Breast Cancer

Original article by Tom Leach | Last updated on 28/6/2014
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Remember, although rare, men can also get breast cancer. Less than 1% of breast cancers occur in men.
Benign breast masses are 15x more common than breast cancer
 

Epidemiology

In the UK, a woman has a 1/9 chance of developing breast cancer
It is the most common cause of death in women aged 35-55

  • The most common cancer in female non-smokers
  • In other developed countries (e.g. Australia) it is the most common cancer in women

It is responsible for 20% of all cancer in women

 

Aetiology

Increased risk 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 >30 years
  • HRT / the pill (possibly)
  • Not breast-feeding

Obesity / high fat diet

  • Increases the risk in those over 60

Family history

  • BRCA1 and BRCA2 genes

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, and post menopausal weight likely to be greater.
 

Genetics

The family history risk for breast cancer is only significant if it involves first degree relatives e.g. mother, sister, daughter.
Many cases of familial breast cancer behave like an autosomal dominant trait. Analysis of these cases may show evidence of one of two genes:

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 (women) and prostatic cancer (men)

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

  • Similar lifetime risk to BRCA1
  • Slightly increased risk of ovarian cancer, but low 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 Anaemiain 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/neu
The HER2 protein is a cell membrane tyrosine kinase receptor.
The HER2 gene, is a proto-oncogene found on the long arm of chromosome 17.
In breast cancer tissue and some other cancers (ovarian, stomach, uterine) there is over-expression of the HER2 gene. It is not an inherited genotypic deficiency. It is a proto-oncogene which everybody carries, and mutations involving this gene are more likely to result in cancers.
  • 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). The will bind to the receptor, and cause the production of p27 within the cell, which reduced 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

The typical presentation is a painless breast mass, with/without:
  • Discharge
  • Nipple changes
  • Skin tethering
  • Tethering to underlying tissues, e.g. muscle
  • Ulceration (late sign)
  • Oedema / erythema
The mass is usually firm, and can be 10-100mm in diameter, although is usually 20-30mm on presentation. It may also be tethered to underlying tissue
 

Screening

In the UK, all women aged 50 - 70 are screened every 3 years. It involves a mammogram of each breast.

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 50th birthday, but before the 53rd.
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.
In 2012, the scheme will be extended to all women aged 47-73.

  • This means that all women will now receive their first invitation by their 50th birthday, and all women will get an extra 2 invitations for screening

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

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

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

The procedure

  • 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 described to the patient 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

Physiology of breast tissue development
  • At the menopause, the breast tissue will involute. During this process, much of the glandular tissue becomes fat, and the general density of the breast reduces.
  • The average age of the menopause in UK women is 50.
 
Pathology of breast cancer
Virtually all breast cancers are adenocarcinomas – where the tumour is derived from the epithelial cells of glands or ducts.
 
Non-invasive carcinoma

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.
  • If large ducts are involved, it is associated with nipple discharge
  • May present as Paget’s Disease of the nipple
  • Accounts for 5% of breast cancers at presentation – often breast cancer presents 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
  • 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 carcinomas (Malignant disease)
An invasive tumour is one that has gone through the basement membrane of the tissue of origin, and spread to other tissues.  

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

Spread

Like most metastatic carcinomas, spread can be:

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

Triple assessment
All breast lumps should undergo Triple assessment procedure, which includes:
  • Examination
  • Fine need aspiration (Cytology)
  • Imaging (can be Mammography, MRI or USS)
Any patient referred to hospital for a breast problem will have a triple assessment to try to find the underlying cause.
 
Grading of the triple assessment

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
 
Quadruple assessment
This term is sometimes used in place of Triple assessment, and describes an assessment involving both ultrasound and mammography – i.e. the imaging techniques are not grouped together.
 

Staging and Prognosis

Only about 20% of cancers are diagnosed with no microscopic evidence of nodal spread.
Poor prognostic indicators include:
  • Young age / premenopausal
  • Large primary tumour size
  • High grade tumour
  • Oestrogen and progesterone receptor negative
  • Positive lymph nodes
 
The type of tumour present also influences the outcome. For example, the common invasive ductal carcinomas, and invasive lobular carcinomas carry a worse prognosis than the rarer mucous and tubular tumours.
 
About 75% of breast cancers will express oestrogen receptors, and thus the growth of these cancers can be influenced by oestrogen. 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.
 
Examples of prognosis:
  • Small (<1cm tumour) with no spread – 90% survival
  • Large, high-grade tumour. With >3 nodes involved – 20% survival
 
Staging may be done with the TNM scale, or may be done in relation to the triple therapy scale described above.
 
TNM grading
T1
Tumour <20mm, no tethering or nipple retraction
N0
No Nodal involvement
M0
No distant metastasis
T2
Tumour either: <20mm with tethering, or, 20-50mm
N1
Axillary nodes involved but mobile
T3
Tumour either <50mm with infiltration, ulceration or fixation, or, 50-100mm
N2
Axillary nodes fixed
M1
Distant Metastasis
T4
Tumour >100mm, or with ulceration and infiltration wide of the border of the primary tumour
N3
Supraclavicular nodal involvement with/without oedema of the arm
 

Treatment

Early stage disease
Surgery gives the best outcomes
  • May be a wide local excision or mastectomy. Usually also involve 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:
Adjuvant chemotherapy – improves survival, particularly in young patients with node positive disease.  Anthracyclines are usually combined with several other agents, e.g. methotrexate, cyclosporin and 5FU. Tamoxifen and herceptin also have a role (below)
 
Endocrine therapies

Suitable for all tumours with oestrogen and/or progesterone receptors. The growth of these tumours is prevented by tamoxifen.
Oestrogen receptor positive tumours
Treatment aims to decrease oestrogen activity
Tamoxifen is the agent of choice

  • Given to all women with Oestrogen receptor positive disease for 5 years post op.
  • Mechanism – binds to oestrogen receptors, preventing oestrogen from doing so, and resulting in a lack of DNA synthesis. It is non-steroidal. It causes the affected cell to remain in the G0 /G1 phases of the cell cycle.
  • Tamoxifen is actually a pro-drug – and metabolised into its active agent endoxifen.
  • Side effects
  • Bone – the action of tamoxifen as an antagonist depends upon the target tissue. In bone, tamoxifen acts as an oestrogen agonist – and thus is protective against osteoporosis.
  • Drugs whose oestrogen activity is dependent upon the target tissue are known as selective oestrogen receptor modulators (SERMs).
  • Endometrium – the SERM activity on the endometrium is that of an oestrogen agonist – and as such, it increases the risk of endometrial cancer
  • This is rare, although you should warn all women prescribed tamoxifen to be watchful of vaginal bleeding and report symptoms immediately.
  • Cardiovascular - Slight increase on the risk of DVT, Increased risk of fatty liver
  • CNS - Some evidence to suggest reduced cognition
  • Reduced libido

Aromatase inhibitors

  • 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.
  • 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 adrenalsand thus are only suitable as treatment for BC in post-menopausal women.
 
Herceptin
Herceptin is suitable for that 20% of women whose tumours are HER2 positive. It is a monoclonal antibody that interferes with the HER2 receptor.
It is very expensive. Clinical trials show benefit of its use for 1 year after treatment of the primary tumour. Some trials indicate that 9 weeks therapy is just as effective as 1 year. As a result, its use is the result of some controversy in the NHS. Nice recommends its use in:
  • Women with breast cancer with HER levels at 3+ in who have had chemotherapy (including anthracycline ± tamoxifen [if appropriate]
  • Women with breast cancer who cannot tolerate anthracycline