Introduction

Breast cancer is the most common cancer in women, and the second most common cause of death from cancer, after lung cancer.

There are more published studies (on PubMed) on breast cancer, than on any other disease.

Breast cancer is broadly classified as:

• Ductal – tumours arising from the epithelial lining of the ducts
  • This is by far the most common type
• Lobular – tumours arising from the epithelial lining of the terminal ducts of the lobules

Breast cancers can also be classified as invasive or in situ. Most breast cancers are invasive – and therefore more dangerous.

Epidemiology

In the UK, a woman has a 1/9 chance of developing breast cancer

• Incidence about 95 per 100 000
• Mortality of about 23 per 100 000
• Has a mortality rate of about 25%
  • Mortality rate is decreasing due to earlier diagnosis (from screening) and improved treatments
  • Mortality rate is typically higher than many other cancers because breast cancer often presents late. It often does not cause any symptoms until it has spread to other tissues
• About 5% are metastatic at the time of diagnosis

It is the most common cause of death in women aged 35-55

• In some developed countries (e.g. Australia) it is the most common cancer in women. In others, it is a close second to lung cancer
• Incidence increases with age
  • <5% of cases in women <35
  • 25% in women <50
  • The remaining 70+% of cases are in women aged >50

It is responsible for 20% of all cancer in women

Aetiology

Risk increases with age
Oestrogen exposure – long, uninterrupted periods
Large gap between menarche and menopause

• Early first period
• Late menopause
  • Women with 40 years of active menstruation have 2x the risk of those with 30 years
• Nulliparity
• First pregnancy  at age >30 years
• HRT
  • HRT with oestrogen only – little to no increased risk
  • HRT with oestrogen and progestogen increases the risk of breast cancer
  • Increased risk is related to the period of use of HRT. Risk reduces after HRT is stopped. Risk if <5 years of HRT is thought to be minimal.
• The Pill
  • Risk thought to be very low
  • Correlated to the age at which the pill is ceased (older age = greater risk) rather than the duration of use of the pill
  • 10 years after ceasing the pill the risk has returned to baseline
• Not breast-feeding
• Radiation to the chest
• Obesity / high fat diet / alcohol
  • Increases the risk particularly in those over 60
• Breast augmentation is NOT correlated with an increased risk of breast cancer

Family history

• BRCA1 and BRCA2 genes
  • Account for about 5% of breast cancers
• BRCA1:
  • Mutation on chromosome 17
  • Lifetime risk of breast cancer is about 75%
  • Lifetime risk of ovarian cancer is about 50%
  • Men with the gene also at increased risk
• BRCA2:
  • Mutation on chromosome 13
  • Lifetime risk of breast cancer 40-85%
  • Lifetime risk of ovarian cancer <25%
  • Lifetime risk of breast cancer for men is about 6%

Atypical epithelial hyperplasia
Geographical variation

• Highest incidence in the ‘Western World’ i.e. North America, Europe, Australia, NZ. Incidence is lowest in Africa and South-East Asia
• These variation are probably the result of the other above risk factors, e.g. in these western countries, menarche is likely to be earlier, first pregnancy likely to be later, diets high in processed foods, alcohol intake and post menopausal weight likely to be greater.

Genetics

BRCA1 – on chromosome 17, accounts for around 50% of familial cases that appear to be inherited in an autosomal dominant fashion.

• 60-85% lifetime risk of breast cancer.
• Also increased risk of bowel cancer, ovarian cancer (50% lifetime risk) and prostatic cancer (men)

BRCA2 – on chromosome 13 – less common than BRCA1, accounts for 30-40% of familial cases.

• Similar lifetime risk to BRCA1
• Increased risk of ovarian cancer (25% lifetime risk), but lower risk of other cancers compared to risk of other cancers from BRCA1
• Men with BRCA2 have a 6% chance of developing breast cancer (100x greater than the normal population)

Both BRCA1 and BRCA2 are tumour suppressor genes, responsible for the production of proteins which help repair damaged DNA during cell reproduction. In the mutated forms of these genes, the protein produced is ineffective, allowing DNA defects to accumulate over time.

• Typically, mutated BRCA1 genes produce a protein that is too short, and is unable to perform the normal repair process.
• There are hundreds of different mutations – but all have the same result
• Most people only have one defective copy and one normal copy
• Those who have two copies of BRCA2 will also have:
  • Fanconi Anaemia – in this condition there is: short stature, skeletal abnormalities, increased incidence of solid tumours and leukaemia, and bone marrow failure.
• There is also an increased risk of ovarian cancer in women with BRCA1 and BRCA2, but the risk is less with BRCA2.

• HER2 mutation occurs in about 20% of breast cancers
• It is associated with a worse prognostic outcome
• Has specific treatment in the form of the monoclonal antibody Trastuzumab (Herceptin). This will bind to the receptor, and cause the production of p27 within the cell, which reduces cell proliferation
• As a result of this specific treatment, breast cancers are routinely tested for HER2/neu presence.
  • HER2 expression is reduced by the presence of oestrogen. In some tumours treated with tamoxifen, HER2 expression can increase.

Presentation

• Discharge
• Nipple changes
• Skin tethering or dimpling
• Tethering to underlying tissues, e.g. muscle
• Ulceration (late sign)
• Oedema / erythema
• Paget’s disease of the nipple
  • A complication of ductal carcinomas
  • Causes itching, redness, crusting and discharge from the nipple
  • Accounts for about 1% of cases of breast cancer

• Most commonly seen in the upper, outer segment

Screening

UK

Originally set up in 1988. Costs £75m per year (roughly £45 per woman screened, or £37 per woman invited).
The programme is run on a three yearly rotation basis depending on the GP practice, which means the first invitation for screening will be received any time after the woman’s 50^th birthday, but before the 53^rd.
After a woman reaches the upper age limit (70), then invitations are not routinely sent, but women are still encouraged to and entitled to make their own NHS appointments if they wish.

It is estimated that the screening program saves around 1400 lives per year (or 1 in every 500 women screened). This is roughly a 35% reduction in mortality when compared to a non-screened population.
Screening is also available for women under 50 who:

• Have had a previous cancer
• Have had a first degree relative with cancer <50 years
• Have a known BRCA1, BRCA2 or TP53 gene

Australia

• Is typically performed every 2 years
• Offered to all women aged 50-74
• Should be offered to women aged 40-49 with:
  • Moderately increased risk (see below)
• Consider screening every year in people with moderately increased risk

Moderately increased risk

Affects about 4% of the population. Defined as:

• x1 first degree relative with a breast cancer diagnosis at age <50
• >1 first degree relative with breast cancer diagnosis at any age

Potentially High risk

Affects about 1% of the population. Defined as:

• Women with TWO 1st OR 2nd degree relatives with BREAST or OVARIAN cancer PLUS at least one of the following:
  • >2 relatives affected
  • Breast cancer diagnosed at <40 years
  • Bilateral breast cancer
  • Breast and ovarian cancer in the same woman
  • Jewish ancestry
  • Breast cancer in a male relative
• One 1st or 2nd degree relative with breast cancer diagnosis at <45 years PLUS relative on same side of family with sarcoma at age <45
• Family member with known high risk breast cancer gene (BRCA1 or BRCA 2)

The procedure

Mammography – an x-ray of the breast tissue. Usually anteroposterior and lateral images of the breast are taken.

• Sensitivity – 75-95%
• Specificity – 95%
• It is not effective at detecting the early changes of breast cancer in women <35 years – as the breast tissue in women of this age is more dense, and thus the subtle density changes of early dysplasia cannot be seen. USS is used to assess breast lumps in women <35

• It is usually a bit uncomfortable, and in some women it may cause pain. One study suggests that good explanation of the procedure beforehand reduces the perception of pain. Taking aspirin or paracetomol before the procedure does not alter the perception of pain.
• Sometimes products on the skin (e.g. deodorant, talcum powder) may appear as calcifications.
• Results usually available within 1-2 weeks, but can take up to 4.
• 5% (1 in 20) screened women are called back for further review – but only about 13% of these (or, about 0.65% of the total) will actually have cancer. So, for every 8 women called back for review, only 1 of them will have cancer.

Digital Mammography – FFDM – Full field digital mammography –  a newer technique, that provides higher resolution imaging, and in theory is more sensitive in younger women with more dense breast tissue. However, in trials, FFDM has not been shown to be any more effective at detecting cancer than traditional mammography, and it is not routinely used.
MRI – MRI scanning is recommended by NICE for some women with a very high risk (e.g. known gene defects), as it is more sensitive, but much more expensive.

Pathology

• Most of the breast is made of adipose (fatty) tissue
• Coopers ligaments attach at one end to the underlying pectoral muscles, ad at the other end, to the skin, and help support the breast
• Glandular tissue is grouped into lobules
  • Within these lobules are alveoli – sore of like modified sweat glands that make mild instead of sweat

• The glandular tissue respond to several hormones
  • Oestrogen
  • Progesterone
  • Prolactin
  • In response to these hormones, the alveolar cells divide and the lobules enlarge
  • Without these hormones, the cells undergo programmed cell death (apoptosis)
  • As such, every menstrual cycle, the alveolar cells go through a period of division and then apoptosis
  • Every time a cell divides, there is a chance of a mutation that can lead to a tumour formation
  • Thus – factors that increase the number of menstrual cycles in a woman lifetime increase the risk e.g. early menarche, late menopause
  • Also, this is why medications containing oestrogen increase the risk
• At the menopause, the breast tissue will involute. During this process, much of the glandular tissue dies (undergoes apoptosis), and is replaced by fat.  The general density of the breast reduces.
  • This is in response to the lack of oestrogen
  • The average age of the menopause in UK women is 50

• A single mutated epithelial (duct) cell will start to replicate out of control

Tumour confined to the ducts, or the acini of the lobules, and there is no infiltration of the basement membrane. Although described as non-invasive, these tumours have the potential to become invasive, and all invasive carcinomas will have at some time been non-invasive.

Non-invasive carcinomas therefore, are a stage of pre-malignancy, although not all non-invasive carcinomas will become malignant.

Can be:

Ductal carcinoma in situ

• Occur in both premenopausal and post-menopausal women. Usually patients are 40-60 years of age. May be extensive, and associated with fibrosis, in which case it will be a large palpable mass.
• Defined as a cancer that has not spread beyond the basement membrane of the ducts
• If large ducts are involved, it is associated with nipple discharge
• May present as Paget’s Disease of the nipple
  • In these cases, the initial tumour will have originated in one of the ducts, but at some stage, a cancerous cell will have migrated down the duct and become attached to the epithelial skin on the outside of the nipple
• Accounts for 5% of breast cancers at presentation – often breast cancer presents later in the invasive phase.
• Typically 10-100mm in diameter and unilateral/unifocal
• Histologically typically occur in small and medium sized ducts
• Lesions may have a solid centre, or a necrotic centre, which can subsequently calcify, making the lesions visible on mammography
• Spread locally along the ducts
• Have a risk of 30-50% of becoming invasive
• If completely excised, prognosis is excellent

Lobular carcinoma in situ

• Usually occur in pre-menopausal women
• Occurs in the lobules and don’t affect the ducts
• Very difficult to detect – as it does not present as a lump, or cause many other signs.
• Often multifocal and bilateral
• No specific features on mammography
• 25-30% of cases will become invasive (i.e. malignant)

Invasive ductal carcinomas

• Account for 75% of all invasive carcinomas
• Occur in both pre and post menopausal women

Invasive lobular carcinoma

• Account for about 10% of invasive carcinomas

Mucinous carcinoma

• Account for 2-3% of invasive carcinomas
• Their borders are not well defined, and they do not cause inversion of the nipple, or tethering of the skin.
• Better prognosis than invasive ductal or lobular carcinomas

Tubular carcinomas

• Cells arrange as tubules
• 1-2% of invasive carcinomas
• Account for a higher proportion of breast cancers detected at screening
• Prognosis is very good

• Rare
• Usually large and well circumscribed
• Histologically show lymphocytic infiltrate and macrophages
• Better prognosis than for invasive ductal carcinomas

Spread

Local – directly into surrounding tissue
Via lymph nodes – in this case typically to the axillary and peri-clavicular nodes

• Sentinel node biopsy is a technique used to asses lymph node spread, without the need for dissection and biopsy of many nodes of the axilla. The sentinel node is the first axillary node along the lymphatic chain – thus all lymph from the breast will drain here first, before moving on through the lymphatic system. However, it is not an anatomical location, as the number and distribution of nodes varies between individuals. To identify the sentinel node a solution containing the radioactive isotope technithium and a blue dye is injected around the nipple/areolar and around the breast cancer itself. Then, a few hours later, the women undergoes surgery of the axilla, and using a hand-held Geiger counter-counter, and by looking which node has turned the deepest shade of blue(!) the surgeon can identify the sentinel lymph node. It removed and sent for histology. Sometimes several nodes may be removed if the spread of dye/isotope is more evenly spread between a few nodes.

Via the blood – to distant sites, in this case, the lungs and bones are most often affected. Other common sites include liver, brain and adrenal glands. The contralateral breast is also often a site of spread.
Unusual characteristics – breast cancers can recur as metastatic disease with / without local disease many years after the removal of the primary tumour. The reason why this occurs in unknown. It could be that the cancerous cells lie dormant, or that there is an alteration in the host immune system many years down the line that results in active disease.

• This can occur up to 20 years after removal of the primary tumour.

Investigations

• Examination
• Fine need aspiration (Cytology)
• Imaging (can be Mammography, MRI or USS)

Examination

• E1 – Normal (no lump)
• E2 – Benign lump
• E3 – A lump
• E4 – A suspicious lump
• E5 – Probable cancer

Cytology

• C1: Inadequate
• C2: Benign
• C3: Atypia, probably benign
• C4: Atypia, probably malignant
• C5: Malignant

Radiology

• R1: Normal
• R2: Benign
• R3: Indeterminate
• R4: Suspicious
• R5: Malignant

Staging and Prognosis

• Young age / premenopausal
• Large primary tumour size
• High grade tumour
• Oestrogen and progesterone receptor negative
• Positive lymph nodes

• Oestrogen acts on nuclear receptors, and controls varies pathways in relation to cell differentiation and growth.

About 50% of tumours have progesterone receptors

• Those with receptor positivity have a greater chance of survival due to treatment methods that can target this mechanism. The fact that the tumour is receptor positive also indicates a higher-level of cell differentiation – which for cancer generally is a good prognostic sign
  • i.e. it hasn’t differentiated to an extent as to become unrecognisable.

• Small (<1cm tumour) with no spread – 90% survival
• Large, high-grade tumour, with >3 nodes involved – 20% survival

• Tumours are also frequently categories by their molecular type, in related to oestrogen, progesterone and HER receptors
• See below in ‘treatment’ for more info

Treatment

Early stage disease

Defined as localised tumours without metastatic spread. Not all of these tumours can be cured with surgery alone.

• 20-30% of breast cancer initially thought to be early stage, localised disease will later recur with metatastatic disease.

• May be a wide local excision or mastectomy. Usually also involves reconstructive surgery.
• Axillary node sampling at the very least (e.g. sentinel node biopsy – above), but usually, axillary node clearance is performed.
• Local excision + radiotherapy – this gives equal survival to surgery, but the risk of recurrence is greater.
• Adjuvant radiotherapy – is given to the chest wall after mastectomy for tumours with a high risk of recurrence
  • Radiotherapy to the axilla – is usually performed if there are +ve nodes on sampling, and node clearance was not performed.
• Side effects of radiotherapy to the chest wall / axilla:
  • Pneumonitis
  • Rib fracture
  • Pericarditis
  • Lymphodema
  • Brachial plexus injury

Advanced Breast Cancer

Advanced breast cancers include locally advanced cancers that cannot be cured with surgery alone, and metastatic breast cancers. Common metastatic sites are bone, brain, lung and liver. 

• Hormone receptor positive is sometimes referred to as HR+, not to be confused with HER2+ !

Suitable for all tumours with oestrogen and/or progesterone receptors – including all HR+ positive tumours, and some HER2+ tumours which are also HR+.The growth of these tumours is restricted or completely prevented by treatments that restrict the tumour access to oestrogen (and / or progesterone).

Oestrogen receptor positive tumours
Treatment aims to decrease oestrogen activity
Tamoxifen is the first line agent

• Given to all women with Oestrogen receptor positive disease for 5 years post op.
• Mechanism – is complicated. It is a selective oestrogen receptor modulator (SERM) – with mixed activity.
• In breast tissue it is an oestrogen receptor antagonist – it binds to oestrogen receptors, preventing oestrogen from doing so, and resulting in a lack of DNA synthesis inside the cancer cells. It is non-steroidal. It causes the affected cell to remain in the G0 /G1 phases of the cell cycle.
• In bone and endometrial tissue it acts as an oestrogen agonist and stimulates the oestrogen receptors. This improves bone density (good – and thus is protective against osteoporosis) but increases the risk of endometrial cancer (bad).
• Tamoxifen is actually a pro-drug – and metabolised into its active agent endoxifen.
• Side effects
  • Fatigue
  • Hot flushes
  • Mood changes
  • Increased risk of endometrial cancer – warn all women prescribed tamoxifen to be watchful of vaginal bleeding and report symptoms immediately.
  • Cardiovascular – Slight increase on the risk of VTE (venous thromboembolism), increased risk of fatty liver
  • CNS – Some evidence to suggest reduced cognition
  • Reduced libido

Aromatase inhibitors  – e.g. letrozole, anastrozole

• Second line agents for oestrogen suppression
• Newer than tamoxifen, and sometimes better tolerated. Again, only suitable for women with oestrogen receptor positive disease.
• Only suitable in post-menopausal women
• Mechanism – aromatase is an enzyme involved in oestrogen synthesis. By inhibiting the enzyme, oestrogen is not synthesised.
• In pre-menopausal women, the majority of oestrogen production occurs in the ovary
• In post-menopausal women, the majority of oestrogen production occurs in the adrenal gland, from the conversion of androgens. Oestrogen is also produced by adipose tissue.
• Aromatse inhibitors inhibit the conversion of androgens to oestrogen in the adrenals – and thus are only suitable as treatment for BC in post-menopausal women.

• Lapatinib – a tyrosine kinase inhibitor given orally. Side effects include diarrhoea, fatigue, nausea, vomiting and rashes
• Cyclin-dependent kinase inhibitors (CKD inhibitors). These are newer agents that show similar efficacy to the above options, and are more effective than endocrine therapy alone.

Chemotherapy

• Often used in conjunction with eh above agents
• Consider the risks vs benefits of any regimen
• Combination regímenes often have a significantly more onerous burden of side effects, and should be avoided in the palliative setting, where quality of life should be prioritised

Triple Negative Tumours

• Chemotherapy is the mainstay of treatment – HR and HER specific treatments are ineffective
• Clinical trials are currently focussing on immunotherapy options

Localised treatment options

• Surgery or radiotherapy may be considered for primary tumours or metastasis that are causing localised issues – for example – a large fungating primary breast tumour, spinal cord compression from bony metastases, or a pleural effusion (which should be drained)
• Brain metastases may be treated with corticosteroids to reduce brain swelling

Bone metastases

• Osteoclast inhibitors – such as zolendronic acid or denostaba (both used in the treatment of osteoporosis) reduce the incidence of pathological fractures and other bone related side effects
• Radiotherapy is often used fro individual bony metastases pain

The MDT

• The multidisciplinary team is an import part of management o the advanced cancer patient – attempting to manage the medical and psychosocial needs of the patient. A typical team might include:
  • Medical oncologist
  • Radiation oncologist
  • Palliative care physician
  • GP
  • Breast cancer nurse
  • Palliative care nurse
  • Psychologist
• It is recommended to involve palliative care services early as they have been shown to improve quality of life

Prognosis

Advanced Brest cancer

• Median survival is 2 years, but is widely variable and depends on the subtype. Median survivals by subtype:
  • HR+ 6 years
  • HER2+ 4-5 years
  • Triple negative 12 months
• Since the mid 1980s 5 year survival has improved from 10% to about 30%
• Herceptin (tratuzumab) has been the most effective new treatment during this period

References

• RACGP – The Red Book – Breast Cancer
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Breast Cancer – Patient.info
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Advanced Breast Cancer – AJGP

Read more about our sources

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