All done here! Check out our other subjects!
Core
Aetiology (the causes of the disease)
Breast cancer is the most common cancer in the UK, accounting for more than 15% of all newly diagnosed cancers in the UK and for more than 20% of female malignancies. Approximately one in every seven women will develop breast cancer in their lifetime. About 90% of malignant neoplasms in the breast are adenocarcinomas[1] (cancers that start in gland cells), due to the highly glandular structure of the breast.
The largest risk factors of breast cancer are female sex and older age.
Risk is also associated with increased exposure to oestrogen. The cells of the breast glandular tissue have hormone receptors on their cell surface that allow them to respond accordingly to different levels of hormones, specifically oestrogen, progesterone and prolactin (the hormone that drives milk production). When oestrogen is higher, the glandular tissue proliferates (divides and multiplies). Milk production itself is driven mainly by prolactin rather than oestrogen. With increased division and proliferation of these cells, there is a higher chance of an error occurring and uncontrolled cell growth as a result.
Things which increase oestrogen exposure include: female sex, early menarche (first period before the age of 12), late menopause (after the age of 55), older age at first birth (the risk rises by about 3% for each year older) and nulliparity (never having children).
Exogenous oestrogens (those which have their origin outside the body) from hormone replacement therapy (HRT) can affect breast cancer risk. Combined HRT (oestrogen plus a progestogen, a progesterone-like drug) increases the risk, and the increase rises with the length of use. NICE reports very little or no increase in risk with oestrogen-only HRT.
Other risk factors for malignant breast disease include previous breast cancer, atypical changes (abnormal-looking cells) on a previous biopsy, some previous cancers of other types, radiation exposure (mostly from radiotherapy, and to a lesser extent diagnostic X-rays) and a family history of breast cancer. Having one first-degree relative (a parent, sibling or child) with breast cancer roughly doubles the risk, although most women with an affected relative never develop the disease. Drinking alcohol also increases the risk, and the risk rises with the amount drunk.
Autosomal dominant mutations (passed on through a non-sex chromosome, where one altered copy is enough to raise the risk) in tumour suppressor genes (genes that normally stop cells dividing out of control), BRCA1 (breast cancer associated gene 1) & BRCA2 (breast cancer associated gene 2), are the cause of about 2% of all breast cancers. They explain about 15 to 20% of breast cancers in women with a first-degree relative who also had the disease. Carriers of these mutations have a higher risk of breast cancer than the general population at every age. A woman with a BRCA1 or BRCA2 mutation has about a 45 to 65% chance of developing breast cancer by age 70. As a result, some carriers choose to undergo prophylactic double mastectomies (removal of both breasts to prevent them from developing any cancer).
Male breast cancer is far rarer, comprising only 1% of all breast cancer diagnoses. Specific risks include Klinefelter syndrome, where the male has an additional X chromosome thus a genotype of 47, XXY. Again, as in females, the risk rises with oestrogen exposure and with BRCA gene mutations.
Obesity increases the risk of breast cancer after the menopause, as endogenous androgens (male-type hormones made in the body) are converted into oestrogen in any peripherally stored fat by the enzyme aromatase. The more fat present, the higher the conversion, production and exposure to oestrogens. Before the menopause, a higher body mass index (BMI) is instead linked with a lower risk.
Breast feeding is associated with a lower risk of breast cancer: the risk is about 16% lower in women who have ever breastfed than in women who have never done so. A fall in lifetime oestrogen exposure may partly explain this, because lactation suppresses ovulation and so the breast cells are exposed to less oestrogen.
If a GP suspects that a breast mass may be cancerous, the patient is referred to a clinic run by breast surgeons using a suspected cancer pathway referral (an urgent referral that aims to diagnose or rule out cancer within 28 days). The mass is then investigated using the triple assessment technique, a universal three-part process involving clinical history and examination, radiographic imaging and histological examination.
- The surgeon will take an in-depth history about the presentation of the breast lump, asking when and how it was noticed, how it feels to the patient, whether the lump has changed, and whether the patient has noticed any other changes in themselves, specifically any concerning features. They will also ask whether the patient has any of the risk factors above. Systemic symptoms (symptoms that affect the whole body) such as tiredness, unexplained weight loss or night sweats are non-specific and are uncommon in early breast cancer.
- After a thorough history, the surgeon will then examine the lump. They will be looking at the surrounding skin for any signs, the location of the lump (malignancies often present in the upper outer quadrant of the breast), the texture of the lump, if the lump is mobile or tethered (fixed to the tissue underneath) and if there is any lymph node involvement in the axilla (armpit).
- After the consultation the patient will then be taken for radiographic imaging of the lump, either by mammogram (a breast X-ray; see benign breast disease article) or ultrasound scanning. This will assist in differentiating any abnormal changes compared to the normal breast tissue, and identify the nature of this mass.
- The surgeon or radiologist may then take a sample of the tissue for review by a histopathologist (a doctor who examines tissue samples under the microscope) to look for any cell changes. The sample is usually taken as a core biopsy (a needle is used to take a small piece of tissue). This is more sensitive and specific than a fine needle aspiration (drawing cells out through a thin needle).
Diagram: a biopsy of a breast mass for histological analysis
Creative commons source by BruceBlaus [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
About 90% of breast carcinomas are adenocarcinomas, which are then classified in two different ways, by the structure of origin and the metastatic potential (in situ or invasive). An In-situ carcinoma describes when the neoplasm is restrained by the basement membrane (the thin layer under the lining cells) so is contained within the lobules (the milk-making glands) or ducts, and has not invaded into other tissues. Invasive carcinomas are those which have broken through into other tissues and are able to metastasise as a result.
There are two main types of non-invasive breast carcinomas named after the structure of origin, Ductal Carcinoma In Situ (DCIS) and Lobular Carcinoma In Situ (LCIS).
Ductal Carcinoma In Situ is a malignancy originating from the epithelial cells lining the lactiferous ducts (the milk ducts), with an intact myoepithelial layer (the thin layer of muscle-like cells around the ducts) and basement membrane. DCIS is usually asymptomatic (it causes no symptoms) and is detected incidentally (by chance) through the NHS breast screening programme. DCIS has the potential to progress to invasive cancer, and therefore is usually surgically removed either as a lumpectomy (wide local excision, which removes the lump with a rim of normal tissue) or mastectomy.
Lobular Carcinoma In Situ is less common. It originates from the secretory lobules of the breast and has not invaded into surrounding tissue. It is often an incidental finding during a biopsy, because it is mostly asymptomatic. LCIS is considered a marker of increased risk of developing invasive breast cancer in either breast. It is not thought to be a direct precursor lesion (a direct early stage of cancer). So observation alone is often possible rather than surgical resection.
Paget’s disease of the nipple is an unusual presentation which is usually associated with an underlying neoplasm. Paget’s is characterised by the development of a red, scaly rash of the nipple and areola (the darker skin around the nipple). There may be an itchy or burning sensation associated with pain and possible abnormal discharge from the nipple. The nipple may also become inverted.
Paget’s disease of the breast has no known cause. One theory is that malignant cells spread along the duct to involve the nipple epidermis (the skin of the nipple). It is usually associated with an underlying ductal carcinoma in situ or invasive carcinoma. It is easily mistaken for dermatitis or eczema (itchy, inflamed skin), and so this presentation should be treated with high suspicion and referred to a specialist. Surgery is the main treatment. This is either a central excision (breast-conserving surgery that removes the nipple and areola together with the breast tissue beneath) or a mastectomy. Any further treatment depends on the underlying neoplasm.
Image: the reddening and ulceration of the nipple associated with Paget’s disease
Public Domain Source by Lily Chu, National Naval Medical Center Bethesda [Public domain]
Carcinomas become invasive when they have broken through the basement membrane into the stroma (the supporting connective tissue) and surrounding structures of the breast. As a result, these tumours can potentially metastasise through either lymphatic drainage or blood vessels. The first place the cancer often spreads to is the lymph nodes in the ipsilateral axilla. The first lymph node that a given area of the breast drains to is known as the sentinel lymph node. If any lymph node contains metastases, this is the most likely one. Distant metastases, which are most commonly found in bone and also occur in the lungs, liver and brain, spread through the blood vessels.
Invasive carcinoma of the breast is classified by the structure of origin, with invasive ductal carcinoma (also known as No Special Type or NST). This is by far the most common type, making up around 70% of invasive breast malignancy diagnoses. The structure of invasive ductal carcinoma depends on how differentiated the tumour is. A well differentiated neoplasm consists of tubules (small tube-like structures) lined by atypical cells. A poorly differentiated neoplasm consists of sheets of pleomorphic cells (lots of variability in size, shape and type). Invasive ductal carcinoma can develop from DCIS that has not been treated, although not all DCIS becomes invasive.
Invasive lobular carcinoma originates from the secretory lobules of the breast and is the second most common breast cancer. It generates around 15% of invasive breast malignancy diagnoses.
Breast cancer can be linked to mutations in the tumour suppressor genes BRCA 1 and 2, as mentioned previously. Some breast cancers can also have amplification (extra copies) of the Human Epidermal Growth Factor Receptor 2 gene, which leads to increased production of the HER2 receptor. The normal action of this receptor is to stimulate cell growth. Amplification of this gene is the main cause of overexpression (too much of the protein being made) of these surface proteins, and contributes to the uncontrolled proliferation of cells. HER2 positive cells are those that have an increased amount of this receptor protein on their surface compared to normal HER2 negative cells. Oestrogen receptors are also key in breast cancers for their role in cell proliferation as described above.
Like the glandular cells they develop from, the breast cancer cells can have hormone receptors on the surface. As a result, the tumour can be classified not just by location and invasiveness but also by the different receptors that are present on its surface. Knowing the expression of certain receptors allows for treatment to be tailored to that specific tumour. There are three major types:
- ER positive (oestrogen receptor labelled as ER from the American spelling of Estrogen) and HER2 negative carcinoma. This is the most common pattern. In US cancer registry data (SEER), about 70% of female breast cancers are hormone receptor positive (oestrogen and/or progesterone receptor positive) and HER2 negative. It has the best survival compared with the other subtypes.
- HER2 positive carcinoma, with ER either positive or negative
- HER2 negative and ER negative carcinoma ‘triple negative’ cancer (the cells have no oestrogen receptors, no progesterone receptors and no HER2 receptors).
About 15 to 20% of breast cancers are HER2 positive. They are more aggressive and have a higher recurrence rate than HER2 negative cancers. Drugs such as trastuzumab (Herceptin) can be used to specifically target these cells. ER positive breast cancers can be targeted using drugs such as Tamoxifen.
Lymphatic vessels can become blocked through either compression from a tumour or a neoplasm invading the vessel walls. This can cause issues with the drainage of fluid from the breast and so leads to swelling, presenting as the clinical sign of peau d’orange (skin dimpled like orange peel) discussed in the previous article.
The local inflammation that is responding to the tumour can lead to fibrosis of the suspensory ligaments (the ligaments that support the breast) and the lactiferous ducts. This can pull on the skin and nipple, causing skin dimpling and an inverted nipple.
Tumours can metastasise to various points around the body causing different effects depending on that location.
Management of Primary Breast Cancer
The mainstay of primary breast cancer treatment is surgery to remove the tumour, and then additional adjuvant treatments (extra treatments given alongside or after surgery) such as chemotherapy (anti-cancer drugs), radiotherapy (high-energy radiation) and hormonal therapy (drugs that block oestrogen or lower its levels) to increase the overall effectiveness of the treatment. The level of treatment depends on the type, stage (how far the cancer has spread) and grade (how abnormal the cells look) of the cancer.
Breast surgery involves removing the tumour. This can be done as a lumpectomy; removal of the tumour using a wide excision of the surrounding breast tissue to prevent any cancer from remaining in the breast. This technique is suitable when the tumour is small relative to the size of the breast. A mastectomy (removal of the entire breast) may be needed if there is more than one area of cancer in the breast, if the tumour is large relative to the breast, or by patient choice. Mastectomies are sometimes done prophylactically on women who carry mutations in BRCA1 and BRCA2 genes to reduce the chance of breast cancer.
Sentinel node biopsy is used to stage the axilla (to check whether cancer has spread to the armpit lymph nodes) in invasive breast cancer. It is used instead of lymph node clearance when ultrasound shows no sign of lymph node involvement, or when an ultrasound-guided needle biopsy of a suspicious node is negative. NICE recommends the dual technique. A radioactive tracer (isotope) and a blue dye are both injected into the tumour or surrounding tissue, and the surgeon then tracks which lymph nodes they drain to first. The sentinel nodes are found using a gamma probe (a hand-held device that detects radiation from the tracer) and by looking for the blue dye. They are removed for histological assessment. If a sentinel node contains a macrometastasis (a larger deposit of cancer cells), NICE advises offering further axillary treatment. This is either lymph node clearance or radiotherapy to the armpit. Further axillary treatment is not offered if the nodes contain only micrometastases (small deposits) or isolated tumour cells. Lymph node clearance involves dissecting the axilla and removing the lymph nodes, taking care to protect the important structures nearby. It is also offered if a needle biopsy before surgery has already proved cancer in a lymph node. Complications of axillary surgery include lymphoedema (swelling of the arm from fluid that cannot drain), seroma (a collection of fluid under the skin after surgery) and paraesthesia (altered sensation such as numbness or tingling). Altered sensation is more likely if the intercostobrachial nerve, which supplies skin sensation in the armpit and inner upper arm, is divided. Injury to the brachial plexus is rare.
Medical treatment is often used to reduce the risk of recurrence of breast cancer post-surgery or as the mainstay of treatment for those unfit for surgery. Alongside chemotherapy and radiotherapy, hormonal therapies are very commonly used in breast cancer management. Immunotherapies (drugs that use the immune system against cancer) are used in selected cases, for example pembrolizumab given with chemotherapy for some triple negative breast cancers.
- Tamoxifen is an anti-oestrogen used to target ER positive breast cancers. NICE advises it for people with male reproductive organs. Premenopausal and perimenopausal (around the time of the menopause) women can choose between tamoxifen alone, ovarian function suppression (treatment that stops the ovaries making oestrogen) with tamoxifen, or ovarian function suppression with an aromatase inhibitor. After the menopause, tamoxifen is used for people at low risk of recurrence, or when an aromatase inhibitor is not tolerated or is unsuitable. It binds to the oestrogen receptors and inhibits the proliferative oestrogen stimulus on the tumour, and so reduces any further malignant growth.
- Aromatase inhibitors such as anastrozole also deprive the cancer cells of oestrogen stimulus but by a different mechanism. They reduce the peripheral conversion of androgens to oestrogen, and so are commonly used in post-menopausal women who have no other supply of oestrogen.
- Trastuzumab (Herceptin) is a targeted biological medication. It is a monoclonal antibody (a lab-made antibody aimed at one target) that targets the receptors on HER2 positive cancers. It blocks them from receiving growth signals and so restricts the growth of the cancer. These antibodies can also encourage the body's immune system to target and destroy the cancerous cells to which they have bound. NICE advises offering adjuvant trastuzumab (given after surgery) for most HER2 positive invasive breast cancers, at 3-week intervals for 1 year alongside other treatments as appropriate. It is used with caution in people with heart disease.
We use Cancer Research UK’s statistics throughout this article https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer#heading-Zero
Any specific references can be sourced below.
[1] https://training.seer.cancer.gov/breast/intro/types.html
Edited by: Dr. Christopher Bradley MD, FRCP, Consultant Oncologist
Edited by: Dr. Ben Appleby
Review by: Dr. Thomas Burnell
Reviewed by: Dr. Marcus Judge
- 4069
