Specialist Cancers

Question 1

Breast Cancer: summarise the epidemiology of breast cancer

Answer 1

Breast Overview

• Breast cancer is the leading female cancer (1 in 5 deaths).
• Whilst 1 in 8 develop it, 1 in 5 die from it.
• Breast cancer incidence is increasing (mortality is falling).
• Due to – early diagnosis, chemo, hormonal therapies.
• The breast is the only organ to develop after birth and every part of the gland (all cells) can have a type of cancer.
• Most breast cancer originates in the luminal epithelium

Question 2

Breast Cancer: recall the pathological and clinical features of breast cancer

Answer 2

Cell organisation of a mammary gland

• Between the tubules you have fatty stromal cells

There are TWO layers of epithelial cells:

1. Luminal epithelial cells
2. Myoepithelial cells (surrounding the luminal cells)

• Myoepithelial cells have a contractile phenotype and they will contract when they receive the correct hormonal signals
• Myoepithelial cells are very important in the development of the gland -­‐ they are responsible for the formation of tubules (the luminal cells lie passively underneath)
• Oestrogen receptors are ONLY expressed by luminal epithelial cells but not all luminal epithelial cells express oestrogen receptors (only about 10-­‐15%)
• In a normal gland, the response to oestrogen is to stimulate growth
• The cells that are oestrogen receptor positive do NOT grow in response to oestrogen -­‐ they act as beacons to produce growth factors that stimulate the growth of nearby cells
• In breast cancer we see the REVERSAL of this effect -­‐ the oestrogen responsive cells directly respond to oestrogen as a growth factor and stimulates their own growth

Progression of Normal to Malignant Breast

• Benign/carcinoma in situ -­‐ there is proliferation of the luminal cells but the myoepithelium is still around it -­‐ this is a possible precancerous state
• Lobular carcinoma -­‐ the tumour has some resemblance of the architecture of the gland -­‐ there are tubules of some form
• Medullary carcinoma -­‐ the tumour cells don’t look anything like the epithelial cells from the mammary gland
• The majority of breast cancers aren’t medullary or lobular so they are just called breast carcinoma (80% of breast cancer)

Major histological types of invasive breast cancer:

• IDC – infiltrating ductal carcinoma – feature no special histological features – 80% of breast cancers.
• OR positive (stains for immunohistochemically staining).

Staining:

• Immunohistochemically staining using ABs against the human OR (oestrogen receptor) is informative.
• This stain marks the nucleus as OR is a steroid receptor.
• >80% of breast cancers are OR+.

Risk factors for breast cancer involve lifetime exposure to oestrogens:

• Early menstruation.
• Late menopause.
• HRT.
• Contraceptive pills.
• Pregnancy.

Question 3

Breast Cancer: explain the pathophysiology of breast cancer

Answer 3

Oestrogen Receptor

• ER is a cytosolic receptor -­‐ inside the cell
• Inside the cell, the ER is bound to a heatshock protein forming a dimer
• Oestrogen is very lipophilic and can pass easily through the cell membrane
• Once inside the cell, the oestrogen binds to the ER (and displaces the heatshock protein)
• Two oestrogen receptors then come together to form a dimer, and this dimerised protein is then able to enter the nucleus (with oestrogen bound) and locate DNA sequences in the genome that are response elements for this transcription factor
• Significance of dimerisation of the ER -­‐ the response elements are present in two halves so each half of the dimer will bind to each half of the response element (shown in diagram above)

Most important target genes of this transcription factor:

• Progesterone receptor
• Cyclin D1
• C-­‐myc
• TGF-­‐alpha

Oestrogen Receptor in Breast Cancer

• Some breast cancers, like the normal breast, are sensitive to the effects of oestrogen
• About 1/3 of PREmenopausal women with advanced breast cancer will respond to oophorectomy (ovary removal surgery)
• Paradoxically, breast cancer in post-­‐menopausal women responds to HIGH-­‐ dose therapy with synthetic oestrogens -­‐ it causes breast tumour regression
• Explanation: if you overstimulate this hormone system it will result in the downregulation of ER so the cells are no longer responsive to oestrogen
• ER is overexpressed in around 70% of breast cancers
• Presence of ER is indicative of a BETTER PROGNOSIS
• Oestrogen withdrawal or competition for binding to the ER using anti-­‐ oestrogens results in a response in about 70% of ER+ cancers and 5-­‐10% of ER-­‐ cancers also respond
• An increased level of expression of ER indicates a good prognosis in FEMALE breast cancer but a WORSE PROGNOSIS in male breast cancer (very rare)

Question 4

Breast Cancer: summarise the basis and role for endocrine therapies in treating breast cancer.

Answer 4

The major treatment options are:

1. Surgery.
2. Radiation therapy.
3. Chemotherapy.
4. Endocrine therapy – the gold-standard or cornerstone treatment:
   
   • Ovarian suppression.
   • Blocking oestrogen production by enzymatic inhibition.
   • Inhibition of oestrogen responses.

Ovarian Ablation (Surgical) and Suppression (Endocrine):

• The ovary is the major source of oestrogens and so ablation aims to eliminate this source. This is done via:
  
  • Surgical oophorectomy.
  • Ovarian irradiation.
• The major problems with this is morbidity and irreversibility so there are more medical suppression techniques.

To overcomes these issues, treatments to produce medical ovarian ablation have been developed

• Reversible and reliable medial ovarian ablation can be achieved using luteinising hormone releasing hormone (LHRH) agonists
• LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release and inhibition of ovarian function, including oestrogen production
• Examples of LHRH agonists: Goserelin, Buserelin, Leuprolide, Triptorelin

Question 5

Breast Cancer: Targets for Breast Cancer Treatment

Answer 5

Treatments – Hormonal Targets:

1. LHRH agonists.
2. Aromatase inhibitors – prevent conversion.
3. Antioestrogens.

Oestrogens & Anti-Oestrogens: Tamoxifen

• Tamoxifen – OR-blocker or a SERM – competitive inhibitor.
  
  • This negates the effects of oestrogens so the cell is arrested at the G1 phase.
  • Oestrogenic in bone and the CVS (decrease risk of osteoporosis and atherosclerosis risk).
• Tamoxifen is the drug of choice for metastatic cancer in post-menopausal patients.
• Few side effects – bar hot flushes.
• Evidence of increased risk of thromboembolic events and can cause endometrial hyperplasia (cancer possibility).
• Toremifene = analogue of tamoxifen.
• Faslodex = no oestrogen-like activity but effective at controlling oestrogen-stimulated growth.
  
  • Pure anti-oestrogen.
  • Decreases tumour cell invasion and the stimulation of occult endometrial carcinoma.
• Raloxifene = anti-tumour agent in animals.
  
  • Oestrogenic in bone.
  • No activity in breast or uterus.
  • Treats osteoporosis.

Question 6

Tamoxifen

Answer 6

• Tamoxifen reduces the incidence of contralateral breast cancer by a third.
• Tamoxifen trials have shown:
  
  • 38% reduction in overall breast cancer incidence.
  • No effect on OR- breast cancer incidence.
  • No association between prevention and patient age.

Problems with using Tamoxifen as a PROPHYLACTIC drug:

• Endometrial cancer.
• Stroke.
• DVT.
• Cataracts.

Due to these problems, prevention trials are being conducted with – Raloxifene/Faslodex (SERMs) and aromatase inhibitors.

Question 7

Aromatase Inhibitors

Answer 7

• In postmenopausal women, the main source of oestrogen is from the CONVERSION of the adrenal hormones androstenedione and testosterone (to a lesser extent) to oestrone (O2/E2), rather than from the ovaries directly.
  
  • This conversion occurs at the extra-adrenal or peripheral sites – liver, fat and muscle.
  • Catalysed by the aromatase enzyme complex.
• Aromatase:
  
  • Aromatase is a complex with:
    
    • Cytochrome P450 haem containing protein.
    • Flavoprotein NADPH CYP450 reductase.
  • Aromatase catalyses 3 steroid hydroxylations involved in conversion of androstenedione to oestrone.
  • Aromatase can also metabolise androstenedione to produce oestrone sulphate (circulates in plasma).
• Aromatase inhibitors:
  
  • Suicide inhibitors: Exemestane
    
    • Competitive with androstenedione and testosterone for binding to aromatase.
    • Enzyme acts on the inhibitor to create reactive alkylating species which covalently bond the active site of the enzyme à irreversibly inactivated.
  • Competitive inhibitors: Anastrozole
    
    • Binds reversibly to aromatase.

Question 8

Progestins

Answer 8

• Main progestin is progesterone.
• Due to the poor absorption of synthetic progesterone, synthetic derivatives have been made.
• The actions of progestins are complex (don’t need to know much).
• Uses:
  
  • Endocrine treatment of uterine and breast cancers with proven antineoplastic properties.
  • Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megestrol acetate).

Inhibiting Oestrogen Action

• Many patients with breast cancer and all patients with metastatic disease will become resistant to endocrine therapies.
  
  • However, most cases continue to demonstrate oestrogen responses and contain ORs (which we can inhibit).
• As the patients become resistant to endocrine therapy (anti-oestrogens (tamoxifen) and inhibitors of oestrogen synthesis (Exemestane)), the solution is to CONTINUE this therapy and add:
  
  • Additional inhibitors of oestrogen action.