Breast cancer is by far 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. 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 a small minority of 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.
- In 2012, the estimated age-adjusted annual incidence of breast cancer in 40 European countries was 94.2/100,000 and the mortality 23.1/100,000.
- The incidence increased after the introduction of mammography screening and continues to grow with the ageing of the population.
- There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35.
- Approximately 4-6% of breast cancers are metastatic at diagnosis.
- In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups, because of improved treatment and earlier detection. However, breast cancer is still the leading cause of cancer-related deaths in European women.
- Breast cancer in males is rare, contributing to about 1% of cases. The major risk factors for men include clinical disorders carrying hormonal imbalances (especially gynaecomastia and cirrhosis), radiation exposure and a positive family history and genetic predisposition.
Risk factors for malignancy
- Previous history of breast cancer.
- Risk increases with age; ≤5% of cases present before age 35, ≤25% before 50 years.
- Family history of breast cancer in a first-degree relative. Between 6% and 19% of women will have a family history but this may be due to chance, shared environmental or lifestyle risk factors, or increased genetic susceptibility.
- Genetic factors:
- The BRCA1, BRCA2 and TP53 mutations carry very high risk but only about 5% of all breast cancers are largely attributable to inherited mutations in specific genes.
- BRCA1 mutation on chromosome 17: lifetime risk of breast cancer for women with this mutation is 65-85%, and the lifetime risk of ovarian cancer is 40-50%; men with this mutation may also be at increased risk of breast cancer.
- BRCA2 mutation on chromosome 13: for women with this mutation, the lifetime risk of breast cancer is 40-85%, and the lifetime risk of ovarian cancer is 10-25%; for men with this mutation, the lifetime risk of breast cancer is 6%.
- Never having borne a child, or first child after age 30.
- Not having breast-fed (breast-feeding is protective).
- Early menarche and late menopause.
- Radiation to chest (even quite small doses).
- The Western-style diet, obesity and the consumption of alcohol also contribute to the rising incidence of breast cancer.
- Hormone replacement therapy (HRT):
- HRT with oestrogen alone is associated with little or no change in the risk of breast cancer.
- HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer.
- Any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT.
- Combined oral contraception:
- There is a small increase in the risk of having breast cancer diagnosed in women taking the combined oral contraceptive pill.
- However, this relative risk may be due to an earlier diagnosis and the cancers are more likely to be localised to the breast.
- The most important factor for diagnosing breast cancer appears to be the age at which the contraceptive is stopped rather than the duration of use.
- Any increase in the rate of diagnosis diminishes gradually during the 10 years after stopping and disappears by 10 years.
- Breast augmentation is not generally associated with increased risk. Type of implant used may be important.
Most patients present having felt a lump, which is most often painless but may be associated with pain. Other presenting symptoms include nipple change, nipple discharge and skin contour changes. Breast pain/mastalgia alone is a very uncommon presentation. Intraduct carcinoma may present as a bloody discharge from the nipple.
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. See also the separate Breast Cancer Screening article.
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 painless lump in the breast. 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, the 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 still present with a fungating mass that has obviously been neglected for a long time.
See separate Breast Lumps and Breast Examination article.
Referral guidance is available and should be carefully followed. The National Institute for Health and Care Excellence (NICE) guidance for specialist referral states:
- Refer people, using a suspected cancer pathway referral (for an appointment within 2 weeks), for breast cancer if they are aged 30 and over and have an unexplained breast lump with or without pain, or are aged 50 and over with any of the following symptoms in one nipple only: discharge, retraction or any other changes of concern.
- Consider a suspected cancer pathway referral in people with skin changes that suggest breast cancer, or for those aged 30 and over with an unexplained lump in the axilla.
- Consider non-urgent referral in people aged under 30 with an unexplained breast lump with or without pain.
Management of women at high risk of breast cancer
The risk of breast cancer is multifactorial but some women will have a high risk because of a genetic predisposition or, rarely, as a consequence of radiotherapy at a young age. Women with a family history suggestive of a genetic predisposition to cancer should be referred to local genetics services for formal assessment. See also the separate Familial Breast Cancer article.
Guidelines on the clinical assessment and techniques for accurate diagnosis have been produced. Investigations should take place in secondary care.
Imaging includes bilateral mammography and ultrasound of the breast and regional lymph nodes.
An MRI of the breast is not routinely recommended but should be considered in cases of familial breast cancer associated with BRCA mutations, breast implants, lobular cancers, suspicion of multifocality/multicentricity (particularly in lobular breast cancer) or large discrepancies between conventional imaging and clinical examination, and before and
during neoadjuvant chemotherapy.
Ultrasound is very effective (especially in younger women). It is particularly useful when breast tissue is dense. In young patients it can be diagnostically more useful than mammography.
Various procedures are used and it is useful to understand what they are and the indications for the different techniques used when counselling patients:
- Core needle biopsy (image-guided):
- The method of choice and should be obtained before any surgery.
- Ultrasound or stereotactic mammographic guidance can be used.
- Open biopsy (needle localisation):
- Radio-opaque needles used to guide biopsy.
- It can usually be done under local anaesthetic.
- There are fewer false negatives.
- Fine-needle aspiration (FNA):
- High accuracy combined with mammography.
- Negative results do not exclude carcinoma.
- False negatives are high (especially if the lesion is small).
- False positives are very low.
- Core needle biopsy:
- Generally used for larger lesions.
- Gives pathological result (can include even oestrogen receptor (ER) status).
- Excision biopsy (entire lesion removed):
- Can be done under local anaesthesia.
- Margins should be inked after removal.
- Incisional biopsy (part of lesion removed):
- For lesions 4 cms or larger.
Minimal surgery, rather than lymph node clearance, should be performed to stage the axilla for patients with early invasive breast cancer and no evidence of lymph node involvement on ultrasound or a negative ultrasound-guided needle biopsy. Sentinel lymph node biopsy is the preferred technique.
- 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).
- The prognostic significance of pre-operative carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels in breast cancer is controversial.
- Routine blood tests including LFTs.
- CT scans if metastases are suspected:
- CXR abnormal.
- Neurological symptoms.
- Hepatosplenomegaly or lymphadenopathy (supraclavicular).
- LFTs abnormal.
- Bone scintigraphy if:
- Distant metastases.
- Bone pain.
- Lymph node metastases.
- Advanced local disease.
- 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.
The differential diagnosis includes fibroadenoma and other varieties of benign breast disease, including breast cysts. See also the separate Breast Lumps and Breast Examination and Benign Breast Disease articles.
Staging is based on the T (primary tumour) N (regional lymph nodes) M (presence of metastases) classification.
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. There are online tools which can help health professionals and patients with cancer discuss the risks and benefits of additional therapy (adjuvant therapy: usually chemotherapy, hormone therapy, or both) after surgery.
Multidisciplinary treatment planning involving at least a breast surgeon, radiologist, pathologist and medical and radiation oncologists should be used to integrate local and systemic therapies and their sequence.
The following serves as an outline guide:
- The treatment modalities available include surgery, chemotherapy, hormonal therapy and radiotherapy.
- In western Europe approximately 66% of newly diagnosed cancers are amenable to breast conservation (wide local excision and radiotherapy) but, for the rest, mastectomy is still recommended because of tumour size ≥4 cm diameter, or because the tumour is multifocal.
- When a woman has had wide local excision, greater emphasis is now placed on achieving an acceptable cosmetic result. Breast surgeons are trained to reduce the local volume deficit by using adjacent tissue flaps.
- When a mastectomy has been necessary, breast reconstruction should be available. Immediate reconstruction may make the thought of losing a breast easier for some women but not all are suitable for immediate reconstruction. When radiation therapy is planned, some women will be advised against immediate reconstruction. Radiation may delay wound healing.
- Prophylactic bilateral mastectomy may be offered to women who are at very high risk such as BRCA1 or BRCA2 carriers.
- Regional lymph node status is a strong predictor of long-term prognosis. Sentinel lymph node biopsy (rather than full nodal clearance) is now accepted as the standard of care for axillary staging in early breast cancer, unless axillary node involvement is suspected clinically or on ultrasound.
- Whole breast radiotherapy is recommended after conservative surgery. It reduces the risk of local recurrence and also has a beneficial effect on survival.
- Post-mastectomy radiotherapy is recommended for patients with four or more positive axillary nodes and is also indicated for patients with T3-T4 tumours (independent of the nodal status).
- Adjuvant hormonal therapy is only required if the tumours are positive for hormonal receptors. The most common form is tamoxifen; newer selective oestrogen receptor modulators (SERMs) or aromatase inhibitor hormone antagonists, like anastrozole, are also 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 recommended for patients with endocrine unresponsive tumours and for patients with HER2 over-expressing tumours.
Ductal carcinoma in situ (intraepithelial neoplasia) can be treated with conservation surgery, if clear resection margins can be achieved. There is no accepted consensus on an adequate margin but margins ≤2 mm are considered inadequate. Adjuvant whole breast irradiation afterwards reduces the risk of local recurrence but has no effect on survival.
Inflammatory breast cancer presents with erythema and oedema of the breast, with or without an underlying mass. This type of cancer is less likely to be oestrogen receptor positive and more likely to be HER2 positive than non-inflammatory breast cancers. Optimal treatment is usually pre-operative chemotherapy, followed by surgery or radiotherapy (or both).
Clinical Editor's note
June 2018 - Dr Hayley Willacy draws your attention to the recently published trial in the New England Journal of Medicine showing that chemotherapy may be avoided in about 70% of women with hormone receptor-positive tumours (HER2-negative). The Oncotype DX test is able to determine how active a tumour is by looking at 21 genetic markers in biopsied tumour cells. It then gives a score from 1 to 100 for risk of metastasis or recurrence. Treatment decisions are clear for women whose score is lowest (10 or below) or who score 26 or above. However, the majority of women fall between these two points where the benefits of chemotherapy have been uncertain and treatment decisions are more difficult. The latest findings come from a trial of 10,273 women. Of these, 6,711 fell between the high and low risk recurrence scores and they were randomly assigned to receive either hormone therapy or hormone therapy and chemotherapy as part of the Trial Assigning Individualised Options for Treatment (TailorX). The authors conclude that chemotherapy can be spared in:
- All women older than 50 years with hormone receptor-positive and HER2-negative breast cancer with a recurrence score up to 25 - about 85% of women in this age group.
- All women younger than 50 with a recurrence score of 0 to 15 - about 40% of the women in this age group.
Breast cancer surgery
Two well-established surgical procedures for the local treatment of invasive or in situ breast cancer for disease in the breast itself are:
- Conservation surgery, which involves removal of the tumour together with a rim of surrounding normal breast tissue with retention of the breast.
- Mastectomy, involving removal of the whole breast.
All patients with invasive breast cancer should have surgical management of the axilla.
Hormone treatment in the first five years
- The aim of adjuvant therapy is to increase the chance of cure by eradicating micrometastatic disease.
- About 80% of breast cancers are oestrogen receptor positive. For these cancers, five years of adjuvant tamoxifen, a selective oestrogen receptor modulator, reduces the relative risk of relapse by 41% and death from breast cancer by 31%.
- Tamoxifen remains the standard of care for premenopausal women. For postmenopausal women, aromatase inhibitors have been shown to be superior to tamoxifen.
- Aromatase inhibitors act predominantly by blocking the conversion of androgens to oestrogens in the peripheral tissues. They should not be used in premenopausal women. Anastrozole and letrozole are non-steroidal aromatase inhibitors. Exemestane is a steroidal aromatase inhibitor. Aromatase inhibitors are usually prescribed as initial adjuvant therapy in postmenopausal women with oestrogen-receptor-positive tumours.
- Premenopausal women with oestrogen-receptor-positive breast cancer who decline chemotherapy may benefit from treatment with goserelin or ovarian ablation.
Adjuvant hormonal therapy extended beyond five years
- In oestrogen-receptor-positive breast cancer, as many recurrences occur after five years' follow-up as in the first five years.
- For women who complete five years of tamoxifen and are postmenopausal, there is a 42% relative risk reduction with a further five years of the non-steroidal aromatase inhibitor letrozole.
- For women who remain premenopausal after five years of tamoxifen, or who are intolerant of aromatase inhibitors, evidence suggests benefit of continuing tamoxifen beyond five years.
- Continued adjuvant endocrine therapy for 10 years has become a standard option, especially for women who originally had node-positive breast cancer.
- Cytotoxic chemotherapy is indicated for advanced steroid hormone-receptor-negative tumours and for aggressive disease, particularly when metastases involve visceral sites (eg, the liver) or if the disease-free interval following treatment for early breast cancer is short.
- An anthracycline (such as doxorubicin or epirubicin) combined with fluorouracil and cyclophosphamide, and sometimes also with methotrexate, is effective.
- For metastatic disease, the choice of chemotherapy regimen will depend on whether the patient has previously received adjuvant treatment and the presence of any comorbidity.
- For women who have not previously received chemotherapy, an anthracycline alone or in combination with another cytotoxic drug is the standard initial therapy for metastatic breast disease.
- Combination adjuvant chemotherapy reduces the relative risk of death from breast cancer by about a third, with the absolute risk reduction depending on the risk of relapse.
- However, in many patients who receive adjuvant chemotherapy, the improvement in survival is small, because their chance of being cured by surgery and hormone therapy alone is high.
- Selection of which patients actually need chemotherapy is a major area of research.
- About 15% of breast cancers have amplification of the HER2 gene and these cancers have an intrinsically worse prognosis than other cancers.
- Trastuzumab is a monoclonal antibody against the extracellular domain of the HER2 receptor and given every three weeks for a year, improves disease-free survival and overall survival
- A recent meta-analysis found that treatment with bisphosphonates is associated with a reduced risk of recurrence of breast cancer in postmenopausal women only.
- Currently, this evidence has not translated into routine use of bisphosphonates solely for this purpose.
Neoadjuvant therapy and locally advanced breast cancer
- Patients with large tumours currently not suitable for conservative surgery can be treated with pre-operative chemotherapy, HER2 targeted therapy, or endocrine therapy to downstage the tumour and to facilitate breast-conserving surgery.
- Neoadjuvant therapy in this setting also provides the opportunity to assess sensitivity to systemic therapy by monitoring response during neoadjuvant treatment before surgical excision.
- Patients who achieve a complete pathological response to chemotherapy, especially those with oestrogen-receptor-negative breast cancer, have a good prognosis.
Advanced breast cancer
Advanced breast cancer is a treatable but still generally incurable disease. The goals of care are to optimise both length and quality of life.
Diagnosis and assessment
- The presence and extent of visceral metastases should be assessed using a combination of plain radiography, ultrasound, CT and MRI.
- The presence and extent of metastases in the bones of the axial skeleton should be assessed using bone windows on a CT scan or MRI or bone scintigraphy. Proximal limb bones should be assessed for the risk of pathological fracture in patients with evidence of bone metastases elsewhere, using bone scintigraphy and/or plain radiography.
- MRI should be used to assess bony metastases if other imaging is equivocal for metastatic disease or if more information is needed (eg, if there are lytic metastases encroaching on the spinal canal).
- Positron emission tomography fused with computed tomography (PET-CT) should only be used to make a new diagnosis of metastases for patients with breast cancer whose imaging is suspicious but not diagnostic of metastatic disease.
- Oestrogen receptor and HER2 status should be assessed at the time of disease recurrence if receptor status was not assessed at the time of initial diagnosis. Biopsy of a metastasis may be used to assess ER and HER2 status in the absence of tumour tissue from the primary tumour.
Systemic disease-modifying therapy
- Endocrine therapy should be offered as first-line treatment for the majority of patients with ER-positive advanced breast cancer.
- For patients with advanced breast cancer who are not suitable for anthracyclines (because they are contra-indicated or because of prior anthracycline treatment either in the adjuvant or the metastatic setting), systemic chemotherapy should be offered in the following sequence:
- First-line: single-agent docetaxel.
- Second-line: single-agent vinorelbine or capecitabine.
- Third-line: single-agent capecitabine or vinorelbine.
- For patients who are receiving treatment with trastuzumab for advanced breast cancer, discontinue treatment with trastuzumab at the time of disease progression outside the central nervous system but not if disease progression is within the central nervous system alone.
- Bisphosphonates should be offered to patients newly diagnosed with bone metastases, to prevent skeletal-related events and reduce pain.
- External beam radiotherapy in a single fraction of 8 Gy should be used to treat patients with bone metastases and pain.
- Surgery followed by whole brain radiotherapy should be offered to patients who have a single or small number of potentially resectable brain metastases, a good performance status and no or well-controlled other metastatic disease.
Breast cancer in pregnancy
- Breast cancer occurs in about 1 pregnancy in 3,000-3,500 - most frequently between the ages of 33-34 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 mother's preference, 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 restriction 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.
Post-mastectomy breast reconstruction
- Breast reconstruction restores breast symmetry after a mastectomy by creating a breast mound, similar in size, shape, contour, and 'out of bra position' to the contralateral breast. Post-mastectomy breast reconstruction is associated with improved body image, quality of life, self-confidence and well-being.
- Breast reconstruction should be discussed with all women who undergo mastectomy.
- Breast reconstruction using lipomodelling after breast cancer treatment should
only be carried out by surgeons with specialist expertise and training in the
- Breast reconstruction can be performed at the time of mastectomy (immediate/primary) or at any later date (delayed/secondary). Patients who are uncertain about reconstruction are best advised to consider delayed reconstruction.
- The main advantage of immediate reconstruction is preservation of the native breast skin envelope and inframammary fold, which enables a more natural and symmetrical outcome. However, immediate reconstruction can delay adjuvant therapy if postoperative complications arise.
- Delayed reconstruction is best for patients who want to focus on the cancer treatment or need more time to consider the various breast reconstruction options. Delayed breast reconstruction is technically more challenging because the native skin envelope is removed at the time of standard mastectomy. Extra skin must therefore be recruited from skin expansion or from a donor site. This can result in a less natural and symmetrical appearance and longer scars.
- 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.
- 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.
Despite the increasing incidence of breast cancer, death rates are falling owing to earlier diagnosis, better surgical and radiotherapy techniques and improved systemic therapies.
The prognosis of patients with breast cancer depends on biological characteristics of the cancer and the patient and on appropriate therapy. Clinical parameters can be used in scoring systems that can give a relatively accurate estimation of the probability of recurrence or death from breast cancer.
- The annual hazard of recurrence peaks in the second year after diagnosis but remains at 2-5% for years 5-20 thereafter.
- Patients with node-positive disease tend to have higher annual hazards of recurrence than patients with node-negative cancers.
- The risk of recurrence is higher in patients with oestrogen-receptor-negative cancers but the annual risk of recurrence drops below the level of oestrogen-receptor-positive tumours approximately 5-8 years after diagnosis.
- Relapses of breast cancer have been observed as late as ≥20 years after the initial diagnosis.
Further reading and references
; NICE Guideline (July 2018)
; ESMO (2015)
; European Society for Medical Oncology (2011)
; NICE CKS, December 2013 (UK access only)
; NICE Guidelines (Nov 2015)
; NICE Evidence Services (UK access only)
; Canadian breast implant cohort: Extended follow-up of cancer incidence. Int J Cancer. 2012 Apr 19. doi: 10.1002/ijc.27603.
; NICE Clinical Guideline (2015) (Last updated July 2017)
; Management of women at high risk of breast cancer. BMJ. 2014 Apr 28348:g2756. doi: 10.1136/bmj.g2756.
; Triple-negative breast cancer: adjuvant therapeutic options. Chemother Res Pract. 20112011:696208. Epub 2011 Jun 21.
; Serum levels of CEA and CA15-3 in different molecular subtypes and prognostic value in Chinese breast cancer. Breast. 2014 Feb23(1):88-93. doi: 10.1016/j.breast.2013.11.003. Epub 2013 Dec 2.
; Clinician's guide to imaging and pathologic findings in benign breast disease. Mayo Clin Proc. 2010 Mar85(3):274-9.
; Chemotherapy for breast cancer in pregnancy: evidence and guidance for oncologists. Ther Adv Med Oncol. 2011 Mar3(2):73-83.
; An update on the medical management of breast cancer. BMJ. 2014 Jun 9348:g3608. doi: 10.1136/bmj.g3608.
; Sparano JA et al, New England Journal of Medicine (June 2018)
; Scottish Intercollegiate Guidelines Network - SIGN (Sept 2013)
; NICE Clinical Guideline (July 2014, updated Aug 2017)
; European Society for Medical Oncology (2014)
; Post-mastectomy breast reconstruction. BMJ. 2013 Oct 15347:f5903. doi: 10.1136/bmj.f5903.
; NICE Interventional Procedure Guidance, January 2012
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