Breast cancer is a cancerous tumour of the breast. It is the most common type of cancer in nonsmoking women and the second most common type, after lung cancer, in women who smoke. One woman in every 12 who live to old age will develop breast cancer at some point in her life. Breast cancer can also rarely develop in men.The advancement of techniques for early diagnosis and treatment of breast cancer has improved overall survival rates.
Current theories regarding the causes of breast cancer are focused on hormonal and genetic influences. However, the principal risk factor is age, with a woman’s chances of developing the dis- ease doubling every ten years of her life. The incidence of breast cancer is known to be raised in women whose menstrual periods began at an early age and in those whose menopause was late to commence. The risk is also higher in women who did not have children or those who had their first child late in life. Women whose mothers or sisters have had breast cancer are also at an increased risk.
Diet may also play a part; breast cancer is more common in countries in which the typical diet contains a lot of fat. Studies have shown that hormone replacement therapy (HRT) slightly increases the chances of developing breast cancer; the risk increases with the length of time that HRT has been taken.
Breast cancer in women under the age of 50 may be linked to genetic factors and various genes, including BRCA 1 and BRCA 2, have been identified. These genes seem to account for some of the breast cancers that occur within families. Women with one or more relatives who have developed the disease in their 30s or 40s may wish to seek specialist genetic advice.
Symptoms and signs
The first sign of breast cancer is often a painless lump. However, it is important to note that nine out of ten breast lumps are not cancerous. Other symptoms of breast cancer may include a dark discharge from the nipple, retraction (indentation) of the nipple, and an area of dimpled, creased skin over the lump. In the majority of cases, only one breast is affected. An abnormality may sometimes be detected during a routine mammography, which is offered every three years to all women between the ages of 50 and 65.
Investigation and treatment
If a lump is detected in the breast, an imaging procedure, such as mammography or ultrasound scanning, will be carried out. Cells will then be collected from the lump by needle aspiration (withdrawal by suction) or biopsy (surgical removal of a small sample of tissue for analysis). A small cancerous tumour that is not thought to have spread outside the breast is removed surgically, along with a surrounding margin of normal tissue. Lymph nodes in the armpit are usually removed at the same time. Larger cancers may require mastectomy (surgical removal of the whole breast).
Surgery can be combined with or followed by mammoplasty (breast reconstruction) to help reduce the psychosexual impact of the disease. Any further treatment depends on the size of the tumour; whether or not there is evidence of spread to the lymph nodes; and the sensitivity of the tumour cells to hormones, which is assessed in the laboratory using a technique known as oestrogen receptor testing. The woman’s age and whether or not she has gone through the menopause are also significant factors in determining appropriate treatment.
After surgery, most women have a course of radiotherapy to any remaining breast tissue and to the armpit, and/or chemotherapy (treatment with anticancer drugs). Tamoxifen, an oral anti-oestrogen drug, is commonly prescribed for five years following surgery for breast cancer to reduce the risk of recurrence. Women who are approaching the menopause may be offered treatment to bring on an early menopause if the tumour is oestrogen-sensitive. Secondary tumours in other parts of the body, which may be present at the time of the initial diagnosis or may develop years after apparently successful treatment, are treated with anticancer drugs and hormones.
A complete cure or years of good health can usually be expected after treatment for early breast cancer. Regular check-ups are required to detect recurrence or the development of a new cancer in the other breast. Mammograms should be performed periodically for this reason. If the cancer recurs, it can be controlled, sometimes for years, by drugs and/or radiotherapy.
Breast cancer in more detail - technical
Breast cancer is the most common cause of death in middle-aged women in western countries. In 2004 approximately one and a half million new cases were diagnosed worldwide. In England and Wales, 1 in 12 women will develop the disease during their life-time.
Carcinoma of the breast occurs commonly in the western world, accounting for 3–5% of all deaths in women. In developing coun- tries it accounts for 1–3% of deaths.
Carcinoma of the breast is extremely rare below the age of 20 years but, thereafter, the incidence steadily rises so that by the age of 90 years nearly 20% of women are affected.
Less than 0.5% of patients with breast cancer are male.
It occurs more commonly in women with a family history of breast cancer than in the general population. Breast cancer related to a specific mutation accounts for about 5% of breast cancers yet has far-reaching repercussions in terms of counselling and tumour prevention in these women. This will be discussed more fully in a subsequent section.
Because breast cancer so commonly affects women in the ‘developed’ world, dietary factors may play a part in its causation. There is some evidence that there is a link with diets low in phytoestrogens. A high intake of alcohol is associated with an increased risk of developing breast cancer.
Breast cancer is more common in nulliparous women and breast- feeding in particular appears to be protective. Also protective is having a first child at an early age, especially if associated with late menarche and early menopause. It is known that in post- menopausal women, breast cancer is more common in the obese. This is thought to be because of an increased conversion of steroid hormones to oestradiol in the body fat. Recent studies have clarified the role of exogenous hormones, in particular the oral contraceptive pill and HRT, in the development of breast cancer. For most women the benefits of these treatments will far outweigh the small putative risk; however, long-term exposure to the combined preparation of HRT does significantly increase the risk of developing breast cancer.
This was considered to be of historical interest, with the majority of women exposed to the atomic bombs at Hiroshima and Nagasaki having died. It is, however, a real problem in women who have been treated with mantle radiotherapy as part of the management of Hodgkin’s disease, in which significant doses of radiation to the breast are received. The risk appears about a decade after treatment and is higher if radiotherapy occurred during breast development. A surveillance programme has been organised in the UK with MRI and mammographic screening.
Breast cancer may arise from the epithelium of the duct system anywhere from the nipple end of the major lactiferous ducts to the terminal duct unit, which is in the breast lobule. The disease may be entirely in situ, an increasingly common finding with the advent of breast cancer screening, or may be invasive cancer. The degree of differentiation of the tumour is usually described using three grades: well differentiated, moderately differentiated or poorly differentiated. Commonly, a numerical grading system based on the scoring of three individual factors (nuclear pleomorphism, tubule formation and mitotic rate) is used, with grade III cancers roughly equating to the poorly differentiated group.
Previously, descriptive terms were used to classify breast cancer (‘scirrhous’, meaning woody, or ‘medullary’, meaning brain-like). More recently, histological descriptions have been used. These have been shown to have clinical correlations in the way that the tumour behaves and are likely to be used for the near future. However, with the increasing application of molecular markers there will be a change in the way that breast cancers are classified and it is likely that much more information about an individual tumour will be routinely reported, such as its likelihood of metastasis and to which therapeutic agents it will be susceptible. Gene array analysis of breast cancers has identified five subtypes. Some of these correlate with known markers such as oestrogen receptor status. There are specific gene signatures that are said to correlate with response to chemotherapy or poor prognosis; trials based upon these differences are planned.
Ductal carcinoma is the most common variant with lobular carcinoma occurring in up to 15% of cases. There are subtypes of lobular cancer including the classical type, which carries a better prognosis than the pleomorphic type. Occasionally, the picture may be mixed with both ductal and lobular features. There are different patterns of spread depending on histological type. If there is doubt whether a tumour is predominantly lobular in type, immunohistochemical analysis using the e-cadherin antibody, which reacts positively in lobular cancer, will help in diagnosis.
Rarer histological variants, usually carrying a better prognosis, include colloid carcinoma, whose cells produce abundant mucin, medullary carcinoma, with solid sheets of large cells often associated with a marked lymphocytic reaction, and tubular carcinoma. Invasive lobular carcinoma is commonly multifocal and/or bilateral. Cases detected via the screening programme are often smaller and better differentiated than those presenting to the symptomatic service and are of a special type.
Inflammatory carcinoma is a fortunately rare, highly aggressive cancer that presents as a painful, swollen breast, which is warm with cutaneous oedema. This is the result of blockage of the sub-dermal lymphatics with carcinoma cells.Inflammatory cancer usually involves at least one-third of the breast and may mimic a breast abscess. A biopsy will confirm the diagnosis and show undifferentiated carcinoma cells. It used to be rapidly fatal but with aggressive chemotherapy and radiotherapy and with salvage surgery the prognosis has improved considerably.
In situ carcinoma is pre-invasive cancer that has not breached the epithelial basement membrane. This was previously a rare, usually asymptomatic, finding in breast biopsy specimens but is becoming increasingly common because of the advent of mammographic screening; it now accounts for over 20% of cancers detected by screening in the UK. In situ carcinoma may be ductal (DCIS) or lobular (LCIS), the latter often being multifocal and bilateral. Both are markers for the later development of invasive cancer, which will develop in at least 20% of patients. Although mastectomy is curative, this constitutes overtreatment in many cases. The best treatment for in situ carcinoma is the subject of a number of on-going clinical trials. DCIS may be classified using the Van Nuys system, which combines the patient’s age, type of DCIS and presence of microcalcification, extent of resection margin and size of disease. Patients with a high score benefit from radiotherapy after excision, whereas those of low grade, whose tumour is completely excised, need no further treatment.
Staining for oestrogen and progesterone receptors is now considered routine, as their presence will indicate the use of adjuvant hormonal therapy with tamoxifen or the newer aromatase inhibitors. Tumours are also stained for c-erbB2 (a growth factor receptor) as patients who are positive can be treated with the monoclonal antibody trastuzumab (Herceptin), either in the adjuvant or relapse setting. The pathologist is an important member of the breast cancer team and will increasingly help decide which adjuvant therapies will be appropriate.
Paget’s disease of the nipple
Paget’s disease of the nipple is a superficial manifestation of an underlying breast carcinoma. It presents as an eczema-like condition of the nipple and areola, which persists despite local treatment. The nipple is eroded slowly and eventually disappears. If left, the underlying carcinoma will sooner or later become clinically evident. Nipple eczema should be biopsied if there is any doubt about its cause. Microscopically, Paget’s disease is characterised by the presence of large, ovoid cells withabundant, clear, pale-staining cytoplasm in the Malpighian layer of the epidermis.
The spread of breast cancer
The tumour increases in size and invades other portions of the breast. It tends to involve the skin and to penetrate the pectoral muscles and even the chest wall if diagnosed late.
Lymphatic metastasis occurs primarily to the axillary and the internal mammary lymph nodes. Tumours in the posterior one- third of the breast are more likely to drain to the internal mammary nodes. The involvement of lymph nodes has both bio- logical and chronological significance. It represents not only an evolutional event in the spread of the carcinoma but is also a marker for the metastatic potential of that tumour. Involvement of supraclavicular nodes and of any contralateral lymph nodes represents advanced disease.
Spread by the bloodstream
It is by this route that skeletal metastases occur, although the ini- tial spread may be via the lymphatic system. In order of frequency the lumbar vertebrae, femur, thoracic vertebrae, rib and skull are affected and these deposits are generally osteolytic. Metastases may also commonly occur in the liver, lungs and brain and, occasionally, the adrenal glands and ovaries; they have, in fact, been described in most body sites.
Although any portion of the breast, including the axillary tail, may be involved, breast cancer is found most frequently in the upper outer quadrant. Most breast cancers will present as a hard lump, which may be associated with indraw- ing of the nipple. As the disease advances locally there may be skin involvement with peau d’orange or frank ulceration and fixation to the chest wall. This is described as cancer-en-cuirasse when the disease progresses around the chest wall.
About 5% of breast cancers in the UK will present with either locally advanced disease or symptoms of metastatic disease. This figure is much higher in the developing world. These patients must then undergo a staging evaluation so that the full extent of their disease can be ascertained. This will include a careful clinical examination, chest radiograph, computerised tomography (CT) of the chest and abdomen and an isotope bone scan. This is important for both prognosis and treatment; a patient with widespread visceral metastases may obtain an increased length and quality of survival from systemic hormone therapy or chemotherapy but is unlikely to bene- fit from surgery as she will die from her metastases before local disease becomes a problem. In contrast, patients with relatively small tumours (< 5 cm in diameter) confined to the breast and ipsilateral lymph nodes rarely need staging beyond a good clinical examination as the pick-up rate for distant metastases is so low.
Currently, a chest radiograph, full blood count and liver function tests are all that are recommended for screening of patients with early-stage breast cancer.
Staging of breast cancer
Classical staging of breast cancer by means of the TNM (tumour– node–metastasis) or UICC (Union Internationale Contre le Cancer) criteria is used less often as we gain more knowledge of the biological variables that affect prognosis. It is becoming increasingly clear that it is these factors (discussed in more detail below) rather than anatomical mapping that influence outcome and treatment. Perhaps a more pragmatic approach would be to classify patients according to the treatment that they require (Table 50.4). Treatment recommendations are summarised in consensus statements such as those from the American Society of Clinical Oncology (ASCO) and the St Gallen Conference.
Prognosis of breast cancer
The best indicators of likely prognosis in breast cancer remain tumour size and lymph node status; however, it is realised that some large tumours will remain confined to the breast for decades whereas some very small tumours are incurable at diagnosis. Hence, the prognosis of a cancer depends not on its chronological age but on its invasive and metastatic potential. In an attempt to define which tumours will behave aggressively, and thus require early systemic treatment, a host of prognostic factors have been described. These include the histological grade of the tumour, hormone receptor status, measures of tumour proliferation such as S-phase fraction, growth factor analysis and oncogene or oncogene product measurements.
Many others are under investigation but have proved of little practical value in patient management. Prognostic indices (such as the Nottingham prognostic index) have combined these factors to allow subdivision of patients into discrete prognostic groups. More recently, a computer-aided program (adjuvant online; www.adjuvantonline.com) has been developed, which incorporates the putative benefits of treatment allowing oncologist and patient to visualise the benefits of therapy.
There are commercial enterprises that are trying to combine a gene profile with classical prognostic indicators to give a recurrence score but these must be viewed as unproven at the moment. Other groups have developed ‘gene signatures’ said to be able to detect cancers of good or poor prognosis but there is little consistency between the various signatures developed by different groups and these approaches have not yet been translated into clinical practice.
Treatment of cancer of the breast
The two basic principles of treatment are to reduce the chance of local recurrence and the risk of metastatic spread. Treatment of early breast cancer will usually involve surgery with or without radiotherapy. Systemic therapy such as chemotherapy or hormone therapy is added if there are adverse prognostic factors such as lymph node involvement, indicating a high likelihood of metas- tatic relapse. At the other end of the spectrum, locally advanced or metastatic disease is usually treated by systemic therapy to palliate symptoms, with surgery playing a much smaller role. An algorithm for the management of breast cancer is shown in bullet list 1.
Bullet list 1: Algorithm for management of operable breast cancer
Achieve local control
- Appropriate surgery
- Wide local excision (clear margins) and radiotherapy, or
- Mastectomy ± radiotherapy (offer reconstruction – immediate or delayed)
- Combined with axillary procedure (see text)
- Await pathology and receptor measurements
- Use risk assessment tool; stage if appropriate
Treat risk of systemic disease
- Offer chemotherapy if prognostic factors poor; include Herceptin if Her-2 positive
- Radiotherapy as decided above
- Hormone therapy if oestrogen receptor or progesterone receptor positive
The multidisciplinary team approach
As in all branches of medicine, good doctor–patient communica- tion plays a vital role in helping to alleviate patient anxiety. Participation of the patient in treatment decisions is of particular importance in breast cancer when there may be uncertainty as to the best therapeutic option and the desire to treat the patient within the protocol of a controlled clinical trial. As part of the preoperative and postoperative management of the patient it is often useful to employ the skills of a trained breast counsellor and also to have available advice on breast prostheses, psychological support and physiotherapy, when appropriate.
In many specialist centres the care of breast cancer patients is undertaken as a joint venture between the surgeon, medical oncologist, radiotherapist and allied health professionals such as the clinical nurse specialist. This has been shown to be good for the patient, to lead to higher trial entry and to improve the mental health of the professionals in the breast team. There are published guidelines for the optimal management of patients with breast cancer such as SIGN 84 (Scottish Intercollegiate Guide- lines Network).
Local treatment of early breast cancer
Local control is achieved through surgery and/or radiotherapy (Bullet list 2).
Bullet list 2: Treatment of early breast cancer
The aims of treatment are:
- ‘Cure’: likely in some patients but late recurrence is possible
- Control of local disease in the breast and axilla
- Conservation of local form and function
- Prevention or delay of the occurrence of distant metastases
Surgery still has a central role to play in the management of breast cancer but there has been a gradual shift towards more conservative techniques, backed up by clinical trials that have shown equal efficacy between mastectomy and local excision followed by radiotherapy.
It was initially hoped that avoiding mastectomy would help to alleviate the considerable psychological morbidity associated with breast cancer but recent studies have shown that over 30% of women develop significant anxiety and depression following both radical and conservative surgery. After mastectomy women tend to worry about the effect of the operation on their appearance and relationships, whereas after conservative surgery they may remain fearful of a recurrence.
Mastectomy is indicated for large tumours (in relation to the size of the breast), central tumours beneath or involving the nipple, multifocal disease, local recurrence or patient preference. The radical Halsted mastectomy, which included excision of the breast, axillary lymph nodes and pectoralis major and minor muscles, is no longer indicated as it causes excessive morbidity with no survival benefit. The modified radical (Patey) mastectomy is more commonly performed and is thus described below. Simple mastectomy involves removal of only the breast with no dissection of the axilla, except for the region of the axillary tail of the breast, which usually has attached to it a few nodes low in the anterior group.
The breast and associated structures are dissected en bloc and the excised mass is composed of:
- the whole breast;
- a large portion of skin, the centre of which overlies the tumour but which always includes the nipple;
- all of the fat, fascia and lymph nodes of the axilla.
The pectoralis minor muscle is either divided or retracted to gain access to the upper two-thirds of the axilla. The axillary vein and nerves to the serratus anterior and latissimus dorsi (the thoraco-dorsal trunk) should be preserved. The intercostal brachial nerves are usually divided in this operation and the patient should be warned about sensation changes postoperatively.
The wound is drained using a wide-bore suction tube. Early mobilisation of the arm is encouraged and physiotherapy helps normal function to return very quickly; most patients are able to resume light work or housework within a few weeks.
Conservative breast cancer surgery
This is aimed at removing the tumour plus a rim of at least 1 cm of normal breast tissue. This is commonly referred to as a wide local excision. The term lumpectomy should be reserved for an operation in which a benign tumour is excised and in which a large amount of normal breast tissue is not resected. A quadrantectomy involves removing the entire segment of the breast that contains the tumour. Both of these operations are usually combined with axillary surgery, usually via a separate incision in the axilla. There are various options that can be used to deal with the axilla, including sentinel node biopsy, sampling, removal of the nodes behind and lateral to the pectoralis minor (level II) or a full axillary dissection (level III).
There is a somewhat higher rate of local recurrence following conservative surgery, even if combined with radiotherapy, but the long-term outlook in terms of survival is unchanged. Local recurrence is more common in younger women and in those with high-grade tumours and involved resection margins. Patients whose margins are involved should have a further local excision (or a mastectomy) before going on to radiotherapy. Excision of a breast cancer without radiotherapy leads to an unacceptable local recurrence rate.
The role of axillary surgery is to stage the patient and to treat the axilla. The presence of metastatic disease within the axillary lymph nodes remains the best single marker for prognosis; however, treatment of the axilla does not affect long-term survival, suggesting that the axillary nodes act not as a ‘reservoir’ for disease but as a marker for metastatic potential. It used to be accepted that only pre-menopausal women should have their axilla staged by operation as there was a good case for giving chemotherapy to lymph node-positive patients; however, it is now clear that post-menopausal women also benefit from chemotherapy and so all patients require axillary surgery. In post- menopausal patients, tamoxifen was once given regardless of axil- lary lymph node status, but it is now known that all hormone receptor-positive patients, irrespective of age, benefit from this. If mastectomy is performed it is reasonable to clear the axilla as part of the operation, but if a wide local excision is planned the surgeon should dissect the axilla through a separate incision.
Axillary surgery should not be combined with radiotherapy to the axilla because of excess morbidity. Removal of the internal mammary lymph nodes is unnecessary.
Sentinel node biopsy
This technique is currently becoming the standard of care in the management of the axilla in patients with clinically node-negative disease. The sentinel node is localised peroperatively by the injection of patent blue dye and radioisotope-labelled albumin in the breast. The recommended site of injection is in the subdermal plexus around the nipple although some still inject on the axillary side of the cancer. The marker passes to the primary node draining the area and is detect- ed visually and with a hand-held gamma camera. The excised node can be sent for frozen-section histological analysis or touch imprint cytology (TIC) if preoperative diagnosis is sought. In some cases there are only subcapsular micrometastases that are missed at frozen section. In patients in whom there is no tumour involve- ment of the sentinel node, further axillary dissection can be avoid- ed. A normogram outlining the chances of further axillary node positivity has been developed by the group at Memorial Sloan Kettering Hospital, New York, and is available on their website (www.mskcc.org/mskcc/html/15938.cfm).
Radiotherapy to the chest wall after mastectomy is indicated in selected patients in whom the risks of local recurrence are high. This includes patients with large tumours and those with large numbers of positive nodes or extensive lymphovascular invasion. There is some evidence that postoperative chest wall radiotherapy improves survival in women with node-positive breast cancer.
It is conventional to combine conservative surgery with radio- therapy to the remaining breast tissue. Recurrence rates are too high for treatment by local excision alone except in special cases (small node-negative tumours of a special type). Trials are under way to investigate whether radiotherapy can be given intraopera- tively at one sitting or as an accelerated postoperative course. This would have considerable advantages in making conservative surgery available in areas where radiotherapy is not currently used. It would also relieve the burden of the current demand for radiotherapy, which accounts for up to 40% of activity in some departments.
Extrapolation from the Oxford overviews of systemic therapy (carried out every 5 years) suggests that for every four local recurrences one additional life will be spared at 15 years. This means that it is important to get the first treatments right and avoid local recurrence.
Adjuvant systemic therapy
Over the last 25 years there has been a revolution in our understanding of the biological nature of carcinoma of the breast. It is now widely accepted that the outcomes of treatment are pre-determined by the extent of micrometastatic disease at the time of diagnosis. Variations in the radical extent of local therapy might influence local relapse but probably do not alter long-term mortality from the disease. However, systemic therapy targeted at these putative micrometastases might be expected to delay relapse and prolong survival. As a result of many international clinical trials and recent world overview analyses it can be stated with statistical confidence that the appropriate use of adjuvant chemotherapy or hormone therapy will improve relapse-free survival by approximately 30%, which ultimately translates into an absolute improvement in survival of the order of 10% at 15 years. Bearing in mind how common the disease is in northern Europe and the USA, these figures are of major public health importance.
Who to treat and with what are still questions for which absolute answers have yet to found, but the data from the overviews of recent trials show that lymph node-positive and many higher risk node-negative women should be recommended adjuvant combined chemotherapy. Women with hormone receptor-positive tumours will obtain a worthwhile benefit from about 5 years of endocrine therapy, either 20 mg daily of tamoxifen if pre-menopausal or the newer aromatase inhibitors (anastrozole, letrozole and exemestane) if post-menopausal. It is no longer appropriate to give hormone therapy to women who do not have oestrogen or progesterone receptor-positive disease.
Tamoxifen has been the most widely used ‘hormonal’ treatment in breast cancer. Its efficacy as an adjuvant therapy was first reported in 1983 and it has now been shown to reduce the annual rate of recurrence by 25%, with a 17% reduction in the annual rate of death. The beneficial effects of tamoxifen in reducing the risk of tumours in the contralateral breast have also been observed, as has its role as a preventative agent (IBIS-I and NSABP-P1 trials). Trials studying the optimal duration of treatment suggest that 5 years of treatment is preferable to 2 years.
Other hormonal agents that are also beneficial as adjuvant therapy have been developed. These include the LHRH agonists, which induce a reversible ovarian suppression and thus have the same beneficial effects as surgical or radiation-induced ovarian ablation in pre-menopausal receptor-positive women, and the oral aromatase inhibitors for post-menopausal women. The latter group of compounds are now licensed for treatment of recurrent disease, in which they have been shown to be superior to tamoxifen. A large trial comparing anastrazole to tamoxifen in the adjuvant setting has shown a beneficial effect for the aromatase inhibitor in terms of relapse-free survival, although the data are still immature for overall survival. There is an additional reduction in contralateral disease, which makes this drug suitable for a study of prevention, and the side-effect profile is different from that of tamoxifen. However, it is currently considerably more expensive.
Chemotherapy using a first-generation regimen such as a 6-monthly cycle of cyclophosphamide, methotrexate and 5- fluorouracil (CMF) will achieve a 25% reduction in the risk of relapse over a 10- to 15-year period. It is important to understand that this 25% reduction refers to the likelihood of an event happening. For example, a woman with a 96% chance of survival at, say, 5 years only has a 4% chance of death over this time and the absolute benefit from chemotherapy would be an increase in survival rate of 1%, to 97%. This would not be a sufficient gain to offset the side-effects of this potentially toxic therapy. However, for a woman with a 60% chance of dying (40% survival rate) a 25% reduction in risk would increase her likelihood of survival to 55% and thus treatment would be worthwhile. CMF is no longer considered adequate adjuvant chemotherapy and modern regimens include an anthracycline (doxorubicin or epirubicin) and the newer agents such as the taxanes.
Chemotherapy was once confined to pre-menopausal women with a poor prognosis (in whom its effects are likely to be the result, in part, of a chemical castration effect) but is being increasingly offered to post-menopausal women with poor-prognosis disease as well. Chemotherapy may be considered in node-negative patients if other prognostic factors, such as tumour grade, imply a high risk of recurrence. The effect of combining hormone and chemotherapy is additive although hormone therapy is started after completion of chemotherapy to reduce side-effects.
High-dose chemotherapy with stem cell rescue for patients with heavy lymph node involvement has now been shown in controlled trials to offer no advantage and has been abandoned.
Primary chemotherapy (neoadjuvant) is being used in many centres for large but operable tumours that would traditionally require a mastectomy (and almost certainly postoperative adju- vant chemotherapy). The aim of this treatment is to shrink the tumour to enable breast-conserving surgery to be performed. This approach is successful in up to 80% of cases but is not associated with improvements in survival compared with conventionally timed chemotherapy. For older patients with breast cancers strongly positive for hormone receptors a similar effect can be seen with 3 months of endocrine treatment.
Newer ‘biological’ agents will be used more frequently as molecular targets are identified – the first of these, trastuzamab (Herceptin), is active against tumours containing the growth factor receptor c-erbB2. Other agents currently available include bevacizumab, a vascular growth factor receptor inhibitor, and lapitinab, a combined growth factor receptor inhibitor. It is unclear how and when these agents will be used, whether in com- bination or instead of standard chemotherapy agents.
Follow-up of breast cancer patients
Patients with breast cancer used to be followed for life to detect recurrence and dissemination. This led to large clinics with little value for either patient or doctor. It is current practice to arrange yearly or 2-yearly mammography of the treated and contralateral breast. There is a move to return the patient early to the care of the general practitioner with fast-track access back to the breast clinic if suspicious symptoms appear. There is currently no routine role for repeated measurements of tumour markers or imaging other than mammography.
Phenomena resulting from lymphatic obstruction in advanced breast cancer
Peau d’orange is caused by cutaneous lymphatic oedema. Where the infiltrated skin is tethered by the sweat ducts it cannot swell, leading to an appearance like orange skin. Occasionally, the same phenomenon is seen over a chronic abscess.
Late oedema of the arm is a troublesome complication of breast cancer treatment, fortunately seen less often now that radical axillary dissection and radiotherapy are rarely combined. However, it does still occur occasionally after either mode of treatment alone and appears at any time from months to years after treatment. There is usually no precipitating cause but recurrent tumour should be excluded because neoplastic infiltration of the axilla can cause arm swelling as a result of both lymphatic and venous blockage. This neoplastic infiltration is often painful because of brachial plexus nerve involvement.
An oedematous limb is susceptible to bacterial infections following quite minor trauma and these require vigorous antibiotic treatment. Antibiotics may need to be given for much longer than is normal and patients at risk of infection should have antibiotics readily available to enable treatment to be started promptly. Treatment of late oedema is difficult but limb elevation, elastic arm stockings and pneumatic compression devices can be useful.
The skin of the chest is infiltrated with carcinoma and has been likened to a coat. It may be associated with a grossly swollen arm. This usually occurs in cases with local recurrence after mastectomy and is occasionally seen to follow the distribution of irradiation to the chest wall. The condition may respond to palliative systemic treatment but prognosis in terms of survival is poor.
Lymphangiosarcoma is a rare complication of lymphoedema with an onset many years after the original treatment. It takes the form of multiple subcutaneous nodules in the upper limb and must be distinguished from recurrent carcinoma of the breast. The prognosis is poor but some cases respond to cytotoxic therapy or irradiation. Interscapulothoracic (forequarter) amputation is rarely indicated.
Despite an increasing trend towards conservative surgery, up to 50% of women still require, or want, a mastectomy. These women can now be offered immediate or delayed reconstruction of the breast. Few contraindications to breast reconstruction exist. Even those with a limited life expectancy may benefit from the improved quality of life; however, patients do require counselling before this procedure so that their expectations of cosmetic out- come are not unrealistic.
The easiest type of reconstruction is using a silicone gel implant under the pectoralis major muscle. This may be combined with prior tissue expansion using an expandable saline prosthesis first (or a combined device), which creates some ptosis of the new breast. If the skin at the mastectomy site is poor (e.g. following radiotherapy) or if a larger volume of tissue is required, a musculocutaneous flap can be constructed either from the latissimus dorsi muscle (an LD flap) or using the transversus abdominis muscle (a TRAM flap). The latter gives an excellent cosmetic result in experienced hands but is a lengthy procedure and requires careful patient selection. It is now usually performed as a free transfer using microvascular anastomosis, although the pedicled TRAM from the contralateral side is still used. Variations on the TRAM flap requiring less muscle harvesting, such as the DIEP flap (based on deep inferior epigastric vessels), are increasingly being used.
The timing of reconstruction is difficult. Impediments to immediate reconstruction include insufficient theatre time and a lack of experienced reconstructive surgeons. In addition, if a patient is likely to need postoperative radiotherapy then a delayed reconstruction using a flap often gives a better result. Radiotherapy onto a prosthesis often leads to a high incidence of capsular contracture and unacceptable results.
Nipple reconstruction is a relatively simple procedure that can be performed under a local anaesthetic. Many different types of nipple reconstruction are described but the majority lose height with time. Tattooing of the reconstructed nipple is often required. Alternatively, the patient can be fitted with a prosthetic nipple. To achieve symmetry the opposite breast may require a cosmetic procedure such as reduction or augmentation mammoplasty, or mastopexy. A breast reconstructive service can be offered by a suitably trained breast surgeon, a plastic surgeon or, ideally, using a combined oncoplastic approach. The patient needs to be warned that breast reconstruction is seldom, if ever, one operation.
External breast prostheses that fit within the bra are the most common method of restoring volume fill and should be available for all women who do not have an immediate reconstruction.
Screening for breast cancer
Because the prognosis of breast cancer is closely related to stage at diagnosis it would seem reasonable to hope that a population screening programme that could detect tumours before they come to the patient’s notice might reduce mortality from breast cancer. Indeed, a number of studies have shown that breast screening by mammography in women over the age of 50 years will reduce cause-specific mortality by up to 30%. Following the publication in 1987 of the Forrest report, the National Health Service in the UK launched a programme of 3-yearly mammographic screening for women between the ages of 50 and 64 years (now increased to 70 years). The introduction of this programme has undoubtedly improved the quality of breast cancer services but a number of questions remain unanswered, including the value of screening women under 50 years and the ideal interval between screenings. The psychological consequences of false alarms or false reassurances still need to be addressed and self-examination programmes that have failed to show any benefit for the population in terms of earlier detection of or decreased mortality from breast cancer remain controversial.
Familial breast cancer
Recent developments in molecular genetics and the identification of a number of breast cancer predisposition genes (BRCA1, BRCA2 and p53) have done much to stimulate interest in this area. Yet women whose breast cancer is due to an inherited genetic change actually account for less than 5% of all cases of breast cancer, that is about 1250 cases per year in the UK and 9000 cases in the USA. A much larger number of women will have a risk that is elevated above normal because of an as yet unspecified familial inheritance. These women have a risk of developing breast cancer that is 2–10 times above baseline. The risks associated with family history are summarised in Table 50.5.
|No. of family cases under 50 years of age||BRCA1 (%) a||BRCA2 (%) b|
a BRCA1 is also associated with ovarian and, to a lesser extent, colorectal and prostate cancer.
b BRCA2 is associated with familial male breast cancer.
The BRCA1 gene has been cloned and is located on the long arm of chromosome 17 (17q). The gene frequency in the population is approximately 0.0006. It does, however, occur with greater frequency in certain populations such as Ashkenazi Jews, in whom there is often a common (founder) mutation. BRCA2 is located on chromosome 13q and there is an association with male breast cancer. Women who are thought to be gene carriers may be offered breast screening (and ovarian screening in the case of BRCA1, which is known to impart a 50% lifetime risk of ovarian cancer), usually as part of a research programme, or genetic counselling and mutation analysis. Those who prove to be ‘gene positive’ have a 50–80% risk of developing breast cancer, predominantly while pre-menopausal. Many will opt for prophylactic mastectomy. Although this does not completely eliminate the risk, it does reduce it considerably. This work should be carried out in specialist centres.
For the great majority of women with a positive family history, who are unlikely to be carriers of a breast cancer gene, there are no currently proven breast cancer screening manoeuvres, although this is under investigation. Tamoxifen given for 5 years appears to reduce the risk of breast cancer by 30–50% and newer agents are currently under trial. Thus, these women are best served by being assessed and followed-up, preferably in a properly organised family history clinic.
The effects of pregnancy on breast cancer are not well studied but it is thought that breast cancer presenting during pregnancy or lactation tends to be at a later stage, presumably because the symptoms are masked by the pregnancy; however, in other respects it behaves in a similar way to breast cancer in a non-pregnant young woman and should be treated accordingly. Thus, treatment is similar with some provisos: radiotherapy should be avoided during pregnancy, making mastectomy a more frequent option than breast conservation surgery; chemotherapy should be avoided during the first trimester but appears safe subsequently; most tumours are hormone receptor negative and so hormone treatment, which is potentially teratogenic, is not required. Becoming pregnant subsequent to a diagnosis of breast cancer appears not to alter the likely outcome, but women are usually advised to wait at least 2 years as it is within this time that recurrence most often occurs. The risk of developing breast cancer with oral contraceptive use is only slight, and disappears 10 years after stopping the oral contraceptive pill.
Hormone replacement therapy
HRT does increase the risk of developing breast cancer if taken for prolonged periods and in certain high-risk groups. HRT may also prolong symptoms of benign breast disorders such as cysts and mastalgia and make mammographic appearances more difficult to interpret.
Patients who develop breast cancer while on HRT appear to have a more favourable prognosis. The consequences in terms of recurrence in women using HRT following breast cancer are unknown.
Treatment of advanced breast cancer
Breast cancer may occasionally present as metastatic disease without evidence of a primary tumour (that is with an occult primary). The diagnosis is made partly by exclusion of another site for the primary tumour and may be confirmed by histology with special immunohistological stains of the metastatic lesions. Management should be aimed at palliation of the symptoms and treatment of the breast cancer, usually by endocrine manipulation with or without radiotherapy.
Locally advanced inoperable breast cancer
Locally advanced inoperable breast cancer, including inflammatory breast cancer, is usually treated with systemic therapy, either chemotherapy or hormone therapy.
Occasionally, ‘toilet mastectomy’ or radiotherapy is required to control a fungating tumour but often incision through microscopically permeated tissues results in a worse outcome.
Metastatic carcinoma of the breast
Metastatic carcinoma of the breast will also require palliative systemic therapy to alleviate symptoms. Hormone manipulation is often the first-line treatment because of its minimal side- effects. It is particularly useful for bony metastases. However, only about 30% of these tumours will be hormone responsive and, unfortunately, in time even these will become resistant to treatment. First-line hormone therapy for post-menopausal women is now anastrazole or one of the other third-generation aromatase inhibitors. Tamoxifen, ovarian suppression by surgery (for pre-menopausal women), radiotherapy and medical treatment are all in common use. When resistance to these has developed, other hormonal agents can prove useful, with about one-half of the response rate seen in the first-line therapy. The newer agents such as anti-progestins, pure anti-oestrogens and growth factor tyrosine kinase inhibitors are all candidates for this role.
Cytotoxic therapy is used particularly in younger women or those with visceral metastases and rapidly growing tumours. A variety of regimens is available and, although none prolongs survival, contrary to expectations, quality of life and symptom control is often better with more aggressive treatments, with responses being seen in up to 70% of patients. Local treatment may also prove useful for some metastatic disease such as radiotherapy for painful bony deposits and internal fixation of pathological fractures.
Carcinoma of the male breast
Carcinoma of the male breast accounts for less than 0.5% of all cases of breast cancer. The known predisposing causes include gynaecomastia and excess endogenous or exogenous oestrogen. As in the female it tends to present as a lump and is most commonly an infiltrating ductal carcinoma.
Stage for stage the treatment is the same as for carcinoma in the female breast and prognosis depends upon stage at presentation. Adequate local excision, because of the small size of the breast, should always be with a ‘mastectomy’.