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Breast cancer: symptoms and treatment

Breast cancer

Breast cancer arises from the lining of the milk ducts or from the lobules that produce milk. The early state of the disease is called ductal carcinoma in situ (or lobular carcinoma in situ) and is a pre-cancerous condition curable by local excision. Two sub-types of breast cancer are commonly recognised; ductal breast cancer which is the commonest form (75% of all cases) arising from the ductal cells and lobular cancer (10% of all cases) arising from the milk duct lobules. Rarer breast cancers include medullary cancer, colloid cancer, papillary cancer, mucinous cancer and cribiform cancer.

 

In addition to the description of the type of breast cancer, the pathologist can also provide a classification of aggressiveness (grade 1 to 3), the presence of hormone receptors and other molecular markers such as the oncogene HER2. 

 

Incidence of breast cancer

Approximately 25,000 women develop breast cancer annually in the UK. Many women still die from this disease each year in spite of increased cure rates over the last two decades. The age specific incidence rises by a factor four as the age rises from 35-70 years and by the age of 80 there is a 1/12 chance for women developing this disease. Male breast cancer counts for less than 1% of cases.

 

Many risk factors have been associated with breast cancer. These include age, race, previous benign breast disease, previous breast cancer diagnoses, lifestyle habits, reproductive factors, family history and genetic factors, exposure to radiation and environmental factors.

 

Breast cancer incidence rates, taken from a large database of American patients, suggests a decline over the last few years which may be linked to discontinuation of hormone replacement therapy.

 

Breast cancer incidence rates are highest in northern Europe and North America but the rates are rising in other countries suggesting a relationship to societal change.

 

Overall, death from breast cancer continues to decline and this is thought to be due to the early detection of breast cancer and the more widely available adjuvant early therapies consisting of surgery, radiotherapy, chemotherapy, hormone therapy and biological treatments.

 

Causes of breast cancer

Many risk factors have been associated with breast cancer. These include age, race, previous benign breast disease, previous breast cancer diagnoses, lifestyle habits, reproductive factors, family history and genetic factors, exposure to radiation and environmental factors.

 

There is now good evidence for the involvement of female sex hormones in the incidence of breast cancer. The risk appears to be related to prolonged cumulative exposure of the milk duct cells to unopposed oestrogens. The rate of cancer rises up to the age of 45 to 50, following which there is a less gradual rise up to the age of 75.

 

There is a striking variation in incidence in different countries across the world which cannot be explained by genetic make-up alone. For example, there is a striking difference between the incidences of breast cancer in the USA (high) versus Japan (low). This correlates with differences in age at the beginning of menstruation and post-menopausal weight, the heavier post-menopausal women having higher serum levels of oestrogen circulating.

 

Benign breast disease can marginally increase the risk for breast cancer. Examples of these conditions include atypical lobular hyperplasia, atypical ductal hyperplasia, fibroadenoma, intra-ductal papillomas.

 

A history of breast cancer in one breast can pre-dispose to development of cancer in the other breast; this can be high for lobular cancer.

 

Lifestyle factors which may influence a patient’s reproductive history can impact on the development of the breast cancer. An early menarche, late first pregnancy, low parity and a late menopause all increase the risk of breast cancer in an individual woman.

 

A positive family history of breast cancer, particularly several first degree relatives developing the disease at an early age suggest the genetic origin, and this may account for perhaps up to 10% of all cases. Specific genetic mutations that pre-dispose to breast cancer include BRCA1, BRCA2, P53, ATM and PTEN.

 

Hormone replacement therapy has recently been the subject of a number of large studies. Long term use of hormone replacement therapy is associated with an increased risk of breast cancer when women were taking a combined preparation for up to five years. This has led to recommendations for more vigilant administration of hormone replacement therapy.

 

Patients previously exposed to ionising radiation such as survivors of the atom bomb or those patients treated for a condition called Hodgkin’s lymphoma are at increased risk of breast cancer. There is no known link between breast cancer and low levels of radiation such as those used in imaging tests unless there is a possible genetic susceptibility to breast cancer.

 

One of the most interesting epidemiological features of breast cancer is the striking variation in incidence in different countries across the world. There is a five fold difference in incidence between the incidence in some western countries and low risk areas of the world (see main figure in the Incidence section). These differences cannot be entirely explained by differences in the genetic make up of the populations. For example, there is a striking difference between the incidences of breast cancer in the USA (high) versus Japan (low). This correlates with the differences in age at menarche and postmenopausal weight (heavier post menopausal women having higher serum levels of oestrogens circulating).

 

Where there is a strong family history in first degree relatives, there are now available tests for the oncogenes that have been found to predispose to this disease. The common ones to be responsible such familial breast cancer are the BRCA-1/ BRCA-2 and the p53 genes and the routine testing for these genes in families with such strong incidences is something for which clinical geneticist counselling is now available.

 

Amongst patients with a strong family history of breast cancer, there have been several studies looking at the chances of a specific gene being at fault: The Breast Cancer Linkage Consortium recently published a study of 237 families with at least four cases of breast cancer within the family. They found that 52% of families were harbouring the BRCA 1 gene, 32% the BRCA 2 gene and 16% were due to some other genetic predisposition. Almost all families with breast and ovarian cancer represented within the family were associated with one of the BRCA genes (81% BRCA 1 and 14% BRCA 2 and only 5% unidentified). In families with one or more cases of male breast cancer (usually only 1% of the overall cases of breast cancer) there was a greater than 75% chance of the predisposing gene being BRCA 2 gene, which also seemed to be more likely to cause very large percentage of the risk (i.e. to be associated with 6 or more family members to be affected).

 

There are dilemmas for patients who undergo such testing: On the one hand the patient will know, if she tests positive, that she falls into a category of patient who is at very high risk of developing a breast cancer or ovarian cancer, or, if she has already had one breast cancer, that she is at an 85% risk of developing another, and the whole issue of bilateral prophylactic/insurance mastectomies (or even prophylactic removal ovaries) then comes into discussion.

 

Next, patients have to consider the issues of having subsequent life insurance premiums loaded against them or mortgages etc – because for sure they will be required to disclose these results in the application forms in the future.

 

Lastly, they have to consider that all these points will apply to their children. The medical discovery of genetic predisposition genes (oncogenes) and the knowledge by patients of their possession within their genetic code and the whole question of testing is a highly controversial and important one in breast cancer, and many other cancers at present.

 

Statistical models based on the above data have been researched to estimate a patient's chance of having the BRCA 1 or 2 mutation based on their family and personal medical histories. Computer modelling estimates probabilities of breast cancer risk and one of these is now available via the internet: www.isds.duke.edu/~gp/brcapro.html. Whilst all such modelling contains flaws (biases due to selection) they give an overall band of risk category for patients which can then be further discussed with clinical geneticists if appropriate.

 

Symptoms of breast cancer

A proportion of women may not have any symptoms of breast cancer but detection is made via mammography. A patient may also note a lump in the breast that would require specialist assessment with appropriate tests to identify the nature of the lump.

 

Advanced cases of breast cancer can present with a larger lump, inversion of the nipple, involvement of the skin or bleeding. There may also be signs of spread of the breast cancer with swelling of the lymph glands under the arm pit or secondary tumours (metastases) that have spread to other sites. These may cause, for example, bone pains due to bone spread, general ill health or signs referable to the organ where the cancer has spread.

 

Treatment of breast cancer

 

Pre Invasive Breast Cancer 

If the result of a diagnostic assessment suggests a pre invasive cancer DCIS or LCIS, then surgery is the curative therapy of choice. A mastectomy (removal of the whole breast) may need to be considered if the mammogram suggests widespread pre invasive cancer changes. Following a mastectomy there is usually no further need for other therapy apart from standard surveillance. Where breast conserving surgery has been involved, post operative radiotherapy to the breast reduces the recurrence rate of DCIS and invasive breast cancer.

 

The use of hormonal therapies is under further evaluation as there is some evidence to suggest it may further reduce the incidence of recurrent DCIS and invasive cancer in the involved and contra lateral breast.

    

Treatment of invasive breast cancer  

Treatment should be ideally discussed between the surgeon and oncologist as it may involve a multi modal approach including surgery, radiotherapy, chemotherapy, hormone therapy and biological treatments. For all patients where the staging has demonstrated localised disease or disease confined to the breast and lymph nodes in the axilla, the commonest approach would be to consider surgery followed by a combination of chemotherapy, radiotherapy, hormone therapy and biological treatments. In certain patients, prior treatment with chemotherapy or hormone therapy may allow a reduction in the size of the tumour so that the surgeon can perform breast conserving surgery. The decision for radiotherapy, chemotherapy, hormone therapy and biological treatments would be based on certain characteristics of the tumour. The oncologist would discuss when a treatment would not be needed if there was no substantial benefit.

 

The initial assessment at the time of a diagnosis of the breast cancer may, in a small proportion of patients, demonstrate spread of the breast cancer beyond the breast and the lymph nodes in the axilla. Treatment for these patients may not be curative and the oncologist and his team looking after the patient would determine which options of therapy summarised above may be best utilised to prevent progression of the cancer.

 

Surgery

Surgery plays a key role in the management of most patients with breast cancer. For all patients treated with curative intent, surgery would involve removing of the breast tumour with breast conservation or removal of the breast (mastectomy). Surgery also plays an important role in the assessment of the lymph nodes in the axilla and removal of lymph nodes as a diagnostic and therapeutic procedure. Surgery would also need to be considered for biopsies of abnormal areas detected on staging and surgery can play a role in palliation e.g. orthopaedic surgery for fixation of a broken limb involved with cancer. The role of surgery in the management of primary breast cancer and axilla is further addressed here.

  

Breast Conserving Surgery

Small primary invasive cancers of the breast may be treated with breast conservation. The operation being called a lumpectomy (a radical mastectomy), quadrantectomy, (wide local excision). This should allow preservation of the breast in a reasonable cosmetic form but excision of the tumour such that there is no evidence of residual cancer under the microscope at the edges of the specimen (microscopic clearance). The surgeon would also need to consider that pre invasive cancer, which can often account for the invasive cancer, is also cleared. In the majority of patients undergoing breast conserving therapy would need consideration of post operative radiotherapy; this is discussed later in the radiotherapy section.

 

Mastectomy

A mastectomy should be considered when the cancer is advanced with involvement of the skin or underlying muscle, where a cosmetic result of residual breast may be unacceptable, and where the tumour may involve the nipple and duct complex, and for specific patients where there may be concerns of compliance with radiotherapy follow up. The surgeons should in be in a position to discuss the possibility of reconstruction either immediately following the mastectomy or at a later date depending on the patient’s wishes and suitability.

 

The surgeon will discuss the type of mastectomy undertaken which may be a simple mastectomy, modified radical mastectomy or radical mastectomy. These procedures involve excising different areas of tissue with the intent of also removing a number of lymph glands from the axilla. A subcutaneous mastectomy may also be an option as it allows maintenance of normal breast tissue and nipple. However, there is some breast tissue which may not be completely removed.

 

Surgical Treatment for the Axilla

Assessment of the lymph nodes by surgery can help guide further treatment. This may be further surgery, radiotherapy or chemotherapy. The surgeon would discuss investigation of the axilla which may involve injecting tracer dyes and removal of a sentinel lymph node. Further surgery would be considered where there is evidence of cancer of the axillary lymph nodes.

 

Radiotherapy

Radiotherapy plays a key role in the management of patients who have undergone breast conserving surgery.

Radiotherapy would also be considered as treatment to lymph nodes where there is a higher risk of recurrence, palliation of breast cancer recurrence, palliation of bone pain and brain metastases. The commonest form of radiotherapy is external beam radiotherapy using mega voltage photons on linear accelerators. There are studies underway to assess radiotherapy directly targeted to the tumour bed (intra operative radiotherapy, mammosite). In selected centres, radiotherapy may be delivered by a technique called brachytherapy.

 

The treating oncologist would advise on the mode of radiotherapy.

 

Chemotherapy

Chemotherapy can provide substantial benefits to patients treated with curative intent. Certain prognostic factors such as a large tumour, a high histological grade, the presence of involved malignant nodes and the results of the receptors would suggest a benefit to different chemotherapy agents. The treating oncologist would advise the patient as to which regime is best suited for their cancer with the resulting benefit of chemotherapy.

 

Chemotherapy can also help in the treatment of patients with metastatic disease and this may be combined with palliative radiotherapy.

 

For patients with tumour profiles that suggest sensitivity to oestrogen and/or progestrogen there is a benefit to considering hormonal therapy. The aim of hormonal therapy is to minimise exposure of a potential cancer cell to oestrogen. The available drugs can achieve this by different mechanisms. These drugs include Tamoxifen, aromatase inhibitors (Anastrazole, Letrozole, Exemestane). In general, a single drug or a combination would be recommended for a minimum period of five years. For post menopausal patients with a high risk of recurrence, there may be an extension to their hormonal therapy beyond five years.

 

The use of the hormonal therapies is also determined by the menopausal status of the patient. For pre menopausal patients Tamoxifen is the standard drug of choice as the aromatase inhibitors are not suitable for patients who are still menstruating. In the post menopausal setting, the aromatase inhibitors can offer a small survival advantage for those patients with higher risk tumours. The treating oncologist would discuss the ideal hormonal therapy with due consideration to both acute and late side effects.

 

Biological Therapies

Breast cancer cells can express a surplus protein called HER2. This protein expression suggests the cancer cells may be more aggressive. The drug Trastuzumab/Herceptin is an antibody aimed at the HER2 receptor in the cancer cells and when added to chemotherapy has improved survival in the earlier stages of disease. Herceptin therapy should be considered in patients who are positive for HER2 expression if chemotherapy is recommended as part of their treatment programme.

 

Herceptin therapy has also demonstrated increased response rate in advanced metastatic disease.

 

Preliminary studies of a drug targeting a vascular growth factor, Bevacizumab (Avastin) have demonstrated increased response rates with a combination of chemotherapy for patients with metastatic disease.

 

Bisphosphonates are a class of drugs that are aimed at stablisation of the bone architecture. Early studies have suggested a reduction of bone metastases for patients with poor prognostic characteristics at the time or their original diagnosis. This class of drugs is the subject of further continued studies for early adjuvant multimodal therapy. Bisphosphonates are regularly used in patients with metastatic bone cancer to reduce symptoms and prevent the progression of bony disease.

 


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