BB3204-BB3704

The biology, genetics and

treatment of human cancer

Dr Predrag Slijepcevic
 Key Issues
• Incidence of prostate cancer.

• Environmental and inherited risk factors associated with

prostate cancer

• Symptoms and diagnosis of prostate cancer.

• Key genetic changes associated with prostate cancer

• Difficult to construct a genetic model

• Treatment – current and future perspectives

 Incidence of prostate Cancer
• About 330,000 new diagnoses of cancer in the UK each year.

• 41,736 prostate cancer cases in the UK in 2011

– Represents 12.6% of all new diagnoses of cancer.

• The most common cancer in men.

– 1 in 8 men will get prostate cancer.

• 10,837 men died as a result of prostate cancer in the UK in

2011.
– About 26% of all prostate cancers
 Risk factors associated with prostate
cancer
• Age is the most significant risk factor with over 1/3rd of cases
occurring in men over 75yrs. 1% of cases in men under 50.
• Family history: Increases risk by 2-3 fold
– Small proportion of inherited prostate cancers.

• Ethnicity: More common in black and Caribbean men (2-3 fold

increased risk. Asian men how lower risk then white men.
• Previous cancer including kidney, bladder, lung, thyroid and
melanoma skin cancer.
– 2-3 fold increased risk
 Risk factors - continued
• Minor risk factors include
– High Calcium diet
– High testosterone levels
– Vasectomy
– Increased cadmium in the diet.
– Inflammation of the prostate – prostatitis
– Height and body weight
• Tall men have a slightly increased risk
 What protects from prostate cancer?
• Dietary factors and vitamin supplements
– Diets high is lycopene and selenium may offer some protection

• NSAIDS
– Aspirin and Ibuprofen may offer some protection??

• Men with diabetes have slightly lower incidence than the general
population.

• Physical activity: May reduce the risk of prostate cancer.

Symptoms of prostate cancer
• Urinary frequency
– Rushing to toilet.

– Night time urination.

– Slow flow and difficulty in starting

and stopping.

– Pain when urinating (rare).

– Blood in the urine/semen (rare).

 Diagnosing prostate cancer
• General practitioner
– Digital rectal examination
– Blood test for prostate specific antigen (PSA)
• Serum glycoprotein 1.3ng/ml is normal range. Increased levels
indicates a 25% chance of having prostate cancer.
• PSA test would be repeated again if levels were abnormal.
• PSA test is very inaccurate and can be influenced by many non-
cancer conditions
– Prostatitis
– Trauma – bicycle riding
– DRE
• PCA3 test: Prostate cancer gene 3, prostate specific mRNA (non
coding) some promise as a marker for prostate cancer.
 Hospital tests that may be carried out

• Another PSA blood test.

• Another DRE.
• A prostate biopsy.
• An MRI scan.
• A CT scan.
• A bone scan with or without X-rays.
• An ultrasound scan.
• A urine flow test.
Biopsy and MRI
 CT and Bone Scan
• CAT scan will reveal similar
information as MRI

• A PET scan may be used to

reveal bone or node
involvement if tumour has
spread beyond the prostate.
Urine Flow Analysis

Normal
BPH/Cancer
TNM Staging
 TNM Staging Lymph nodes

• NX – The lymph nodes cannot be checked

• N0 – There are no cancer cells in lymph nodes
close to the prostate
• N1 – There are cancer cells present in lymph
nodes
 TNM Staging Metastases

• M staging – metastases (cancer spread)

• M0 – No cancer has spread outside the pelvis
• M1 – Cancer has spread outside the pelvis
• M1a – There are cancer cells in lymph nodes outside
the pelvis
• M1b – There are cancer cells in the bone
• M1c – There are cancer cells in other places
 Prostate grading: Gleason Slice

A Gleason Slice of Prostate Cancer showing

reduction in differentiation
Most grading is given by two scores (e.g. 5+3 = 8)
 Treating prostate Cancer

• A valid approach is to do nothing.

– Watchful waiting

• A variety of surgical approaches to remove all or part of the

prostate.

• Radio-therapeutic approaches.

• Chemotherapeutic approaches.

• Hormone ablation therapy.

 Surgery

• Radical prostatectomy –
retropubic or perineal to
remove entire prostate gland
and seminal vesicles.

• Often associated with erectile

dysfunction.

• Problems with incontinence.

 Surgery

• TURP: Transurethral resection of the prostate

– Resection of the enlarged prostate tissue juxtaposed to the urethra
causing obstruction.
– Surgical resection.
– Laser ablation
 Other Surgical Methods

• HIFU: High Intensity focused ultrasound.

– Heats up tissue and destroy prostate cancer cells.

• Cryotherapy: Perineal insertion of a probe to freeze the

cancer cells within the prostate.
• Orchidectomy
– Testicular removal for hormone ablation
 Radiotherapy for Prostate cancer

• PSA >20 and stage 1 and 2 disease

• Two basic methods of radiotherapy for prostate cancer
– External beam radiotherapy – teletherapy
– Internal radiotherapy – brachytherapy.

• Teletherapy: NICE guidelines dictate 74Gy in 2Gy fractions

– IMRT
– IGRT
– 2DXRT
– Proton beam
 Radiotherapy – Prostate Cancer

• Brachytherapy
– Seeding of radioactive material in the prostate
• Low dose rate: 7 days (0.5 -2 Gy/hr)
• High dose rate: A few minutes (12Gy/hr)

• Cesium137
• Cobalt60
• Iridium192
• Iodine125
• Palladium103
• Ruthenium106
 Chemotherapy for late stage prostate Cancer

• Docetaxel q3w + Prednisone

Docetaxel (Taxotere) 75 mg/m2 iv over 1 h q3w x 10 cycles
Prednisone 5 mg po bid
– Berthold DR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in
the TAX 327 study. J Clin Oncol 2008; 26:242

• Docetaxel + Estramustine→Goserelin + Bicalutamide

Docetaxel (Taxotere) 70 mg/m2 iv over 1 h d2
Estramustine 280 mg po tid d1-5
Warfarin 1 mg po qd for prophylaxis of thrombosis
Q3w x 4 cycles
Followed by hormonal therapy starting on week 13:
Goserelin (Zoladex) 10.8 mg sc q3m x 15 months
Bicalutamide (Casodex) 50 mg po qd x 15 months
– Taplin ME et al. Decetaxel, estramustine, and 15-month androgen deprivation for men with prostate-specific antigen
progression after definitive local therapy for prostate cancer. J Clin Oncol 2006; 24:5408
Common genetics changes associated with
prostate cancer
 Key Genes
• Down regulation of NKX3 gene; homoebox gene associated with prostate
epithelial cell differentiation. (Epigenetic down-regulation).

• Myc upregulation in many prostate.

• TMPRSS2-ERG fusion gene,

– resulting in expression of N-terminally truncated transcription factor controlled by
androgen responsive promoter TMPRSS2 (50% of prostate cancers).

• PTEN inactivation phosphatase suppressing AKT signalling. Mutated in

many advanced prostate cancers.

• PTEN inactivation can also lead to increased AKT and mTOR signalling.
 Key genes

• The Polycomb group gene EZH2 encodes a histone lysine

methyltransferase frequently up-regulated in advanced prostate
cancer.
– EZH2 expression is negatively regulated by miR-101, and miR-101 expression
decreases during cancer progression, concomitant with somatic loss of one or
both miR-101 alleles.

• P53 mutations do occur in prostate cancer but very rarely in

advanced disease.

• P16 mutation may important in prostate cancer but difficult to

define mechanism.
 Summary

• Incidence – a very common cancer.

• Risk factors.
– Contributing factors
– Protective factors
• Basic methods of diagnosis
• Treatment of prostate cancer
– Many routes and methods of treatment.
• Genetics of prostate cancer
– Rather a poorly defined tumour genetically.