Big 4 - Breast Cancer Flashcards
What is the UK breast cancer risk and what factor is incidence related to?
What is survival like?
- the UK lifetime breast cancer risk is 1 in 8 (12%)
- survival is increasing with a 10 year survival rate of 80%
- the incidence is age related, with >50% of cases occurring in women >50
- less than 5% of cases occur in women <40
How can the risk factors for breast cancer be subdivided?
- there is not a single more prominent cause of breast cancer (unlike lung)
Uninterrupted oestrogen exposure:
- early menarche and/or late menopause
- nulliparity / first child at older age
- use of HRT (particularly combined)
- obesity
- combined oral contraceptive pill
Lifestyle:
- alcohol consumption (>14 units / week)
- smoking
- diet
Genetic:
- BRCA1
- BRCA2
- P53
Other:
- chest wall / mediastinal radiotherapy
- dense breast tissue
- personal / family history
What factors might make you question whether someone has a gene that could result in breast cancer?
when asking about family history, note:
- cluster of cases in the family that are also affecting younger people
- history of ovarian cancer and bilateral breast cancer
- history of men in the family with breast cancer
What are the roles of BRCA1 and 2 genes?
How can they lead to cancer development?
- they are tumour suppressor genes that repair damaged DNA
- mutations can produce pathogenic variants, which can lead to cancer developing at a younger age
- most commonly breast and ovarian cancer, but also linked to others
- a harmful BRCA gene can be inherited from either parent (50% chance of inheritance)
- these are germline mutations that are present from birth in all cells of the body
- the normal copy of the BRCA gene from the other parent can be lost or changed via a somatic alteration
- once this has occurred, cells without any functioning BRCA1 or 2 can grow out of control and become cancer
What are 4 important factors that must be considered in a screening programme?
- the cancer should be common
- need to be able to pick up the cancer early, allowing for early intervention
- the tool should be user-friendly, otherwise people will not take up the screening
- the tool should be sensitive, specific and cost-effective
What is involved in the breast screening programme?
- women aged 50-70 years are offered a routine mammogram every 3 years
- the mammogram uses XRs to identify cancers that may be too small to see or feel
- a cancer that occurs in between these 3 year periods is an interval cancer
What are some breast changes that are associated with breast cancer?
- a new lump or thickening in the breast or axilla
- a change in size, shape or feel of the breast
- redness of the skin
- nipple inversion
- spontaneous nipple discharge
- tethering of the skin (skin pulled in when arm is raised)
- orange peel skin
- dimpling or indentation of the skin
- growing prominent veins
How does the presentation of inflammatory breast cancer differ?
What is it often confused with?
- a very aggressive cancer that presents with a short history of very swollen, painful, red and oedematous breasts
- there is not usually a lump
- it is often confused with mastitis and the patient is sent away with antibiotics
- important to bring the patient back to ensure symptoms of mastitis have settled - if not then urgent 2WW referral
Why does inflammatory breast cancer tend to have a worse prognosis?
- it is more aggressive - it grows and spreads much faster
- it is always at a locally advanced stage (at least stage III) when diagnosed as the breast cancer cells have grown into the skin
- in 1 in 3 cases, it has already metastasised when diagnosed
- it tends to occur in younger women (<40)
- it may not show up on a mammogram, making diagnosis more difficult
What happens after a patient has presented with symptoms or been detected through screening?
- the patient attends the breast clinic for the triple assessment
- this involves clinical examination, imaging and biopsy
- performing all 3 of these stages results in a confident diagnosis in 99% of cases
What questions are important to ask in the clinical examination stage of the triple assessment?
- how long have the symptoms been present for?
- any skin / nipple changes?
- assess the symptom severity - any discharge / pain?
- are the symptoms related to the menstrual cycle?
- any previous breast lumps?
- any lumps under the arm?
- family history?
- current medications
What are the typical imaging modalities used in the triple assessment?
Mammography:
- involves compression views of the breast across 2 views - oblique + craniocaudal
- allows for detection of mass lesions or microcalcifications
Ultrasound:
- more useful in men and women < 35 due to the dense breast tissue
When might CT, MRI and PET CT scans be used in breast cancer?
- they are not used as part of the triple assessment
- CT is used when there is a concern about metastases
- PET CT is used when considering radical treatment in locally advanced disease
- MRI is used to assess lobular breast cancers and to assess the response to neoadjuvant chemotherapy
What are the 2 different methods of biopsy used in the triple assessment?
Fine needle aspiration cytology (FNAC):
- this only provides cytology and is not as commonly used
- used in women with recurrent cystic disease to relieve symptoms
Core biopsy:
- this provides full histology, allowing differentiation between invasive and in-situ carcinoma
- higher sensitivity and specificity compared to FNAC and can be used for tumour grading / staging
After performing the triple assessment, how is this scored?
- at each stage, the suspicion for malignancy is graded to create an overall risk index
- each stage is graded out of 5 depending on the likeliness of malignancy
- the overall score is used to determine whether the patient may need further intervention
What are the 2 different treatment plans for breast cancer?
What types of treatment does this involve?
Curative treatment:
- aims to eradicate all disease (macro and microscopic) to provide a cure
Palliative treatment:
- cure is not possible
- aim is to control symptoms and improve quality of life
What are the 2 different routes of curative treatment?
Start with surgery:
- there is initial surgery to remove cancer within the breast and axilla
- this is followed up with adjuvant systemic treatment to eradicate micrometastatic disease and prevent spread
- locoregional treatment may also be required to remove microscopic disease within the breast
Wait for surgery:
- neoadjuvant systemic treatment is given prior to surgery to downstage the tumour
What is the aim of curative local treatment?
How is this acheived?
this involves surgery to remove local macroscopic disease
- breast surgery is acheived via wide local excision or mastectomy
- if surgeon opts for mastectomy, patient is offered reconstruction immediately or in the future
- axillary surgery is acheived via sentinel node biopsy or axillary clearance
- axillary clearance is performed to remove the nodes when it has already been confirmed from imaging that they contain cancer
- sentinel node biopsy is performed to surgically stage the axilla when it is not indicated that the nodes are positive
- sentinel node is examined to ensure there is no microscopic disease
- if this result comes back as positive, axillary clearance or radiotherapy is required
What is the role of adjuvant treatment in curative therapy?
What are the 2 different categories?
adjuvant treatment targets microscopic disease
- the surgeon removes the breast lump, but this may have already thrown off micrometastatic disease
- this commonly travels to the lungs, bone or liver and over time will become macrometastasis and secondary cancer
- adjuvant treatments eradicate the micrometastasis and can be locoregional or systemic
What is the difference between locoregional and systemic adjuvant treatment?
Adjuvant locoregional treatment:
- this involves radiotherapy to remove local microscopic disease within the breast
Adjuvant systemic treatment:
- this involves treatment in the bloodstream to remove distant microscopic disease
- performed via chemotherapy, hormonal therapy or targeted therapy (Her2)
What is the role of neo-adjuvant treatment in curative therapy?
What tends to be used for this?
this is used to down-stage the disease prior to surgery
- needed to make definitive local curative treatment possible or to reduce the extent of local treament required
- chemotherapy is used - especially in locally advanced disease or inflammatory breast cancer
- ER -ve / Her2 +ve disease responds the most
How is breast cancer staged?
TNM system
What are the 3 different types of systemic treatment used in breast cancer?
Chemotherapy:
- this is not very targeted and involves throwing drugs at a cancer in the hope it will damage the DNA and eradicate it
Endocrine therapy:
- can only be used when a tumour is oestrogen sensitive (ER+)
Anti-Her2 treatment:
- can only be used when the tumour expresses HER2 protein
In what settings can chemotherapy be used?
What drugs are most commonly used and how do they work?
- can be used in an adjuvant, neoadjuvant and palliative setting
- EC (epirubicin and cyclophosphamide) and Docetaxel are most commonly used
- FEC (5-FU, epi and cyclo) and Paclitaxel are sometimes used
- oral chemotherapy with Capecitabine is used in the palliative setting
- all these drugs work by causing DNA damage
Why is a combination of drugs usually used in chemotherapy?
How often is it given and what factors need to be considered?
- combination of drugs avoids overlapping toxicities and cross resistance
- all drugs can be used to their full potential and will not all be toxic to the same organ
- it is given as cycles (usually 6-8) every 3 weeks
- need to evaluate the benefit to the patient, their general health and the risk of toxicity
What are the general side effects associated with chemotherapy toxicity?
- fatigue
- hair loss
- nausea and vomiting
- mucositis
- gastritis
- diarrhoea / constipation
- thrombocytopenia
- anaemia
- MYELOSUPPRESSION** - can result in **NEUTROPENIC SEPSIS
What is meant by organ-specific chemotherapy toxicity?
Why is this significant?
- this is usually drug-specific and is important to take into account if the patient has pre-existing comorbidities
- many of the effects are long-term and irreversible:
- infertility
- secondary malignancies
- cardiotoxicity
- pulmonary toxicity
- nephrotoxicity
- neurotoxicity
What is meant by an ER+ breast cancer?
What % of breast cancers fit into this category?
- an ER+ breast cancer is “oestrogen-receptor positive”
- the cells of the cancer have oestrogen receptors on the surface of the nucleus within the cell (lock)
- oestrogen from the bloodstream (key) fits into these receptors and causes the breast cancer cells to grow
What is the difference in sites of oestrogen synthesis in premenopausal and postmenopausal women?
Premenopausal:
- oestrogen is produced within the ovaries
Postmenopausal:
- the ovaries no longer produce oestrogen
- synthesis takes place in adipose tissue, skin, liver, muscle and breast tissue
What are the 2 different methods of action of hormonal therapies?
- need to block oestrogen (key) from fitting into the oestrogen receptor (lock)
- or block oestrogen production (premenopausal women) / extra-ovarian oestrogen production (postmenopausal women) and eradicate the key
How does hormonal therapy work to block oestrogen production in premenopausal women?
- younger women are producing large quantities of oestrogen from the ovaries
- a surgical oophorectomy is performed to remove the ovaries
- or a medical oophorectomy can be performed using Goserelin (Zoladex) to interrupt the pituitary-ovarian axis
- aromatase inhibitors are given to block extra-ovarian oestrogen production from the breast, fat and adrenal glands
How is extra-ovarian oestrogen production blocked in postmenopausal women?
aromatase inhibitors
- this includes Anastrozole, Letrozole and Exemestane
- these work by stopping the enzyme aromatase from changing other hormones into oestrogen, which can fuel the growth of breast cancer cells
- this is the only treatment needed in postmenopausal women as the ovaries are already dead
What hormonal therapy is used to block the oestrogen from entering the oestrogen receptor?
Who is this suitable for?
Tamoxifen
- this works by competitive inhibition to seal the lock and prevent the key from entering
- it lies on the surface of the oestrogen receptor, preventing oestrogen from entering and allowing growth of cancer cells
- it can be used in both pre- and post-menopausal women
What are some of the adverse effects associated with Tamoxifen?
- mood changes
- vaginal discharge
- loss of libido
- body image
- endometrial changes - both benign and malignant
- changes to periods
- N&V
- hot flushes / skin rashes
-
increased thrombotic risk - risk of DVT / stroke
- if a patient on Tamoxifen becomes suddenly breathless - request CTPA and think PE
What are the common side effects associated with aromatase inhibitors?
- mood changes
- vaginal dryness
- loss of libido
- body image
- arthralgia and myalgia (can be extreme)
- decrease in bone density
- hot flushes / night sweats
What is meant by a Her-2 positive breast cancer?
What % of breast cancers are accounted for by this?
- the breast cancers have cells that over-express Her-2 protein
- this is a cell-surface receptor that controls cell growth and division
- usually each cell possesses 2 genes that encode the Her-2 protein, but gene amplification results in these cells containing many more
- too many HER2 receptors send more signals, resulting in cells growing too quickly
- affects 15% of all breast cancers
What treatments are used in Her-2 +ve breast cancer?
Trastuzumab (Herceptin)** and **Pertuzumab
- these are monoclonal antibodies against the Her-2 protein
- is it NOT chemotherapy - they are antibodies that will kill the Her-2 protein and block the cell-signalling pathway
- given IV or s/c every 3 weeks
What are the side effects associated with Herceptin?
- there is a risk of allergic reaction
- it can be cardiotoxic, so patients need to have adequate cardiac function and this needs to be monitored during treatment
Why and when is adjuvant radiotherapy used in breast cancer?
How is the treatment dose and number of treatments measured?
- it uses high energy X-rays to kill cancer cells by causing non-repairable DNA damage
- the treatment dose is measured in Grays (Gy)
- the number of treatments is referred to as fractions
What is the typical course of adjuvant radiotherapy given in breast cancer?
Why is this done?
- adjuvant radiotherapy to the adjuvant breast +/- lymph node areas delivers 40 Gy in 15 fractions over 3 weeks
- more recently, 26 Gy in 5 fractions
- the purpose is to improve local control and reduce the risk of local relapse
What factors can mean that someone with breast cancer has a poorer prognosis?
- higher TNM stage of cancer
- higher grade (3 > 2 > 1) / how differentiated the cancer is
- molecular markers
- these are proteins expressed by cancer cells detected with immunohistochemistry
- ER negative disease
- HER-2 positive disease
- triple negative disease has the worst prognosis
- age - younger women and very old women tend to have biologically bad cancers
