Breast Cancer Flashcards
How many women develop breast cancer, how many die, what is the structure of the breast?
- This is the only organ that develops after birth
- There is a tubular network within the breast that comes together at the nipple
- Every part of the gland, anatomically and cellularly, can have some type of cancer
- E.g. phyllodes tumour - this is in the fatty stromal area - it is a very rare and very aggressive type of tumour
- Lobular breast cancer is the most common type and it is a carcinoma
- The majority of breast cancer (>90%) originates in the luminal epithelium
- Breast cancer incidence is decreasing but mortality is falling (early prognosis, chemo, hormonal therapies)
- 1 in 8 develop, 1 in 5 die
What is the Cellular Organisation of the Mammary Gland, which cells have the OE receptor and what happens in cancer?
- Between the tubules you have fatty stromal cells
- There are TWO layers of epithelial cells:
- Luminal epithelial cells
- Myoepithelial cells (surrounding the luminal cells) this is the second layer, they support the structures of the tubule
- Myoepithelial cells have a contractile phenotype and they will contract when they receive the correct hormonal signals, and the luminal cells release the milk in the luminary space
- 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%)
- NORMAL response to oestrogen – stimulates growth via production of growth factors by the luminal cells expressing receptors (not the cells themselves).
- Breast cancer response – REVERSAL – oestrogen-responsive cells directly respond to oestrogen as a GF and stimulate their own growth.
Describe the Progression of Normal to Malignant Breast, what are the different types of carcinoma that can arise?
- Benign/carcinoma in situ - there is proliferation of the luminal cells but the myoepithelium is still around it - this is a possible precancerous state
- The laminar space has increased, and it holds the benign cells
- 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% or more of all breast cancer fall in this category
Main Histological Types of Invasive Breast Cancer
- Staining the tissue samples for oestrogen receptor (ER) is a good way of classifying breast tumours as:
- ER positive
- ER negative
- It is the nuclei that are being stained in this test because ER is a transcription factor that is found in the nucleus
- Over 80% (of the 85%) of breast cancers are ER positive
What are the main risk factors for breast cancer?
- NOTE: breast cancer growth is oestrogen-regulated
- Important risk factors include life time exposure to oestrogens:
- Early age of onset of menstruation
- Late age to menopause
- Age to first full-term pregnancy
- Some contraceptive pills
- Some HRTs
Describe the structure, position of the Oestrogen Receptor and state the cascade of reactions, which genes are mostly affected?
- 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 dimerization 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
Which are the major treatment options for breast cancer?
How does endocrine therapy work?
What is the different treatment for post and pre menopausal women?
- Oestrogen can also affect some breast cancers like it affects the normal breast.
- Thus, approx. 1/3rd of premenopausal women will respond to an oophorectomy.
- Paradoxically, breast cancer in post-menopausal women respond to high-dose oestrogen therapy – due to downregulation of ORs as there is a high concentration of oestrogen.
- OR is over-expressed in around 70% of breast cancers – presence is indicative of a better prognosis.
- OR+ cases can have oestrogen withdrawn or antagonised with anti-oestrogens to result in ~70% response in OR+ cancers and 10-15% in OR- cancers.
- OR expression in females = GOOD PROGNOSIS.
- OR expression in males = BAD PROGNOSIS.
What are the major treatment options for breast cancer?
- Surgery
- Radiation
- Chemotherapy
- Endocrine Therapy
Endocrine therapy is the cornerstone of breast cancer treatment - it can be achieved at the following levels:
- Ovarian suppression
- Blocking oestrogen production by enzymatic inhibition
- Inhibiting oestrogen responses
- Ovaries are the main site of production of oestrogen in pre-menopausal women
- Levels of oestrogen production depend on the stage of the menstrual cycle - it is highest at the end of the follicular stage
- Post-menopausal women make oestrogen through aromatisation of androgens in peripheral tissues
How can ovarian Ablation be achieved?
Ovarian Ablation and Suppression
Ovarian ablation aims to eliminate this source of oestrogen and this can be carried out by:
- Surgical oophorectomy
- Ovarian irradiation
- Major problems:
- Morbidity
- Irreversibility
- 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
- Triptorelin
- Leuprolide
Which are the main targets for Breast Cancer Treatment?
- We can inhibit aromatase thus preventing the conversion of androgens to oestrogens (fatty tissue)
- LHRH agonists
- Antioestrogens
Give an example of an Oestrogens and Anti-Oestrogens drug state its actions and side-effects, how does it affect breast cancer?
- Tamoxifen is an ER receptor blocker (competitive inhibitor) (OR blocker or SERM)
- This negates the stimulatory effects of oestrogen causing the cells to be held at the G1 phase of the cell cycle
- Tamoxifen is the endocrine treatment of choice for metastatic disease in post-menopausal patients (about 1/3 of patients respond)
- Few side effects - hot flushes is the most commonly reported
- Tamoxifen is a SERM (selective oestrogen receptor modulator)
- Tamoxifen is oestrogenic in bone so it can protect post menopausal women against osteoporosis
- Tamoxifen is oestrogenic on the cardiovascular system so it can decrease atherosclerosis risk in women
- However, there has been some evidence that tamoxifen increases the risk of thromboembolic events and it can cause endometrial hyperplasia (increases risk of endometrial cancer)
How does Tamoxifen affect breast cancer, can it be used as prophylactic therapy?
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.
Summary of Oestrogen Targets and Effects of Tamoxifen
- Toremifene is a structural derivative of tamoxifen with similar effects
-
Faslodex shows no oestrogen like activity in laboratory tests, but it is effective in controlling oestrogen-stimulated growth
- Faslodex is a pure anti-oestrogen
- It may offer advantages over tamoxifen by decreasing tumour cell invasion and the stimulation of occult endometrial carcinoma
-
Raloxifene is an antitumour agent in animals
- It is an agonist in bone but has no activity in the breast or uterus
- It is used in the treatment of osteoporosis in post-menopausal women
When do we use Aromatase Inhibitors in Breast Cancer, what are the different types and what is their action?
- In post-menopausal women, the major source of oestrogen derives not from the ovaries but from the conversion of the adrenal hormones (androstenedione and (to a lesser extent) testosterone) to oestrone
- The enzymatic conversion occurs at extra-adrenal or peripheral sites such as fat, liver and muscle
- The conversion is catalysed by the aromatase enzyme complex
- Aromatase consists of a complex containing
- CYP450 heme containing protein
- flavoprotein NADPH CYP450 reductase
- Aromatase catalyses three separate steroid hydroxylations involved in the conversion of androstenedione to oestrone
- Aromatase metabolises androstenedione to oestrone sulfate, which then circulates in the plasma
Types of aromatase inhibitors:
Suicide Inhibitors- Exemestane
- Initially compete with the natural substrate (androstenedione or testosterone) for binding to the active site
- The enzyme then specifically acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme
- Through this mechanism the enzyme is irreversibly inactivated
- Single dose results in a major drop in plasma oestrogens
- Side effects are mild - e.g. hot flushes, nausea, fatigue
Competitive Inhibitors- Anastrozole
Binds reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
What is the use of Progestins in Breast Cancer?
- Progesterone is the dominant naturally occurring progestin
- The poor absorption of progesterone has been overcome by some of the synthetic derivatives progestins
- Progestins response in the breast is complex and influences both proliferation and differentiation function
- Progestins are used in the endocrine treatment of uterine and breast cancer with clinically proven anti-neoplastic properties
- Progestin therapy for metastatic breast cancer has been used principally as a second or third-line therapy following selective oestrogen
- The main progestin used for metastatic breast cancer has been megestrol acetate
What happens when patients are resistant to endocrine therapies?
- A significant proportion of patients presenting with breast cancer and, ALL patients with metastatic disease become resistant to endocrine therapies
- However, most cases continue to demonstrate oestrogen responses and contain oestrogen receptor
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.
Describe Screening for Breast Cancer
