Breast Cancer

Breast cancer is the most common cancer in women and the second 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
• 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 most common cancer in women, with about 45,000 new cases in the UK each year.¹ It represents almost 1 in 3 of all malignancies in women.
• 1 in 9 women in England and Wales will develop breast cancer during their lifetime.¹
• The incidence of breast cancer has been increasing for many years in developed countries. In Britain the age-standardised incidence of breast cancer per 100,000 women increased from 75 in 1977 to 122 in 2006.¹
• In 2005, deaths from breast cancer in England and Wales were 11,040 women and 81 men.² The number of years of life lost in women under 65 is higher for breast cancer than for coronary heart disease.
• 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.
• Breast cancer can occur in men, usually in men aged over 50 years.

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.⁷Guidance for familial breast cancer is now available.⁵
• If there is a personal history of breast cancer there is an increased risk of another primary tumour.
• Men with Klinefelter's 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 neither 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. Since 1988 the UK has had the National Health Service Breast Screening Programme (NHSBSP). Patients 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 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 patients (usually elderly, but not always) will present with a fungating mass that has obviously been neglected for a long time.
• 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

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

• Women attending the NHSBSP
• Women with a family history of breast cancer⁵
• Women with symptoms suggestive of breast cancer¹⁰
• Women requiring treatment for breast cancer

Referral guidance is available and should be carefully followed.¹¹ See separate article Breast Lumps and Breast Examination. 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.¹² Core biopsy techniques are preferred over fine needle aspiration.¹² There is a good case for consulting with local breast cancer services when seeking guidance on referral.

Guidelines on the clinical assessment and techniques for accurate diagnosis have been produced.¹²
It is important to understand the procedures that may be used to establish accurate diagnosis and staging of breast cancer.¹³

• In primary care:
  • If carcinoma of breast is suspected, time should not be taken with investigations
  • Referral should be prompt (according to guidance above)¹⁴
• 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.¹⁵
  • 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 operation¹⁶
  • Positron emission tomography (PET):
    • Can be used to detect distant metastases
    • Can fail to detect low-grade lesions and those less than 5 mm 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) - the result has major implications for management (see below)
  • Epidermal growth factors including, for example, human epidermal growth factor receptor 2 (HER2) status (monoclonal antibody techniques )- the result has major implications for management (see below)
  • CA 15-3 tumour marker may be measured and is useful as a marker for prognosis but not as a screening or detection tool.¹⁷
  • Diagnostic procedures:

• Fibroadenoma and other varieties of benign breast disease¹⁸
• Cysts

Ductal carcinoma in situ (DCIS) is a very low-grade malignancy. It has been suggested that it should be renamed as ductal intraepithelial neoplasia to emphasise its comparatively benign state. The 5-year survival rate is around 98%. Women with breast cancer are allocated to 1 of 5 clinical staging groups according to extent of disease at presentation. These are often collapsed into three subgroups:

1. Ductal carcinoma in situ 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 are shown in the box below. There is also the TNM staging system.

Treatment should be patient-centred, taking into account patients' individual needs and preferences. Good communication is essential, supported by evidence-based information, to allow patients to reach informed decisions about their care. Discussion and involvement of patients' families should, with their consent, be facilitated.¹⁹

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 accurate diagnosis, histopathology, staging and receptor status. Over recent years there have been important developments in the investigation and management of breast cancer, including new chemotherapies and biological and hormonal agents.^19,20 It can seem daunting and complex.

The following serves as an outline guide to be considered in conjunction with the boxed priorities below:

• 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.²¹
• Adjuvant hormonal therapy is only required if the tumours are positive for hormonal receptors. The most common form is tamoxifen, given for 5 years; however, newer selective oestrogen receptor modulators (SERMs), like anastrozole, are now used. 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.
• Adjuvant chemotherapy is most effective if multiple agents are used. Doxorubicin and cyclophosphamide are the most common. This is not required in Stages I or II if the tumour is under 0.5 cm in diameter.
• Radiotherapy can reduce local recurrence and improve long-term survival. It is indicated if the tumour is larger than 5 cm, if the margins are positive for disease and if more than 4 nodes are involved.
• Trastuzumab, also known by the trade name Herceptin®, 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 two other regimes have been tried. Those who have positive oestrogen receptors should also have hormonal manipulation. Trastuzumab is a humanised monoclonal antibody specific for HER-2/neu.²²The treatment seems to be very well tolerated except when it is combined with doxorubicin when it has considerable cardiotoxicity.²³
• In the future breast cancer vaccines may be used alone or in combination with chemotherapeutic agents to target breast cancer.²⁴

Early breast cancer

Early breast cancer is subdivided into:

• In situ ductal disease
• Invasive cancer

Advanced breast cancer

• 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 (TOP) 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 postpartum 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.

• After adjuvant treatment (including chemotherapy and/or radiotherapy, where indicated) is completed, discuss with patients where they would like follow-up to be undertaken. They may choose primary, secondary or shared care.¹⁹
• Patients should follow an agreed care plan written with the patient by a healthcare professional. Copies should be sent to the GP and held by the patient. It should include:
  • Designated named healthcare professionals
  • Dates for review of any adjuvant therapy
  • Details of surveillance mammography
  • Contact details for immediate referral to specialist care
  • Contact details for support services; for example, support for patients with lymphoedema

• 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.²⁵
• The 5-year survival rate 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-year survival rate 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 most common 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.
• See separate article Breast Cancer Screening.
• Consider modification of risk factors particularly in high-risk patients.
• For correct management the reader is referred to the relevant NICE and Clinical Knowledge Summaries websites listed below.

1. UK Breast Cancer Incidence Statistics - Cancer Research UK
2. Mortality Statistics - Review of the Registrar General on deaths by cause, sex and age, in England and Wales, 2005 (National Statistics Office)
3. Breast Cancer at a Glance - Cancer Research UK (2007)
4. Pasche B; Role of transforming growth factor beta in cancer. J Cell Physiol. 2001 Feb;186(2):153-68. [abstract]
5. Familial breast cancer, NICE Clinical Guideline (October 2006); the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care
6. Dumitrescu RG, Shields PG; The etiology of alcohol-induced breast cancer.; Alcohol. 2005 Apr;35(3):213-25. [abstract]
7. No authors listed; Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease.; Lancet. 2001 Oct 27;358(9291):1389-99. [abstract]
8. Weiss JR, Moysich KB, Swede H; Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):20-6. [abstract]
9. Friis S, Holmich LR, McLaughlin JK, et al; Cancer risk among Danish women with cosmetic breast implants.; Int J Cancer. 2006 Feb 15;118(4):998-1003. [abstract]
10. Surgical guidelines for the management of breast cancer, British Association of Surgical Oncology (January 2009)
11. NICE/National Collaborating Centre for Primary Care; Referral Guidelines for Suspected Cancer in Adults and Children, June 2006.; See page 65 for breast cancer
12. Clinical Guidelines for Breast Cancer Screening Assessment, NHS Breast Cancer Screening Publications (2005)
13. The Right Results: Guide to the Correct Processing and Issuing of Results, NHS Breast Cancer Screening Publications (2003)
14. Improving outcomes in breast cancer, NICE Clinical Guideline (2002)
15. Benson SR, Blue J, Judd K, et al; Ultrasound is now better than mammography for the detection of invasive breast cancer. Am J Surg. 2004 Oct;188(4):381-5. [abstract]
16. Veronesi U, Boyle P, Goldhirsch A, et al; Breast cancer. Lancet. 2005 May 14-20;365(9472):1727-41. [abstract]
17. Duffy MJ, Duggan C, Keane R, et al; High preoperative CA 15-3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: study of 600 patients with histologically confirmed breast cancer. Clin Chem. 2004 Mar;50(3):559-63. Epub 2004 Jan 15. [abstract]
18. Vaidyanathan L, Barnard K, Elniki DM Benign breast disease: When to treat, when to reassure, when to refer. Review. Cleveland Clinic Journal of Medicine, May 2002
19. Early and locally advanced breast cancer, NICE Clinical Guideline (February 2009); Early and locally advanced breast cancer: diagnosis and treatment
20. Advanced breast cancer, NICE Clinical Guideline (February 2009); Advanced breast cancer: diagnosis and treatment
21. Intra M, Rotmensz N, Mattar D, et al; Unnecessary axillary node dissections in the sentinel lymph node era. Eur J Cancer. 2007 Oct 9;. [abstract]
22. Emens LA; Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer. Am J Ther. 2005 May-Jun;12(3):243-53. [abstract]
23. Willems A, Gauger K, Henrichs C, et al; Antibody therapy for breast cancer. Anticancer Res. 2005 May-Jun;25(3A):1483-9. [abstract]
24. Emens LA; Towards a therapeutic breast cancer vaccine: the next steps. Expert Rev Vaccines. 2005 Dec;4(6):831-41. [abstract]
25. Carter CL, Allen C, Henson DE; Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989 Jan 1;63(1):181-7. [abstract]

• Department of Health; The Health of the Nation - a policy assessed
• Breast cancer - managing family history, Clinical Knowledge Summaries (November 2009)
• NHS Breast Cancer Screening Programme
• Breast cancer - suspected, Clinical Knowledge Summaries (2005)
• Improving outcomes in breast cancer, NICE Clinical Guideline (2002)
• Management of breast cancer in women, SIGN (2005)
• Cancer UK.
• Breast Cancer at a Glance - Cancer Research UK (2007)