Cancer as a disease: Breast Cancer Flashcards
Describe a typical presentation of breast cancer
72 year old female (mostly post-menopausal women)
Presenting Complaint: lump right breast (self-detected)
Past Medical History: Hypertension, nil else
Family history: nil significant
Social history: independent of all daily activities, never smoked, minimal alcohol intake
Presents to GP - examined and referred to Breast surgeons (under 2 week wait target)
Summarise the key investigations in the breast clinic
Breast Clinic:
Consultation and clinical examination
Mammography
Core needle biopsy
Diagnosis: 2cm Grade 1 ER+, PR+, HER2- Invasive Ductal Carcinoma
No clinical evidence of lymph node involvement or metastases
Stage T1N0M0
Summarise the role of the MDT in this case
Discussed at Multidisciplinary Team meeting – investigations reviewed and treatment options confirmed
Sentinel lymph node biopsy - negative
Surgery (Wide local excision)
Adjuvant endocrine therapy (Letrozole)
Annual surveillance mammograms for at least 5 years - important curative window- as recurrence > 5 years is likely to be a different cancer/tumour
Describe the epidmeiology of breast cancer in 1997
Breast cancer is the leading female cancer, accounting for almost 1 in 5 cancer deaths among women.
1 in 9 women in the UK and the USA will develop the disease in their lifetime
Describe the epidemiology of breast cancer today
Breast cancer is the leading female cancer, accounting for almost 1 in 5 cancer deaths among women.
1 in 8 women in the UK and the USA will develop the disease in their lifetime.
Currently, around 55,000 women develop breast cancer every year in the UK.
Breast cancer incidence is rising.
1979: 75 cases per 100,000
2000: 114 cases per 100,000
2008: 127 cases per 100,000
2014: 167 cases per 100,000
Compare the incidence rates of breast cancer across the world
Since the early 1990s, breast cancer incidence rates have increased by around a fifth (19%) in the UK. In the UK- 150 new cases of BC diagnosed a day. Scotland is the only nation in the UK where breast cancer is not the most common cancer overall; here, lung cancer is more common. Worldwide, it is estimated that more than 1.68 million women were diagnosed with breast cancer in 2012, with incidence rates varying across the world. In general, developed countries have higher rates than developing countries eg Central Africa five fold less than Western Europe.
What is happening to the moralist of breast cancers and why
Breast cancer mortality is falling.
1989: 42 women per 100, 000 died
2014: 35 women per 100, 000 died
A 17% fall in deaths (1989-2014).
Reason: Early Diagnosis, Chemo/Radiotherapies (more targeted)
Hormonal Therapies.
What percentage of deaths does breast cancer account for
Since peaking in the mid-1980s, female breast cancer death rates have fallen by 40% in the UK.In 2014 in the UK around 11,400 women died from breast cancer, that’s around 31 every day. In the UK breast cancer is the second most common cause of death from cancer in women after lung cancer and accounts for 7% of all cancer deaths.
Summarise the growth and development of the breast throughout life
In humans the mammary gland undergoes dramatic changes in size, shape and function through infantile growth, puberty, pregnancy, lactation, weaning and postmenopausal regression. The main spurt of growth occurs at puberty and is dependent on high levels of estrogen, as well as progesterone produced by the ovary. Post-pubertal development results in cyclical increases in ductal branching, resulting in extensive branching in the fat pad. Estrogen does not seem to be necessary for the prenatal development of the mammary gland, but is required for prepubertal and pubertal gland development. Pregnancy is characterised by large increases in side branching and development of secretory acini from the terminal ductal alveoli. Following weaning the mammary gland regresses to a near pre-pregnancy state through a process involving extensive apoptosis .
What is important to remember about development of the breast
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- carcinoma- tubular epithelial cells
Summarise the anatomy of the breast
Lobules (where lactogenesis takes place) joined by ducts and join to form lactiferous sinus behind the areola, where all the milk collects to be ejected in breast feeding.
Describe Phyllodes tumours of the breast
Sarcomas
Grow in the connective tissue of the breast, not the ducts
Describe the cellular organisation of the mamillary gland
A layer of myoepithelial cells, some of which are slightly vacuolated, is seen just around
the luminal cells, making contact with the basement membrane.
These have a contracitle property- propel the milk in the ducts to the lactiferous sinu squeezes milk into luminal space upon contraction.
Between the tubules are fatty stromal cells.
Summarise the pathogenesis of breast cancer
Breast cancers: carcinomas - tumours of epithelial cells
Pathogenesis of breast tumours: luminal epithelial cells become cancerous and proliferate within the basement membrane (carcinoma in situ), before breaking through basement membrane to spread
What is the difference between lobular and medullary carcinoma
Lobular – the tumour has some resemblance of the architecture of the gland (there are tubules of some form)- just without the BM and myoepithelium
Medullary – the tumour cells don’t look anything like the epithelial cells from the mammary gland - full of secretory vesicles- surrounded by lymphocytes- associated with a worse prognosis.
Could just get a carcinoma that isn’t medullar or lobular
What is the most common form of breast cancer
The general picture that emerges for the most common BC types, invasive ductal carcinoma (up to 80% of all BC) and invasive lobular carcinoma (5-15%) is that these cancers all originate in the terminal duct lobular unit and progress from an initial hyperproliferative stage, to a pre-cancerous, in situ carcinoma stage and then to invasive BC.
Describe the major histological types of breast cancer
Infiltrating ductal carcinoma (IDC), many of which feature no special type of histological structure, account for almost 80% of breast cancers
Immunohistochemical staining using antibodies against the Human Estrogen Receptor (ER) is informative.
About 80% of breast cancers are estrogen-receptor positive.
What is the key difference between lobular carcinomas and medullary carcinomas
Medullary carcinomas: full of vesicles - do not resemble epithelial cells
Lobular carcinomas: preserve the lumen
Describe the different cut off points for ER-receptor positive breast cancers in different labs
Different pathology labs have different cutoff points for calling the cancer either ER-positive or ER-negative. For example, if less than 10% of the cells stain positive (fewer than 1 in 10), one lab might call this a negative result. Another lab might consider this positive, even though it is a low test result. Research studies have shown that any positive result, no matter how low, suggests that hormonal therapy couldhelp treat the cancer. A score of “0” is needed to completely rule out hormonal therapy as a treatmentoption.
Summarise the discovery of the role of oestrogen and its role in breast cancer growth
1889: Albert Schinzinger noted that atrophy of the breast follows cessation of ovarian function and proposed ovariectomy as a treatment for breast cancer
1896: George Beatson demonstrated that ovariectomy in pre-menopausal women resulted in disease regression and improved prognosis.
In 1923 Allen and Doisy identified the ovarian hormone “estrogen”. This was subsequently shown to stimulate breast cancer development and growth.
Further studies have elucidated the mechanisms by which estrogen action is mediated
Describe some risk factors for the development of breast cancer
Important risk factors include lifetime of exposure to estrogens: age of onset of menarche, age to first full-term pregnancy, some contraceptive pills, some hormone-replacement therapies
Describe the discovery of the oestrogen receptor
Although estrogen was identified in the 1920s, estrogen receptors were not identified until the 1960s, with the demonstration that subcutaneous administration of radiolabelled estrogen in rats resulted in label retention in known estrogen target tissues (vagina, uterus), but absence from tissues not associated with estrogen action (e.g. muscle, kidney), and the subsequent purification of an estrogen binding protein from the rat uterus.
Summarise the oestrogen receptor
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.
Describe the key features of the oestrogen receptor
HSP90: heat shock protein 90 bound to nuclear receptor, and on oestrogen binding, HSP90 released to allow dimerisation of receptors
HSP90 is a chaperone- disscoaitates from nuclear oestrogen receptor once oestrogen binds- allowing the oestrogen receptors to dimerise and translocate to the nucleus to up-regulate gene expression,
Describe the genes regulated by oestrogen
Dimerised nuclear oestrogen receptor binds to palindromic response element
This increases the expression of nearby genes by up-regulating their promoter regions (TATA)
Some Important estrogen Regulated Genes;
Progesterone Receptor (PR) -facilitating growth
Cyclin D1- progression of cell cycle
c-myc- resistant to apoptosis- encourages survival signals, growth and proliferation
TGF-a- GROWTH FACTOR FOR NEARBY CELLS
Summarise the role of oestrogen in breast cancer
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 (Sir Alexander Haddow 1944)
Is the presence of oestrogen receipt associated with a better prognosis?
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.
Estrogen withdrawal or competition for binding to the ER using anti-estrogens results in a response in about 70% of ER-positive cancers, 5-10% of ER-negative cancers also respond (due to insensitivity of immunohistochemsitry techniques and lab cut offs)
An increased level of expression of ER indicates a good prognosis in female breast cancer but a worse prognosis in male breast cancer - need to target androgen receptor in men
Describe the role of oestrogen in normal breast tissue
The response to oestrogen is to stimulate growth
The cell that express oestrogen receptors do NOT grow in response to oestrogen
They act as a beacon and produce growth factors the stimulate the growth of nearby cells - via TNF-a
In cancer:
The cells displaying oestrogen receptors directly respond to oestrogen as a growth factor and stimulate their own growth
Where are oestrogen receptors expressed in the breast
They are ONLY expressed by luminal cells
But not all luminal cells express oestrogen receptors (only about 10-15%)
What are the major treatment options for breast cancer
Major treatment approaches
- surgery
- radiation therapy
- chemotherapy
- endocrine therapy
Describe the surgical treatment of breast cancer
Primary therapy is the main treatment used to reduce or eliminate the cancer. 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)
What is the purpose of endocrine therapy in the treatment of breast cancer
Adjuvant alongside surgery- surgery will not get rid of all the cancerous cells- need endocrine therapy to clear this and prevent metastasis/ recurrence.
Can also use endocrine therapy as a Neo-adjuvant- i.e when the tumour is too large or has spread- to reduce the tumour size to a level that can be managed more successfully in surgery.
Summarise the role of endocrine therapy in breast cancer
Endocrine Therapy is the cornerstone of breast cancer treatment. This can be achieved at the following levels;
Inhibits oestrogen action
Gold-standard
Ovarian suppression
Blocking estrogen production by enzymatic inhibition
Inhibiting estrogen responses
When was endocrine therapy for breast cancer first established
By the 1960’s, the standards for the endocrine treatment of breast cancer were established. Premenopausal women were treated with ovarian irradiation therapy or bilateral oophorectomy. However, post-menopausal patients with advanced breast cancer should be treated with high dose of the most potent estrogenic compound diethylstilboestrol Overall 36 % of patients respond favorably to high dose oestrogen therapy
When are oestrogen levels at their highest in the menstrual cycle
Estrogen levels vary through the menstrual cycle, with levels highest near the end of the follicular phase just before ovulation. Daily the ovaries produce milligramme quantities of steroid hormones.
Describe the hormonal control of oestrogen on target tissues
Pre-menopausal:
Hypothalamus releases LHRH (peptide hormone) which acts on the anterior pituitary leading to the release of gonadotrophins (LH and FSH)- also peptide hormones
These act on the ovary - which produces oestrogens and progesterone.
All women:
Pituitary gland releases prolactin and GH which also influence the breast
ACTH released to the adrenal glands
Corticosteroids, progesterone and androgens released
androgens can be peripherally converted to oestrogens by aromatase (particularly in fatty tissues such as the Breast).
Describe ovarian ablation and suppression
The ovary is the major source of estrogen biosynthesis in pre-menopausal women.
Ovarian Ablation aims to eliminate this source. This can be carried out by;
Surgical oophorectomy
Ovarian Irradiation
The major problems associated with these procedures are morbidity and irreversibility (women of child-bearing age won’t be able to have kids)
To overcome these issues treatments to produce medical ovarian ablation have been developed - i.e to make it reversible
Describe the role of LHRH agonists in ovarian ablation and suppression
Reversible and reliable medical ovarian ablation can be achieved using Luteinising Hormone Releasing Hormone (LHRH) agonsists
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.
LHRH agonists include “Goserelin”, “Buserelin”, “Leuprolide” and “Triptorelin”
reversible - can be used for pre-menopausal breast cancer patients
State the hormonal targets for breast cancer treatment
LHRH agonists.
Aromatase inhibitors – prevent conversion.
Antioestrogens.
Describe the principal action of anti-oestrogens
Structurally similar to oestrogen, meaning that they can bind to the nuclear receptors but have no efficacy- they are antagonists and thus reduce the effects of oestrogen on proliferation and growth of the tumour cells.
Summarise anti-oestrogens
As early as 1958 nonsteroidal anti-estrogens were described and their clinical use explored
By the 1960’s the pharmaceutical industry had synthesised a wide range of anti-estrogenic compounds
only Tamoxifen (ICI 46474, Nolvadex) was developed further because of demonstrated efficacy and a low incidence of side effects.
What were the anti-oestrogens originally intended for
Leonard Lerner [1958] reported the first non-steroidal antioestrogen MER25 or ethamoxytriphetol. The compound was antioestrogenic in all species tested and exhibited no oestrogenic properties. When the first clinically useful compound MRL41 or clomiphene was tested in women, it was found not to be a contraceptive, but did the opposite; it induced ovulation. The first clinical study for Tamoxifen took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer. 1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer. It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists’ Collaborative Group showed definitively that tamoxifen saved lives in early breast cancer
Describe tamoxifen
Tamoxifen is a competitive inhibitor of estradiol binding to the ER
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.
Tamoxifen is the endocrine treatment of choice for metastatic disease in postmenopausal patients (approximatley 1/3 patients respond)
Few side effects reported - hot flushes (29%) most commonly reported during Tamoxifen therapy.
Summarise the key features of tamoxifen
Tamoxifen is administered as tamoxifen citrate and undergoes extensive metabolism in the GI tract and the liver, particularly by hydroxylation to generate 4-hydoxytamoxifen (OHT) and endoxifen . Five years of tamoxifen treatment reduces annual recurrence rate by nearly half and BC mortality by a third, compared to control groups, with no difference in recurrence or mortality due to tamoxifen in ERα-negative patients. Tamoxifen is as effective in pre-menopausal as in post-menopausal women.
What class of drug is tamoxifen
Tamoxifen is of a class of drug known as selective estrogen receptor modulators (SERMs)
Explain why tamoxifen is a SERM
Osteoporosis. estrogen is important to maintain bone in premenopausal women. After menopause, hormone replacement therapy is often recommended to prevent the development of osteoporosis. Clearly, the long-term administration of an antiestrogen has the potential to precipitate premature osteoporosis;
Tamoxifen has estrogenic effects in bone
Atherosclerosis. estrogen lowers low-density lipoprotein (LDL) cholesterol levels and raises high-density lipoprotein (HDL) cholesterol levels. Following menopause, women are at the same risk for coronary heart disease as men. It can be argued that the long-term administration of an antiestrogen could produce a population at risk for premature coronary heart disease.
Tamoxifen has estrogenic effects in the cardiovascular system
However, it has anti-oestrogenic effects in breast to reduce the growth and proliferation of the breast cancer
Describe the undesirable effects of tamoxifen
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 therap - thus can cause endometrial cancer
What are the desirable effects of tamoxifen
BREAST
Reduces breast cancer
LIVER & HEART
Lowers cholesterol, reduces atherosclerosis and heart attacks
BONE
Maintains density to help prevent bone loss
What are the desirable effects of oestrogen
BRAIN
Improves cognitive function
BREAST
Programs glands to produce milk
LIVER & HEART
Lowers cholesterol, reduces atherosclerosis and heart attacks
UTERUS
Programs uterus to nourish a foetus
BONE
Maintains density to help prevent bone loss
Describe the negative effects of oestrogen
BREAST
Promotes breast cancer
LIVER
Increases thromboembolism
UTERUS
Promotes endometrial cancer
Describe the negative effects of tamoxifen
HYPOTHALAMUS
Increases vasomotor symptoms
EYE
Increases cataracts
LIVER
Increases thromboembolism
UTERUS
Promotes endometrial cancer, fibroids, polyps & vaginal discharge
What did the success of tamoxifen lead to
The success of Tamoxifen in the treatment of all stages of breast cancer has focused attention on the possibility of developing additional drugs with different pharmacologic properties.
Three compounds, Toremifene, ICI 182780, and Raloxifene merit comment at present.
Describe toremifene
Toremifene (Farnesdon), is a structural derivative of tamoxifen with similar antiestrogenic and estrogenic properties.
Describe ICI 182, 780
ICI 182,780 (Faslodex or Fulvestrant) exhibits no estrogen-like effects in laboratory tests, but it is effective in controlling estrogen-stimulatedgrowth. 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.
Describe raloxifene
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.
Describe how tamoxifen may be given prophylactically to prevent breast cancer
Tamoxifen reduces the incidence of contralateral breast cancer by a third
This has led to clinical trials for Breast Cancer prevention
Trials have focused on “High Risk” patients;
Previous benign breast pathology (5 years)
Previous family history (BRCA 1 and 2)
Tamoxifen vs placebo trials have shown:
38% reduction in overall breast cancer incidence
No effect on ER negative Breast Cancer incidence
No association between prevention and patient age
What has the data regarding tamoxifen demonstrated
Tamoxifen prevents the development of estrogen-dependent tumors in DMBA treated rats and in BC patients it reduces the incidence of contralateral BC by a third. Tamoxifen prevention trials showed a 38% reduction in BC incidence and continued protection 7 years following the end of treatment with substantial reductions in invasive BC rates, as well as rates of non-invasive carcinoma in situ.
What are some of the problems with taking tamoxifen prophylactically include
Problems associated with using Tamoxifen in prevention include:
Increase incidence of endometrial cancer
Stroke
Deep Vein Thrombosis
Cataracts
How can we overcome the problems with taking tamoxifen prophylactically
To overcome these problems, prevention trials are being conducted with:
Raloxifene / Faslodex (SERM)
Aromatase Inhibitors
Describe the studies that showed the problems of taking tamoxifen prophylactically
However tamoxifen prevention suffered from increases in endometrial cancer (29%), thromboembolic events and cataracts. A comparison of 5 years treatment with tamoxifen or raloxifene in the STAR trial for women at high risk of developing BC within 5 years, 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.
Describe the principle of the use of aromatase inhibitors in breast cancer
In postmenopausal women, the major source of estrogen derives not from the ovaries but from the conversion of the 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.
Describe the action of aromatase
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
ES major circulating oestrogen- can be converted back to estrone in tissue
What are the two types of aromatase inhibitors
A convenient classification divides the aromatase inhibitors into the mechanism-based, or suicide, inhibitors (Type I) and those that are competitive inhibitors (Type II).
Describe the type 1 aromatase inhibitors
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.
Describe the type 2 aromatase inhibitors
Bind reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
Give an example of a type 1 aromatase inhibitor
An example of this type of drug is “Exemestane”. Single-dose administration reveals a major reduction of plasma estrogens with this compound. Side effects associated with exemestane treatment were mild and included hot flushes, nausea, and fatigue
Give an example of a type 2 aromatase inhibitor
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.
Describe disease free survival and endocrine therapy
Table 2. ER and Endocrine Therapy in Advanced
Breast Cancer
Response Rate
(%)
ER+ PR+ 77
ER+ PR- 27
ER- PR+ 46
ER- PR- 11
This has lead to therapies targeting progesterone too
Summarise the use of progestins in breast cancer
Progesterone is the dominant naturally occurring progestin
The poor absorption of progesterone has been overcome with some of the synthetic derivative progestins
Progestin response in the human breast is complex and influences both proliferation and differentiated function.
Progestins are used in the endocrine treatment of uterine and breast cancer with clinically proven antineoplastic properties.
Progestin therapy for metastatic breast cancer has been used principally as a second- or third-line therapy following selective estrogen
. The principal progestin used for metastatic breast cancer has been megestrol acetate
What is the ultimate issue with breast cancer 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
Describe the exploitation of oestrogen receptors in breast cancer therapy
In treatment:
>60% of ERa-positive tumours respond to endocrine therapy
Anti-estrogens, e.g. tamoxifen
Inhibitors of estrogen synthesis, e.g. exomestane
Describe the clinical problem with the use of oestrogen receptors in breast cancer therapy
clinical problem:
Initial response but eventual relapse
Relapse due to resistance during prolonged endocrine therapy
NOT due to tumours becoming ER-independent
Recent data shows that resistant tumours have mutated ER
What have studies regarding resistance to endocrine therapy in breast cancer demonstrated
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
Describe how we can overcome resistance to endocrine therapy
Solution-
Continue use endocrine therapies as these are successful
But, require additional therapeutic agents/ strategies for endocrine resistant, metastatic disease
Outline a treatment strategy for pre-menopasual women with breast cancer
Start with ovarian ablation or tamoxifen
Switch when metastatic relapse takes place
Then give aromatase inhibitors after the second relapse
then progestins
then faslodex
same in post-menopausal except you always start with tamoxifen
Summarise the key risk factors for breast cancer
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)
Compare established risks to possible risks
Age Family history Early age of menarche Late menopause Having no children, or children late in life A history of benign disease Lobular carcinoma in-situ Possible risks include:
Contraceptive pill HRT Diet Weight Alcohol Being tall
Summarise the success of screening programmes for breast cancer
The breast screening programme uses mammography to screen all women between 50 and64 who are registered with a GP in the UK.
The screening age is being extended to age 70 across the country.
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
More than 90% of breast tumours are first spotted by women themselves
Outline the full patient history for this patient with Brest cancer
“Lump” detected by Self Examination or GP
Referred to Hospital
Examined by surgical team (mammogram, FNA)
Surgery performed (lumpectomy/mastectomy)
Tumour examined pathologically (ER/PR)
ER+ (90%) or ER-
See Physician for first time
ER+ Tamoxifen (5 years) or ER- Chemotherapy (6 months)
Disease-free period
Patient returns with secondary tumour (no cure)
What are the different types of ER + breast cancers
Luminal A
Luminal B/C
tumours belonging to the so-called luminal B class, tumours express high Ki67, human epidermal growth factor receptor 2 (HER-2) overexpression or a high score on the Oncotype DX gene expression profile. LUM B, is inherently more aggressive, requires more aggressive therapy and thus is generally treated with both endocrine therapy and chemotherapy,
What are the different types of ER - breast cancers
Basal-like
ErbB2 +Ve - give Herceptin
Normal- like
Basal-like can be Metaplastic / Medullary / Mucinous / Others
EGFR overexpression c-kit aß-crystallin BRCA1 deficiency
Gefitinib, erlotinib Imatinib/Gleevec MEK inhibitors DNA damage
Lapatinib PI3K inhibitors PARP inhibitors
CI-1033
