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.
