Breast Cancer

Breast cancer is the most common cause of death from cancer in the UK. It is also a significant cause of morbidity and is a national target area in the Government's Health Strategy The Health of the Nation.

Most breast cancers arise from either

• The epithelial lining of ducts and are called ductal or
• From the epithelium of the terminal ducts of the lobules and are called lobular

Carcinoma can be invasive or in situ. Most cancers arise from intermediate ducts and are invasive. Paget's disease of breast is an infiltrating carcinoma of the nipple epithelium and represents about 1% of all breast cancers. Inflammatory carcinoma occurs in under 3% all cases with a rapidly growing, sometimes painful mass enlarging the breast and causing the overlying skin to become red and warm. There may be diffuse infiltration of tumour.

• Breast cancer is the commonest cancer in women with 44,659 new cases in the UK each year.¹ It represents almost 1 in 3 of all malignancies in women.
• One in 9 women in England and Wales will develop breast cancer during their lifetime.¹
• The number of years of life lost in women under 65 is higher for breast cancer than for coronary heart disease.
• Breast cancer can occur in men, usually in men aged over 50 years.
• In 2005, deaths from breast cancer in England and Wales were 11,040 women and 81 men.²
• Incidence rises with age and over half of deaths are in women over 70 years. 75% of new cases are aged over 50 years. Although 90% of breast cancer deaths occur in women aged over 50 years, it is the most common cause of death in women under 50 years.
• The death rate from breast cancer is falling. This is probably due to better treatment but mammography may also be detecting cases earlier.
• In less than 1% of cases there is simultaneous bilateral breast cancer.

Risk factors

• Breast cancer in a first degree relative increases risk 2 to 3 fold. The importance of family history should not be exaggerated. The majority( 8 of every 9) women who develop the disease do not have a mother, sister or daughter so affected.⁶
• NICE guidance for familial breast cancer is now available.⁵
• High alcohol intake may increase risk in a dose related manner.⁷
• If there is a personal history of breast cancer there is an increased risk of another primary tumour.
• Men with Klinefelters syndrome are at increased risk as are men with other causes of gynaecomastia including the hormonal treatment of carcinoma of prostate or hormones taken to create breast development intentionally.⁸
• Silicone breast implants do not increase the risk of developing breast cancer nor the risk of late presentation.⁹

Organised screening, education programmes, and improved consciousness of the female population have substantially changed the type of patients seen nowadays compared with a few decades ago and the neglected tumour is much rarer than it was. Patient presenting with a lump in the breast will be aware of the possible diagnosis and will be very anxious. This should be taken into account when taking the history and discussing management.

• Most patients present having found a lump in the breast. A third of all women attending a breast unit outpatients will have a painless breast lump of whom 1 in 8 or 9 will have a breast cancer.
• Other symptoms include a lump under the arm, lump in other other regional lymph nodes and with retraction or inversion of the nipple.
• A suspicious mass may have been found at routine mammography.
• Metastases may cause pain in bones or even pathological fractures.
• Metastases at other sites (for example liver, lung or brain) may cause symptoms.
• Intraduct carcinoma may present as a bloody discharge from the nipple.
• The lump of breast cancer is usually painless.
• Occasionally, still patients (usually elderly, but not always) will present with a fungating mass that has obviously been neglected for a long time.
• Direct questions should include the following:
  • When was the lump first noticed?
  • Has it changed in size?
  • Menstrual history
  • Any changes noted through the menstrual cycle?
  • Family history (including breast cancer, other cancers and other conditions)

• Inspect the breasts:
  • Inspect with the patient sitting and then with hands raised above head
  • A lump may be visible
  • Look for:
    • Variations in breast size and contour
    • Nipple retraction
    • Any oedema (may be slight)
    • Redness or retraction of the skin
    • Dimpling of the skin (called peau d'orange and is like orange peel because of inflamed tumour under the skin)
    The peau d'orange appearance is of serious significance. The underlying tumour is likely to be aggressive and classified as stage IIIB.
• Systematic palpation of the breast:
  • Breast examination should be thorough and take about 3 minutes each side
  • It can be taught using silicone models¹⁰
  • Examine with the flat of the hand to avoid pinching up tissue
  • Remember that the breast has an axillary tail
  • Examine both breasts
  • Support the patient's arm to palpate axillary nodes and then feel for supraclavicular and cervical nodes
  • If a lump is found note size, consistency, whether is attached to skin or underlying tissue
  • Breast cancer in men:
    • Is rare (especially under 50 years old)
    • Can present as a unilateral mass (subareolar with or without nipple distortion or associated skin changes)
    • Urgent referral is required

  Clinical features of palpable breast masses
  Malignant breast masses:	Benign breast masses:
  Consistency: hard	Consistency: firm or rubbery
  Painless (90%)	Often painful (consistent with benign breast conditions)
  Irregular margins	Regular or smooth margins
  Fixation to skin or chest wall	Mobile and not fixed
  Skin dimpling may occur	Skin dimpling unlikely
  Discharge: bloody, unilateral	Discharge: no blood and bilateral discharge. Green or yellow colour.
  Nipple retraction may be present	No nipple retraction
  Note: there are no reliable features to distinguish cysts from solid masses

• Since 1987 the UK has had the National Health Service Breast Screening Programme (NHSBSP).¹¹
• Mammography is offered to all women aged between 50 and 70 years.¹¹
• Women may make an informed decision not to be included in the NHSBSP. Other reasons to consider ceasing recall include:¹²
  • Patients who have had bilateral mastectomy (for carcinoma).
  • Patients who are terminally ill (unnecessary distress).
• However the following women should not automatically be ceased from recall for the NHSBSP:¹²
  • Women with breast implants (especially those with cosmetic implants who have breast tissue).
  • Women who have had previous breast surgery.
  • Women who are terminally ill.
  • Women with physical or learning disability.
• Women over 70 years can request mammography. Radiation is a risk factor for breast cancer. This consideration together with lower incidence and reduced efficacy in younger women has led to the suggested starting age for screening of 50.
• Mammography is less effective in the dense breast tissue found in younger women.¹³
• It was felt that if appointments were sent to older women reduced attendance rates would undermine the efficiency of the service (although older patients are at greater risk).
• The upper age for screening has been raised from 65 to 70 years. Older women can still request examination. It is possible that this age may be raised to 75 in the future.¹¹
• Mammography fails to detect 11% of invasive breast cancer.¹⁴
• Research from the NHS scheme suggests that thIs programme has lowered mortality rates from breast cancer in the 55 to 69 age group.¹⁵
• The programme has screened 19 million women and detected around 117,000 cancers. The programme should save 1400 lives every year in England. It should reduce mortality by 25% leading up to 2010.¹¹
• Guidelines on the clinical assessment and techniques for accurate diagnosis have been produced.¹⁶ It is important for GPs to be familiar with these guidelines to fully inform patients.
• It is also important to understand the procedures to be followed when results from screening are abnormal.¹⁷

There are broadly 4 categories of women presenting for referral to breast cancer services:

• Women attending the NHSBSP¹¹
• Women with a family history of breast cancer^5,18
• Women with symptoms suggestive of breast cancer¹⁹
• Women requiring treatment for breast cancer

NICE has recently updated guidance on referral.²⁰ The guidance encourages sharing of information with patients and encouraging particularly the over 50s to be 'breast aware'. Guidelines have also been produced on the clinical assessment following screening.¹⁶ Core biopsy techniques are preferred over fine needle aspiration.¹⁶

• In primary care:
  • If carcinoma of breast is suspected time should not be taken with investigations
  • Referral should be prompt²¹
• In secondary care:
  • Note that detecting ductal carcinoma can be difficult
  • Routine bloods including liver function tests
  • Diagnostic mammography:
    • Mammography is superior for less dense breasts (usual after the menopause).
    • A mammogram is almost invariably performed.
    • A combination of ultrasound and mammography can detect more invasive tumours.¹⁴
  • Ultrasound:
    • Ultrasound is very effective (especially in younger women).
    • Ultrasound is particularly useful when breast tissue is dense.
    • In young patients it can be diagnostically more useful than mammography.
  • Chest X ray
  • CT scans if:
    • CXR abnormal
    • Neurological symptoms
    • Hepatosplenomegaly or lymphadenopathy (supraclavicular)
    • Liver function tests abnormal
  • Bone scans if:
    • Distant metastases
    • Bone pain
    • Lymph node metastases
    • Advanced local disease
  • MRI:
    • Tends to be used to elucidate difficult cases (but false positives are high)
    • A positive result on MRI alone should not result in operation²²
  • Positron emission tomography (PET):
    • Can be used to detect distant metastases
    • Can fail to detect low grade lesions and those less than 5mm in diameter
  • Histopathology- scoring systems are used for:
    • Tubular grade (well to poorly differentiated)
    • Nuclear grade (uniform to polymorphism)
    • Mitotic index (low to high)
    • Histological grade- a composite of the above (well to poorly differentiated)
  • Oestrogen receptor (ER) and progesterone receptor (PR)status (usually monoclonal antibody techniques to assay)- implications for management
  • Epidermal growth factors including for example HER2 status (monoclonal antibody techniques)- implications for management
  • Diagnostic procedures:

• Fibroadenoma and other varieties of benign breast disease²³
• Cysts

Ductal carcinoma in situ is a very low grade malignancy. It has been suggested that it should be renamed as ductal intraepithelial neoplasia to emphasis its comparatively benign state. The 5 years survival is around 98%. Women with breast cancer are allocated to one of five clinical staging groups according to extent of disease at presentation. These are often collapsed into three subgroups:

1. Ductal carcinoma in situ (DCIS) or Stage 0 (about 6% of women)
2. Early breast cancer or Stages I and II (about 76% of women)
3. Advanced breast cancer or Stages III and IV (about 18% of women)

Details of the staging is shown in the box below. There is also the TNM staging system.

For many years the standard treatment for breast cancer was radical mastectomy. This mutilating procedure brought nearly as much fear to women as the disease it was designed to treat. Modern treatment depends on many factors including on accurate diagnosis, histopathology, staging and receptor status. Management can be complex and there are new and promising drugs which have caused controversy. The following serves as an outline guide only:

• In a young woman in whom it is suspected that the lesion is a fibroadenoma it is acceptable to ask her to return after her next menstrual period by when the lump should be much smaller or have disappeared. If there is any doubt then referral should be made to obtain a clear diagnosis and for peace of mind of both patient and doctor.
• If a cyst is suspected the area can be infiltrated with local anaesthetic and the cyst aspirated. It should disappear beneath the fingers as the fluid is withdrawn. If the fluid is frankly bloody it should be submitted for cytology. Otherwise that is unnecessary.²⁴
• Ductal carcinoma requires simple mastectomy. This cures about 98% of cases but it is a more destructive procedure than that used for tumours of much worse prognosis.
• The treatment of invasive carcinoma consists of surgery, chemotherapy, hormonal therapy and radiotherapy.
• Surgery is less radical than it was. An wide excision of the lump now usually replaces routine radical mastectomy.
• Dissection of axillary nodes is required to ascertain whether or not they are involved as this is crucial to staging. However sentinel node biopsy may reduce the number of patients requiring axillary lymph node dissection.²⁵
• Adjuvant hormonal therapy is only required if the tumours are positive for hormonal receptors. The commonest form is tamoxifen, given for 5 years but newer selective oestrogen receptor modulators (SERMs) like anastrozole are very promising. Tamoxifen has a pro-oestrogenic effect on the uterus and so increases the risk of carcinoma of endometrium. Newer agents are more specific but much more expensive. NICE guidance is available for anastrazole, exemestane and letrozole in early oestrogen receptor positive breast cancer.²⁶
• Adjuvant chemotherapy is most effective if multiple agents are used. Doxorubicin and cyclophosphamide are the commonest. This is not required in stages I or II if the tumour is under 0.5cm in diameter.
• There is NICE guidance on a number of the drugs used in advanced breast cancer.^27,28,29,30
• Radiotherapy can reduce local recurrence and improve long term survival. It is indicated if the tumour is larger than 5cm, if the margins are positive for disease and if more than 4 nodes are involved.
• Trastuzumab, also known by the trade name Herceptin® is an agent that is effective in the treatment of those types of breast cancer that over-express the HER2 gene. It has been licenced for use in metastatic breast cancer and was recommended by NICE in March 2002. It is used for women for whom anthracycline is inappropriate. It can be used alone or with docetaxel. It is licensed for monotherapy in metastatic breast cancer after 2 other regimes have been tried. Those who have positive oestrogen receptors should also have hormonal manipulation. Trastuzumab is a humanized monoclonal antibody specific for HER-2/neu.³¹The treatment seems to be very well tolerated except when it is combined with doxorubicin when it has considerable cardiotoxicity.³²
• NICE guidance has also now been produced for the use of trastuzumab in early breast cancer.³³ Guidance for use of docetaxel and paclitaxel has also been produced by NICE.^34,35
• In the future breast cancer vaccines may be used alone or in combination with chemotherapeutic agents to target breast cancer.³⁶

• Breast cancer occurs in about 1 pregnancy in 3,000, most frequently between the ages of 32 and 38 years.
• Although breast cancer, especially in the younger woman, may well be hormone dependent, termination of pregnancy is not recommended as it does not seem to improve survival.
• Treatments like radiotherapy and chemotherapy are toxic to the fetus and TOP may be considered depending upon the stage of the disease, the current gestation and the mother's chance of survival.
• It may be possible to defer treatments other than surgery depending upon stage.
• Chemotherapy should not be given in the first trimester but after that it can cause intrauterine growth retardation or premature labour.
• The effectiveness of hormonal manipulation in pregnancy is not yet known.
• If the mother is post-partum then lactation should be stopped. This is required before surgery as lactation makes the breasts large and very vascular. Many chemotherapeutic agents cross into the milk.

• The diagnosis of breast cancer often has profound psychological implications. These can be reduced by adequate counselling, less destructive surgery including nipple preservation and even reconstructive surgery at times.
• Postoperative complications are as for any surgical procedure.
• Chemotherapeutic agents have a range of adverse effects.
• Lymphoedema of the arm is an additional hazard, especially where lymph nodes have been irradiated. Movement of the shoulder may be impaired.

• Of women with operable breast cancer, 70% are alive 5 years on. The risk of recurrence is highest during those 5 years but it can sometimes occur up to 20 years after presentation.
• Node positive disease has a 50 to 60% risk of recurrence within 5 years, compared with 30 to 35% for node negative disease. A large systematic review found that recurrence by 10 years, was 60 to 70% with positive nodes, compared with 25 to 30% for node negative disease.³⁷
• The 5 years survival for stage IIIA is 84% with 71% being disease free. The prognosis for IIIB is much worse and at 5 years only 44% are alive with only 33% disease free.
• The 5 years survival for stage IV (metastatic disease) is extremely low.
• Pregnancy after previous treatment for breast cancer does not seem to have an adverse effect although some people recommend waiting 2 years so that any recurrence is more easily detected.
• Recent figures suggest that the survival rate in those diagnosed with breast cancer is improving markedly. Two thirds are expected to live at least 20 years. In the age group 50 to 79, the commonest cohort for breast cancer, 80% are expected to live for at least 10 years while 72% will survive for at least 20 years.
• These figures may be underestimates for new diagnoses because of the impact of the aromatase inhibitors and trastuzumab.

• Some women will have concerns about the development of breast cancer because of family history.
• For correct management the reader is referred to the relevant NICE and Clinical Knowledge Summaries websites listed below.

There are a few issues which have raised controversy over the years. These may cause confusion and often anxiety in the minds of some patients. It is worth listing some of the common issues:

• Treatment of in situ disease:
  • Mammography has increased the number of patients diagnosed with DCIS (85% of DCIS is detected mammographically).
  • DCIS represents between 20 and 30% of breast cancer detected by mammography.
  • What the very best treatment is for DCIS remains controversial.
• New drugs in the news:
  • In October 2005 a patient threatened to take her PCT to the European Court of Human rights for not funding a breast cancer drug. In fact her disease was very early and this would have been an off license use of the drug.
  • The PCT acceded (like other PCTs before) and the matter came to public attention. Trials of the drug at an earlier stage were said to be favourable but the makers were not expecting to apply for a licence for use at an earlier stage until February 2006, giving them a response probably in June 2006.
  • In October 2005 the Department of Health issued a statement saying that all women newly diagnosed with the disease should have a Fluorescent Insitu Hybridisation (FISH) test for the HER2 receptor so that when the drug is granted a licence it will be possible to know who might benefit.
  • The statement from the DoH said that of the 35,000 women a year diagnosed with the disease, about 20,000 would be suitable for testing and of those about 25% would have the receptor. It is more likely that the receptor will be positive in pre-menopausal women.
  • The cost of treating these 5,000 women would be about £100 million a year but should save 1,000 lives. This represents £100,000 per life saved.
• Licensing of new drugs:
  • This case highlights some issues around the licensing of drugs.
  • New drugs like trastuzumab (the 'wonder drug') have to go through licensing procedures.
  • The time taken for this procedure can cause public outrage.
  • Politicians reflect this and pressure to expedite the system is applied.
  • This may not be in the interest of the public. A drug is granted a licence for a specific condition after adequate data has been submitted about efficacy, adverse effects, interactions with drugs that are likely to be co-administered and possibly teratogenicity.
  • Getting a licence to treat a condition in adults is not easy but getting the data necessary for a licence to treat children is much harder both in terms of getting trials of an unlicensed drug in children and getting data relating to age or weight. Paediatricians often prescribe off licence because of the difficulty in getting a licence.
  • GPs may prescribe off licence rather more often than they think because they are unaware of the limitations of a licence.
  • The Karolinska Institute in Stockholm has criticised NICE for being unable to cope with the demands for licensing and claims that we are behind only the Czech Republic, Hungary and Poland in Europe for using the latest cancer treatments.
  • Being granted a licence does not guarantee against later difficulties as we found recently with rofecoxib. Thalidomide was once thought to be a very safe drug.
  • It is very difficult to get the correct balance between protecting the public from untested drugs and withholding effective treatments.