prostate cancer

Question 1

What is the epidemiology of prostate cancer *(

Answer 1

1 in 8 men get it in their lifetime - most common male-specific cancer in west

49000 new cases a year in England

incidence increased hy 44% since 1990

good mortality - 10yr LE is 80% - but because of the high incidence this is actually a lot of people (more deaths for men by prostate, than women by breast)

3rd highest mortality (1st colorectal, then prostate, then breast)

lung cancer highest mortality in men followed by prostate

when age 60 there is a dramatic increase in diagnosis - increase in prevalence of latent and clinically detected prostate cancer - only 5% of deaths occuring in men are under 64yrs - however increase in incidence is not soley due to the increasing population

incidence predicted to raise by 12% in the UK between 2-14 and 2035 to 233 cases per 100000 males

Question 2

what are the symptoms of prostate cancer *

Answer 2

Difficulty urinating – prostate surrounds the urethra so if enlarges put pressure on urethra

More frequent and feeling of urgency – then when go difficulty and retention in bladder

rarely lower back pain/blood in the urine

Question 3

what is the problem with interpretation of the symptoms for prostate cancer *

Answer 3

Prostate enlarges in completely healthy people – get some of these symptoms, doesn’t mean you have cancer

this is BPH (benign prostatic hyperplasia) - have milder symptoms than if you had a tumour

Question 4

what are the tests for prostate cancer *

Answer 4

digital rectal examination

PSA - prostate specific antigen

then biopsy - MRI done at same time, newer methods of multi-parameter MRI are being tested to avoid invasive biopsy

Question 5

describe the PSA test *

Answer 5

blood test - immunoassay on the serum

any enlargement of prostate = leakage of PSA into the blood

therefore can be raised with:

• BPH
• UTI (but would get pain when urinating)
• inflammation
• mechanical damage - bike ride/biopsy
• prostatitis - infection of the prostate

if >4ng/ml then have to do something to see if it is cancer (ie biopsy, can rise to 2000 ng/ml and above in aggressive metastatic disease.

Question 6

describe biopsy for prostate cancer *

Answer 6

TRUS - transrectal and US

prostate is very close to the intestinal wall so go through the wall and take 10cores - send to lab

look under microscope and grade the tumour - this is the Gleason’s grading system

biopsy can under and overestimate the tumour grade - extended sampling techniques and repeat biopsies have improved this

Question 7

what are the SE of biopsy *

Answer 7

infection so take AB prophylactically

bleeding in urine for a time

Question 8

what are the 4 types of treatment for prostate cancer *

Answer 8

surgery

radiotherpay

hormone therapy

chemotherapy

Question 9

describe surgery for prostate cancer *

Answer 9

fine for localised tumours

have to remove whole prostate - this is radical prostectomy, it is done laparoscopically with robots

takes 4-5 hrs - major surgery

have to have PSA <10-12ng/ml and age <70yrs - giving the group with the highest survival

Question 10

describe the side effects of surgery for prostate cancer *

Answer 10

incontinence - because have to cut urethra to be able to remove all prostate then reattach around the catheter, then have catheter removed - at this point you hvae incontinance for 2months so told to do pelvic floors

sterility - can freesze eggs (not always important because most people are >60)

impotence - loss of erectile function, reason why people dont want surgery - this is because the nerves are removed, can do nerve sparing tumour but less likely to be able to remove all the tumour

Question 11

describe radiotherapy for prostate cancer *

Answer 11

external beam radiotherapy - focus onto a particular place to try and destroy the tissue - possible if spread out of prostate capsule but not affected the other organs, computer planning is used to limit the toxicity to the bowel and bladder

or, if tumour contained in prostate - brachytherapy - radiactive seeds inserted into tissue so localised source of radiation in tissue

requires multiple visits - every day for a month

Question 12

what are the side effects of radiotherapy for prostate *

Answer 12

incontinence,

erectile dysfunction,

diarrhoea (because the radiotherapy effects the gut)

Question 13

when is hormone therapy used *

Answer 13

Used in combination eg radiotherapy – shrink the tumour so easier to focus the beam on the right place

Question 14

describe the hormone axis to the prostate *

Answer 14

Hypothalamus produces GnRH (also called LHRH)

Bind to pituitary – cause pit to release LH

Act on testes - testes produce androgen

Androgen act on prostate

Question 15

mechanism of action of hormone therapy for prostate cancer *

Answer 15

bilateral orchidectomy (remove the source of testosterone ie the testes) - this is done chemically:

LHRH agonists (eg leuroprorelin) – stimulate the LHRH receptors = overstimulation = downregulation or receptors – cant respond to endogenous hormone (injection every month)

problem is the cancer will get worse initially because of the ‘testosterone flare’ due to increased LHRH stimulation until the receptors are downregulated

to address this - give anti-androgen (flutamide), this combats the other androgens that are produced by the adrenal glands

Abiraterone - CYP17 inhibitor blocks synthesis of androgens – given to men with metastatic prostate cancer (tablets once a day)

there are LHRH antagonists but less effective

Question 16

describe chemotherapy for prostate cancer *

Answer 16

treatment of last resource – giving a few months extra life, often people don’t want it at this point because of the SE

Question 17

how can we monitor the effectiveness of therapies *

Answer 17

PSA would go down dramatically (if surgery to undetectable – therefore people like this because easy to see if it has come back)

If other therapies 1st not as dramatic decline so harder to know if it has come back

Question 18

describe the gleason’s gradig system *

Answer 18

it is a commonly used histopathological reporting of prostate cancer

the 2 largest areas of tumour found are scored 1-5 (1 is least agressive, 5 is most) - the 2 scores are quoted plus their sum

sums 2-4 are low grade

5-7 - intermediate

8-10 high

Question 19

can you tell whether a prostate tumour is slow/fast growing from genetics *

Answer 19

no - there is not a relation between mutations and speed of growth

Question 20

do metastasing prostate cancer cells also produce PSA *

Answer 20

yes

Question 21

What could a PSA test result of 15ng/ml indicate?

Answer 21

prostate cancer or infection

Question 22

why would someone be offered hormone therapy over surgery *

Answer 22

age - so LE and QOL – someone who is 60 more likely to have longer with better QOL than someone 78, long operation under GA that has some risk – older people with longer operation effect mental faculties

Question 23

what mechanism could contribute to recurrance of prostate cancer in spite of continued anti-androgen treatment *

Answer 23

biochemical relapse happens in 13months, symptomatic in 2yrs and death 7months later

tumour develops independent of androgen - however the expression of the androgen receptor (the ligand activated TF that mediates response to androgens is not lost and is often increased by over expression or gene amplification - implying androgen receptor signalling is required for prostate cancer progression

there could be amplifications of the response to low residual levels of androgens, or weak androgens present in patient by increased levels of androgen receptor or other proteins required for androgen receptor signalling (co-activators), decreased level of co-repressors, or mutation of the androgen receptor so it is stimulated by other ligands - oestrogens or anti-androgens

the mutations are rare in primary tumours, increase in frequency in advanced, metastatic hormone-independant disease - they are in 30-50% of these tumours; amplication or overexpression of the androgen receptor is seen in a similar proportion

amplication of co-activator proteins has been seen in breast cancer and has been studied in prostate cancer

another pathway could be ligand-independant activation of the androgen receptor by GF eg in ER in breast cancer

or the androgen receptor could be bypassed altogether by loss of PTEN for eg

eg because of mutations in androgen receptors or signalling pathway from androgen receptor

hormone therapy selects out mutants so PSA starts increasing so might want to start chemo.

dont have to do each type of therapy in isolation

Question 24

how we can go about searching for markers of aggressive versus latent prostate cancer *

Answer 24

genetic approach (RNA or DNA) but don’t know from just biopsy which is aggressive, need clinical info as well.

Ideally less invasive way – cfDNA (tumour cells release small amounts of DNA into the blood), take blood sample and will be able to see what type of prostate tumour it might be

Question 25

There is constant debate about routine PSA testing for men over a certain age to detect early prostate cancer. Can you envisage any potential problems of such a screening programme?

Answer 25

test is not specific (false +ves)

test people who are asymptomatic - if PSA is raised they will have to have invasive tests and a period of anxiety - and there is the possiblity that if the lesion was left alone it would have caused no symptoms in the lifetime

also would have to do a lot of unnecessary biopsies

also pts then have to decide what to do with them – would have to do a lot more surgeries – NHS not capable of this

Question 26

what is the anatomy of the prostate gland

Answer 26

immediately inferior to the bladder in males, responsible for making some of the fluid contents of semen.

It completely surrounds the urethra, thus hyperplasia for any reason constricts the urethra leading to problems in urination.

it is an exocrine gland - secretions from the luminal epithelial cells are released into the duct then the urethra to form part of the seminal fluid

Question 27

genetics of prostate cancer *

Answer 27

heterogenous with respect to oncogenes and tumour suppressors

may have the 4th highest genetic component of common cancers but no genes found that account for >10% of familial cases

2 approaches to genetics have been used: analysis of familial forms of the cancer, and identification of chromosomal abnormalities in tumour biopsies

These have indicated a number of chromosomal loci of cancer susceptibility but have not led to an association of the disease with particular oncogenes or tumour suppressors. - The clearest relationship is with the androgen signalling pathway. Late stage aggressive metastatic prostate cancer frequently becomes androgen-independent.

inactivation of PTEN also shows links to familial prostate cancer - might have a direct impact on androgen independant axtivation of the androgen receptor since PTEN has been shown to antagonise androgen signalling, or may fascilitate anti-apoptotic pathways

BRCA2 involved in familial breast cancer predisposition, is linked to prostate cancer in up to 5% of familial cases

genomic DNA sequencing techniques have identified mutations in a variety of different genes in prostate cancer.

Question 28

describe prostate specific antigen *

Answer 28

it is a kallikrein protein that is secreted by epithelial cells of the prostate into the lumen of the duct

here it joins the semianl fluid and is eventuallt discharged in the urethra

normally - it is prevented by the basement membrane of the gland, basal cell layer and epi gap junctions, from leaving the cells by any other route and so will not be detected in the blood

Question 29

describe ‘watchful waiting’ as a treatment for prostate cancer *

Answer 29

people do nothing for a while to see if it is slow growing because of the side effects of the treatments

favoured in older patients with low grade tumours

Question 30

describe the spreading of prostate cancer *

Answer 30

can spread to seminal vesicles, bladder

metastise to bone/lymph - majority of death is due to metastasis, major symptom of metastatic prostate cancer is bone pain

Question 31

prognosis of prostate cancer *

Answer 31

biopsy and grading is not useful for predicting it

very variable

often slow growing - people die with them rather than of them

in many cases the latent foci are too small to cause any symptoms

no way of testing with histology or PSA which will stay latent and which will become metastatic

people are trying to design a test to see which are life limiting and metastatic - focussing in detectable chanages in serum , urine, semen using proteomics or NMR

Question 32

treatment for metastatic prostate cancer *

Answer 32

hormone therapy sometimes in combination with the other treatments

Question 33

SE of hormone therapy *

Answer 33

osteoporosis

loss of libido

anaemia

muscle atrophy

memory loss

gynaecomastia