/mutate and no longer requires testosterone
- Cells start to grow rapidly again
CRPC
- Androgen Receptor Mutation
- LBD mutation – resistance mechanism
- Allows OTHER hormones to bind to AR
- allows multiple agonists to activate AR
- Oestrogens, Progesterone, Glucocorticoids
- Antagonists can become AGONISTS
- flutamide became a strong agonist with T877A mutation
- T877A Allows conformational change of the receptor to activate genes
relapsed PC Tx
Taxanes - Docetaxal
s/e Docetaxal
Neutropenia
Anemia
Hair loss
Fluid retention
Diarrhea
Nausea
Rash
Mouth sores
Fingernail changes
Tx for Castrate Resistant Disease
Enzalutamide
Who is Enzalutamide reserved for?
patients with metastasis, CRPC disease
Abiraterone MOA
- prevents testosterone biosynthesis
- inhibits CYP17 which prevents conversion of progestens to androgens
- no substrate for AR
- cause mineralocorticoid excess
- decreases cortisol - ACTH is activated
- inc mineralocorticoids
- Tx = prednisone/dexamethasone, to lower ACTH
AR variants
- LBD removed, drugs can’t bind
- resistant to ADT, enzalutamide & abiraterone
- resistance to apoptosis
Tx for CRPC
Abiraterone
&
Enzalutamide
Why enzalutamise > Bicalutamide (Casodex)?
doesn’t become partial agonist when it mutates
