Cancer 12: Breast Cancer Flashcards
(41 cards)
1
Q
Breast cancer statistics
A
- leading female cancer accounting for 1/5th of all cancer deaths
- 1 in 8 women in the UK and US develops breast cancer
- around around 55,000 women develop breast cancer every year in the UK.
- The breast cancer incidence is rising but the rate has slowed down
- breast cancer mortality is falling (early diagnosis, chemo, radio, immunotherapy.
- makes up 7% of cancer deaths in women which is 2nd to lung cancer.
- diagnosis every 10 minutes
2
Q
What is the most frequent breast cancer?
A
- Invasive ductal carcinoma (80% of all BC)
- 80% of this is ER+
3
Q
Why is the mammary gland an unusual gland?
A
- because there are 2 layers of epithelial cells in the gland
- usually/ in other tissues there is one layer
- myoepithelial cells are responsible for squeezing
- luminal epithelial cells are on the inside regarding myopithelial cells
4
Q
Why is 5 years without cancer seen as cured?
A
- because if after 5 years someone comes back with cancer it is as likely to be a new one as a recurrence of the old one.
5
Q
Progression of normal to malignant breast
A
- normal
- benign carcinoma in situ
- this develops to
a) medullary carcinoma (involves infiltration by lymphocytes)
b) ductal carcinoma
c) lobular carcinoma
(in situ -> invasive)
6
Q
How can you know if a cancer is ER+?
A
- immunohistochemical staining using antibodies against the human ER
- allows you to evaluate how many cells in the tumour make ER
- important in the decision of how to treat the Patient
7
Q
What fraction of breast cancers are ER+?
A
80%
8
Q
How did we find the link between oestrogen and BC/
A
1889: ovariectomy as a treatment for breast cancer (because of breast atrophy following cessation of ovarian function)
1896: ovariectomy in pre-menopausal women resulted in disease regression and improved prognosis
9
Q
What are some important risk factors for breast cancer that are essentially longer exposure to oestrogen
A
- age of menarche
- age of menopause
- age of first full term pregnancy
- some HRTherapies
- some contraceptive pills
10
Q
What does the oestrogen receptor mediate and how?
A
- The estrogen Receptor is Activated upon binding estrogen,
- Gene Expression is Induced by Binding to Specific DNA Sequences called estrogen Response Elements,
- The estrogen-Induced Gene Products Increase Cell Proliferation, Resulting in Breast Cancer.
11
Q
What are some important genes that are regulated by the ER?
A
Regulated Genes; Progesterone Receptor (PR) Cyclin D1 c-myc TGF-a
12
Q
ER in BC
A
- Some breast cancers like normal breast, are sensitive to the effects of estrogen.
- Approximately one-third of premenopausal women with advanced breast cancer will respond to oophorectomy
Paradoxically, breast cancer in postmenopausal women responds to high-dose therapy with synthetic estrogens ie causes breast tumour regression - ER is over expressed in around 70% of breast cancers. Presence is indicative of a better prognosis.
- In ER-positive case, estrogen regulates the expression of genes involved in cellular proliferation leading to breast cancer.
- cancers, 5-10% of ER-negative cancers also respond. Estrogen withdrawal or competition for binding to the ER using anti-estrogens results in a response in about 70% of ER-positive
13
Q
Does ER presence make the prognosis better or worse?
A
better in females
worse prognosis in males
In ER-positive case, estrogen regulates the expression of genes involved in cellular proliferation leading to breast cancer.
14
Q
What are the main treatment approaches in breast cancer?
A
- surgery
- chemotherapy
- radiation therapy
- endocrine therapy
15
Q
Surgery in Breast cancer
A
- Primary therapy for breast cancer usually includes surgery—a mastectomy (removal of the breast) or a lumpectomy (surgery to remove the tumor and a small amount of normal tissue around it; a type of breast-conserving surgery).
- During either type of surgery, one or more nearby lymph nodes are also removed to see if cancer cells have spread to the lymphatic system.
- When a woman has breast-conserving surgery, primary therapy almost always includes radiation therapy (randomized prospective trials that have investigated radiation use provide conclusive evidence that radiation reduces ipsilateral breast cancer recurrences)
- sometimes you use methods to shrink the tumour before surgery
16
Q
Adjuvant therapy in breast cancer
A
= any treatment given after primary therapy to increase the chance of long-term disease-free survival.
- Even in early-stage breast cancer, cells may break away from the primary tumor and spread to other parts of the body (metastasize) -> doctors give adjuvant therapy to kill any cancer cells that may have spread, even if they cannot be detected by imaging or laboratory tests.
- Studies have shown that adjuvant therapy for breast cancer may increase the chance of long-term survival by preventing a recurrence.
17
Q
How does endocrine therapy work in breast cancer?
A
- ovarian suppression
- blocking oestrogen production by enzymatic inhibition
- inhibiting oestrogen responses
18
Q
Endogenous sources of oestrogne
A
- In premenopausal women the hypothalamus-pituitary-ovaian axis controls the secretion of oestrogen from the ovaries
- levels vary throughout the cycle
- large quantities (mg) on a daily basis
- the ovary is the major source of oestrogen biosynthesis in premenopausal women
In both pre- and postmenopausal women there is some androgen secretion from the adrenals which is the peripherally converted to oestrogen by aromatase in particular in fatty tissue
- the breast is a fatty tissue
19
Q
Ovarian ablation and suppression
A
- only useful in pre-menopausal women
- ovaries are the primary source of oestrogen biosynthesis in premenopausal women.
- Ovarian Ablation aims to eliminate this source. This can be carried out by:
- ovarian irradiation
- surgical removal of ovaries (oophorectomy)
- majro problem: IRREVERSIBLE (e.g. women of child bearing age would not want this)
Reversible and reliable medical ovarian ablation:
LHRH agonists
20
Q
How do LHRH agonists work in breast cancers?
A
- LHRH agonists bind to LHRH receptors in the pituitary leading to receptor down-regulation and suppression of LH release and inhibition of ovarian function, including estrogen production.
- you can skip this treatment during pregnancy
21
Q
Give examples of LHRH agonists
A
“Goserelin”
“Buserelin”
“Leuprolide”
“Triptorelin”
22
Q
Name some endocrine targets for breast cancer treatment
A
- LHRH agonists
- aromatase inhibitors
- antioestrogens
23
Q
anti-oestrogens
A
- inhibit oestrogen function
- e.g. tamoxifen
24
Q
Tamoxifen
A
- competitive inhibitor of estradiol binding to the ER
- well tolerated, very potent
- Antiestrogens negate the stimulatory effects of estrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle.
- endocrine treatment of choice for metastatic disease in postmenopausal patients (approx. 1/3 patients respond)
- few side effects (e.g. hot flushes 29%)
25
Fulvestrant
ICI 182 780
=> very similar structure to oestrogen but has a carbon chain added
26
SERM
selective estrogen receptor modulators
- e.g tamoxifen
- > oestrogenic in bone and in the cv system (re atherosclerosis)
- > antioestrogenic in breast
However, undesirably,
(Anecdotal reports) associating the administration of tamoxifen for advanced breast cancer with subsequent thromboembolic episodes.
Tamoxifen is known to produce endometrial thickening, hyperplasia, and fibroids following several years of therapy
27
What are some undesirable effects of tamoxifen?
- few side effects (e.g. hot flushes 29%) -> Increases vasomotor symptoms via hypothalamus
- increases cataracts
- (Anecdotal reports) associating the administration of tamoxifen for advanced breast cancer with subsequent thromboembolic episodes.
- Tamoxifen is known to produce endometrial thickening, hyperplasia, and fibroids following several years of therapy -> Promotes endometrial cancer, fibroids, polyps & vaginal discharge
28
What are the frequently used anti-oestrogens?
- tamoxifen
- Toremifene (Farnesdon), is a structural derivative of tamoxifen with similar antiestrogenic and estrogenic properties.
- ICI 182,780 (Faslodex or Fulvestrant) exhibits no estrogen-like effects in laboratory tests, but it is effective in controlling estrogen-stimulated growth. Faslodex is a “pure antiestrogen” and may offer clinical advantages over tamoxifen by decreasing tumor cell invasion and the stimulation of occult endometrial carcinoma. Overall, this class of drugs could have a role as a first-line therapy for advanced breast cancer and as a second-line therapy in patients in whom primary tamoxifen treatment fails. Licensed in the UK for advanced breast cancer in 2004.
- Raloxifene (Evista) is an antitumor agent in animals. Raloxifene is agonistic in bone, with no activity in breast and uterus. Raloxifene is used in the treatment of osteoporosis in post menopausal women.
29
Anti-estrogens and Breast Cancer Prevention
- Tamoxifen reduces the incidence of contralateral breast cancer by a third
-> led to trials for BC prevention:
high risk (previous benign pathology, previous FH)
Results:
- 38% reduction in overall breast cancer incidence
- No effect on ER negative Breast Cancer incidence
- No association between prevention and patient age
30
What are the problems with using tamoxifen as a method of BC prevention?
Increase incidence of endometrial cancer
Stroke
Deep Vein Thrombosis
Cataracts
To overcome these problems, prevention trials are being conducted with:
Raloxifene / Faslodex (SERM)
Aromatase Inhibitors
STAR trail showed raloxifene reduced incidence of BC, but was not as effective as tamoxifen. However, there were fewer cases of endometrial cancer, uterine hyperplasia, thromboemoblic events and cataracts in the raloxifene arm, indicating lower estrogenic activity of raloxifene compared with tamoxifen.
31
Aromatase inhibitors in BC
- In postmenopausal women, the major source of estrogen is from the conversion adrenal hormones Androstenedione (A) and, to a lesser extent, Testosterone, to Estroen (E2).
- This enzymatic conversion occurs at extra-adrenal or peripheral sites such as fat, liver, and muscle.
- This conversion is catalyzed by the aromatase enzyme complex.
32
What are the 2 types of aromatase inhibtitors in BC?
Type 1 = irreversible = suicide inhibitors
| Type 2 = reversible = competitive inhibitors
33
Aromatase structure
- Aromatase consists of a complex containing a cytochrome P450 heme containing protein as well as the flavoprotein NADPH cytochrome P450 reductase.
- Aromatase catalyzes three separate steroid hydroxylations involved in the conversion of androstenedione to estrone.
- Aromatase can metabolise androsteindione, which is produced by the adrenal glands. This leads to the production of Estrone Sulphate, which is circulated in the plasma
34
How do irreversible aromatase inhibitors work?
= the enzyme is then broken and unable to work
- Initially compete with the natural substrate (i.e., androstenedione and testosterone) for binding to the active site of the enzyme.
- 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.
- An example of this type of drug is “Exemestane”.
- Single-dose administration reveals a major reduction of plasma estrogens with this compound.
- SE associated with exemestane treatment were mild and included hot flushes, nausea, and fatigue
35
How do reversiblem aromatase inhibitors work?
= competes for active site
- Bind reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
- An example of this type of drug is “Anastrozole” ( “arimidex”: ICI-D1033). Cause suppression of plasma estrogen to levels approaching the limits of assay sensitivity.
- Anastrozole was the first aromatase inhibitor to be approved in the United States for the management of advanced breast carcinoma in postmenopausal women.
36
Progestins in breast cancer
- PR is an oestrogen regulated gene
- there are no good antiprogestins at the moment but we use drugs that mimic progesterone
- > overstimulation
- > cell self-destruction
- > don't respond top progesterone anymore
These drugs cause lots of discomfort and are difficult to administer (hospital, drip, etc)
37
What is the principal progestin in the body?
Progesterone is the dominant naturally occurring progestin
38
What is a big issue with endocrine therapy?
- 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 estrogen responses and contain estrogen receptor
- in treatment over 60% of breast cancers respond to endocrine therapy including tamoxifen and inhibitors of oestrogen synthesis e.g. exomestane
- Initial response but eventual relapse
Relapse due to resistance during prolonged endocrine therapy
- Although 15% of patients who develop resistance to tamoxifen lose ERa expression, the majority of patients remain ERa positive and often respond to a switch to aromatase inhibitors or pure antiestrogens, indicative of a continued role for ERa in endocrine resistance
Solution-
- Continue use endocrine therapies as these are successful
- But, require additional therapeutic agents/ strategies for endocrine resistant, metastatic disease
39
Risk factors of BC
=> exposure to oestrogens
```
Early age of onset of menarche
Late age to menopause
Age at first full-term pregnancy
Some forms of the contraceptive pill
Hormone Replacement Therapy
Obesity
Diet, physical activity, height, medication (Aspirin)
```
40
BC screening
- The breast screening programme uses mammography to screen all women between 50 and 64 who are registered with a GP in the UK ( age is being extended to age 70)
- Each patient is asked to attend for a test once every 3 years.
- More than 70% of women attend breast screening appointments.
- This means that more than one million, two hundred thousand women are screened for breast cancer each year in the UK.
- Only 6 out of every 100 are asked to go back for more tests
However, 90% of breast cancers are detected by self examination
41
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