Breast Cancer

Breast cancer is by far the most common cancer in women and the second most common cause of death from cancer. It is also a significant cause of morbidity.

Pathology

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% 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.

Epidemiology

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 afamily history but this may be due to chance, shared environmental or lifestyle risk factors, or increased genetic susceptibility.

The BRCA1, BRCA2 and TP53 mutations carry very high risk but only 3-5% of women are likely to carry them on their chromosomes. The lifetime risk of breast cancer in a BRCA1 carrier is 80-85%, with a 60% chance that the cancer will be bilateral.

Never having borne a child, or first child after age 30. Not having breast-fed (breast-feeding is protective).

Early menarche and late menopause.

Continuous combined HRT increases risk.

Radiation to chest (even quite small doses).

High alcohol intake may increase risk in a dose-related manner.

Breast augmentation is not generally associated with increased risk. Type of implant used may be important.

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.

Presentation

In breast cancer:

Most patients present having felt a lump (20% as a painful lump). 10% of patients present with nipple change.

3% of patients present with nipple discharge.

5% of patients present with skin contour changes.

Breast pain/mastalgia alone is a very uncommon presentation. Intraduct carcinoma may present as a bloody discharge from the nipple.

History

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.

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.

Direct questions should include the following:

When was the lump first noticed?

Has it changed in size or in any other way? This includes a nipple becoming inverted.

Menstrual history. If she is premenopausal, when was her last menstrual period?

Any changes noted through the menstrual cycle?

Family history (including breast cancer, other cancers and other conditions).

Is there any discharge from the nipple? Go through the risk factors listed above.

Investigation

Guidelines on the clinical assessment and techniques for accurate diagnosis have been produced. Investigations should take place in secondary care.

Mammography is superior for less dense breasts (usual after the menopause) and is almost invariably performed. A combination of ultrasound and mammography can detect more invasive tumours.

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.

MRI tends to be used in difficult cases such as dense breast tissue (especially in young women), cases of familial breast cancer associated with BRCA mutations, silicone gel implants, positive axillary lymph node status with occult primary tumour in the breast or where multiple tumour foci are suspected. A positive result on MRI alone should not result in operation.

Diagnostic procedures

A variety are used and it is useful to understand what they are and the indications for the different techniques used when counselling patients:

Non-palpable lesions:

Core needle biopsy (image-guided):

1. The method of choice and should be obtained before any surgery.
2. Ultrasound or stereotactic mammographic guidance can be used.
3. Open biopsy (needle localisation):
4. Radio-opaque needles used to guide biopsy.
5. It can usually be done under local anaesthetic.
6. There are fewer false negatives.

Palpable lesions:

Fine-needle aspiration (FNA):

1. High accuracy combined with mammography.
2. Negative results do not exclude carcinoma.
3. Good for T3 and T4 tumours (and recurrences).
4. False negatives are high (especially if the lesion is small <1 cm).
5. False positives are very low (used to plan surgery but frozen sections at surgery are needed to determine whether invasive or not).
6. Some adopt triple negative (clinically benign, negative mammogram and FNA) policy as sufficient to exclude carcinoma

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.

Staging investigations

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).

1. CA 15-3 tumour marker may be measured and is useful as a marker for prognosis but not as a screening or detection tool.
2. Routine blood tests including LFTs. CXR.
3. CT scans if metastases are suspected:
4. CXR abnormal.
5. Neurological symptoms.
6. Hepatosplenomegaly or lymphadenopathy (supraclavicular). LFTs abnormal.
7. Bone scintigraphy if:
8. Distant metastases.
9. Bone pain.
10. Lymph node metastases.
11. Advanced local disease.
12. Positron emission tomography (PET):
13. Can be used to detect distant metastases.
14. Can fail to detect low-grade lesions and those less than 5 mm in diameter.

Differential diagnosis

Fibroadenoma and other varieties of benign breast disease

Cysts.

Staging

Stage 0 is carcinoma in situ and is not invasive.

Stage I has a tumour up to 2 cms in diameter and no lymph node involvement or metastasis.

Stage II has a tumour between 2 and 5 cms in diameter or there is spread to the axillary lymph nodes on the same side and the nodes are not adherent.

Stage IIIA is when the tumour is over 5 cms in diameter or the nodes are adherent.

Stage IIIB is invasive breast cancer in which a tumour of any size has spread to the breast skin, chest wall or internal mammary lymph nodes and includes inflammatory breast cancer with peau d’orange.

Stage IV is spread beyond the breast, axilla and internal mammary nodes. It may have spread to supraclavicular nodes, bone, liver, lung or brain.

Management

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.

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.

Whole breast radiotherapy is recommended after conservative surgery. It reduces the risk of local recurrence by 66% and an additional boost gives a further 50% risk reduction. Radiotherapy also has a beneficial effect on survival.

Post-mastectomy radiotherapy is always 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, given for five years; however, newer selective oestrogen receptor modulators (SERMs) or aromatase inhibitor hormone antagonists, 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 recommended for patients with endocrine unresponsive tumours and for patients with HER2 over-expressing tumours.

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 is a humanised monoclonal antibody specific for HER-2/neu. It lowers the risk of recurrence by about 25-50% and the risk of death by about 17- 33%.

It can be used alone or with a taxane. It is very well tolerated but is cardiotoxic if combined with doxorubicin.

In the future, breast cancer vaccines may be used alone or in combination with chemotherapeutic agents to target breast cancer.

Advanced breast cancer

Diagnosis and assessment:

PET fused with computed tomography (PET-CT) should only be used to make a new diagnosis of metastases when imaging is suspicious but not diagnostic of metastatic disease.

Assess ER and HER2 status at the time of disease recurrence (if receptor status was not assessed at the time of initial diagnosis). If necessary, biopsy metastasis.

Systemic disease-modifying therapy:

Offer endocrine therapy as first-line treatment for the majority of patients with ER-positive advanced breast cancer.

If not suitable for anthracyclines (because they are contra-indicated or because of prior anthracycline treatment either in the adjuvant or 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 (whichever was not used as second-line treatment).

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. Do not discontinue trastuzumab if disease progression is within the central nervous system alone.

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.

Complications

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.

Follow-up

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. 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.

Prognosis

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.

Prevention

Some women will have concerns about the development of breast cancer because of family history. Consider modification of risk factors, particularly in high-risk patients