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Breast cancer 

Breast cancer
Chapter:
Breast cancer
Author(s):

M. Cariati

, L. Holmberg

, J. Mansi

, P. Parker

, G. Pichert

, S. Pinder

, E. Sawyer

, R. Wilson

, and A. Purushotham

DOI:
10.1093/med/9780199204854.003.130803_update_001

May 30, 2013: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Screening—use of MRI in young women at very high risk.

Surgery—discussion of indications for complete axillary lymph node dissection following recent trial.

Updated on 30 November 2011. The previous version of this content can be found here.
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Essentials

Epidemiology and aetiology—over 1 million women worldwide are diagnosed with breast cancer each year, with about 400 000 dying of the disease. Familial breast cancer, most commonly related to the BRCA1 and BRCA2 genes, accounts for only 5% of all cases. Many of the known risk factors are not modifiable because they are inherent or would require unrealistic lifestyle changes, but moderating alcohol consumption, avoiding obesity, and increasing physical activity are all possibly useful interventions.

Prevention—screening for breast cancer is an effective means of achieving earlier diagnosis and provides the opportunity for reducing mortality: X-ray mammography screening alone can be expected to reduce mortality by 30% in women aged 40 to 70 years who participate.

Clinical assessment

Diagnostic assessment of symptomatic breast problems and screen-detected abnormalities is best carried out by multidisciplinary teams following the principles of triple assessment, which involves (1) detailed history and clinical examination of both breasts, axillae and supraclavicular regions; (2) imaging; and (where indicated) (3) cytology/core biopsy. The primary imaging techniques are X-ray mammography and ultrasonography, with MRI when there is diagnostic uncertainty. Ultrasound-guided core needle biopsy is the preferred method for sampling abnormalities. Once the diagnosis has been made, further imaging is used to assess the extent of cancer in the breast and detect the spread of disease to the axilla.

The most significant histological predictors of prognosis are lymph node stage, histological grade, and histological assessment of tumour size, but evaluation of tumour type and the absence or presence of lymphovascular invasion provide additional information, and oestrogen receptor status and HER2 status are predictive markers for selection of therapy.

Management

Surgical treatment—(1) Breast: the main options are modified radical mastectomy, with or without immediate or delayed breast reconstruction, or breast-conserving surgery followed by adjuvant radiotherapy to the breast. (2) Axilla: metastatic involvement of these nodes is the best predictor of risk of recurrence and death, hence accurate assessment of axillary node status is important for staging, prognosis and guiding adjuvant treatment selection; many regard sentinel lymph node biopsy as the best technique.

Radiotherapy—this is an established means of reducing the risk of locoregional recurrence following surgery for invasive breast cancer and also improves survival. It can also be useful for palliation, particularly of bone and brain metastases.

Systemic therapy—(1) endocrine: hormone therapy is only of value in women in whom receptors have been identified histologically by immunohistochemistry; in premenopausal women reduction in oestrogen levels can be achieved by luteinizing hormone releasing hormone (LHRH) agonist or by oophorectomy, or by blocking oestrogen receptors with a SERM (selective oestrogen receptor modulator) such as tamoxifen; in postmenopausal women peripheral aromatization of androgens synthesized by the adrenal glands can be significantly reduced by aromatase inhibitors; (2) chemotherapy: many cytotoxic drugs with different mechanisms of action are available for the treatment of breast cancer (anthracyclines, alkylating agents, antimetabolites, tubulin-binding and platinum-based drugs); (3) biological therapy: Herceptin, a humanized monoclonal antibody against HER2, is active against breast cancers that express this receptor.

Early breast cancer—most women present with local disease confined to the breast, with or without axillary node involvement. Those with hormone-nonresponsive (oestrogen receptor/progesterone receptor, ER/PR –ve) disease should be offered chemotherapy. Those with hormone-responsive (ER/PR +ve) disease should be offered endocrine therapy, with the addition of chemotherapy to some intermediate-risk and all high-risk groups. Herceptin should be given to women following chemotherapy if their tumours are HER2 positive (overexpress the protein or are gene-amplified).

Locally advanced (operable and inoperable), large or inflammatory breast cancers—chemotherapy is the initial treatment of choice, usually anthracycline based followed by a taxane, which can reduce the size of a tumour and render it operable.

Metastatic breast cancer—treatment is aimed at controlling symptoms, improving quality of life, and prolonging survival. Endocrine therapy is usually the treatment of first choice if the tumour is hormone-receptor positive. If the patient has exhausted all endocrine options, or has a hormone-receptor negative tumour, or has rapidly progressive disease, then chemotherapy is the treatment of choice.

Symptomatic treatment—patients with metastatic breast cancer may require pain control with appropriate analgesia; draining of ascites or pleural effusions; radiotherapy for bony pain, brain metastases, or spinal cord compression; and relief of obstructive jaundice by stenting. Symptoms due to bony involvement may be greatly helped by bisphosphonates.

Epidemiology

Disease burden

It is estimated that about 1.2 million women worldwide per year will be diagnosed with breast cancer in the decade 2000–2010, and about 400 000 women will die of the disease per year. About 4.5 million women are alive after a diagnosis of breast cancer. The incidence of the disease rises from a low level before 30 years of age to about 2 women per 1000 per year at the age of 50. After age 50 the risk in Western industrialized countries continues to rise, but less rapidly, and in developing countries the rise in risk after 50 years is substantially less than in the developed world. In countries currently adopting a Westernized lifestyle the risk after age 50 increasingly becomes similar to that in the industrialized world.

Since cancer monitoring with cancer registries started in the 1950s there has been a slow trend of increased breast cancer incidence (see ‘Breast cancer screening’ below). Thus breast cancer will become more common, both as the world’s population ages and as the age-specific breast cancer incidence increases. Breast cancer therefore remains a large health problem, despite the fact that early diagnosis and more effective treatment has lowered the mortality rate in several countries.

Hereditary breast cancer

Women with a family history of breast cancer in first-degree relatives have an increased risk of breast cancer. Familial breast cancer accounts for ≤ 35% of all cases with about 5% due to a mutation in one of the high risk breast cancer genes and 20 to 30% due to a combination of genetic factors increasing the breast cancer risk slightly to moderately above the population risk.

Female reproductive hormones

Many breast cancer risk factors are associated with exposure to female reproductive hormones. Early menarche and late menopause increase the risk, whereas early first birth, high parity, and long duration of breast feeding are protective. Oral contraceptives increase the risk, but have a low population impact since they are taken at an age when underlying breast cancer risk is low. Hormone replacement therapy increases risk, especially if oestrogen is combined with progesterone. A high serum level of oestrogen is associated with a higher risk.

Anthropometric factors

Height is positively correlated with postmenopausal breast cancer risk. Body mass index is inversely correlated with breast cancer risk before the menopause, but high body mass index is a risk factor for postmenopausal breast cancer. Higher physical activity is protective, especially for postmenopausal breast cancer. These factors may partly act as modifiers of endogenous hormonal levels. Each of the hormonal factors and anthropometric factors has a modest impact on risk, but taken together they may account for a substantial part of the difference in incidence between countries.

Diet and other factors

Associations between diet and breast cancer risk have been extensively studied, but the only clear consistent finding has been that the consumption of each additional 10 g of alcohol per day increases the breast cancer risk by 9%, compared with no intake. Many other dietary components have attracted interest, but the findings are equivocal.

Breast cancerIonizing radiation causes breast cancer, even at low doses, and especially if the exposure is around menarche. High breast density at mammography and a previous tissue diagnosis of epithelial atypia in the breast are markers of a higher risk of breast cancer.

Prevention

Modification of lifestyle

Many of the known risk factors for breast cancer are not modifiable because they are inherent (e.g. family history) or they would require unrealistic lifestyle changes (e.g. radically changing patterns of parity). However, moderating alcohol consumption, avoiding obesity, and increasing physical activity are all possible interventions. Even if there are many obstacles to modifying these factors, motivation for changes is enhanced by the fact that they would also help protect against other cancers, cardiovascular disease, and diabetes. Other modifiable factors include considering alternatives to oral contraceptives in older women, and restricting the use of hormonal replacement therapy for menopausal symptoms to those with severe symptoms, and to a few years of treatment.

Chemoprevention

Since the late 1990s it has been known that selective oestrogen receptor modifiers (SERMs) can reduce the risk of breast cancer by around 50%. However, the early SERM, tamoxifen, also has the side effects of increasing the risk of thromboembolic events, stroke, uterine cancer, and cataracts. The risk of side effects seems to be lower with newer generations of SERMs, but so far they have not been tested in prevention as extensively and for as long as tamoxifen. Chemoprevention is today only recommended for women at high risk, and there is ongoing research into how to best select these women (through epidemiological risk models and/or biomarkers) and which drugs to use.

Familial breast cancer

It is estimated that about 5% of all breast cancers result from a mutation in one of the high-risk breast cancer genes, and that a further 20 to 30% of all breast cancers arise from a combination of genetic factors that increase the breast cancer risk slightly to moderately above the population risk. Genes that confer a high risk for breast and other cancers, if mutated, are summarized in Table 13.8.3.1. The two genes most commonly involved in inherited breast and ovarian cancer are BRCA1 and BRCA2. Other genes causing a high risk for breast cancer are TP53, PTEN, STK11, and the E-cadherin gene (CDH1).

Table 13.8.3.1 Inherited predisposition to breast and other cancers

Syndrome

Gene

Mode of inheritance

Significantly increased risk

Inherited breast/ovarian cancer (OMIM #604370, #612555)

BRCA1 BRCA2

Autosomal dominant

  • Breast cancer

  • Ovarian cancer

  • Prostate cancer (BRCA2)

  • Pancreatic cancer (BRCA2)

Li–Fraumeni syndrome

TP53

Autosomal dominant

  • Breast cancer

  • Soft-tissue and bone sarcomas

  • Adrenocortical cancer

  • Brain tumours

  • Leukaemias

  • Other tumours

Cowden’s syndrome (OMIM #158350)

PTEN

Autosomal dominant

  • Breast cancer

  • Thyroid cancer

  • Endometrial cancer

  • Lhermitte–Duclos disease (dysplastic cerebellar gangliocytoma)

Peutz–Jeghers syndrome (OMIM #175200)

STK11

Autosomal dominant

  • Breast cancer

  • Colon cancer

  • Pancreatic cancer

  • Stomach cancer

  • Ovarian cancer

  • Other tumours

Inherited stomach cancer (OMIM #192090)

CDH1

Autosomal dominant

Lobular breast carcinoma Diffuse stomach cancer

Women with an average or slightly increased risk of breast cancer should be reassured in primary care and do not require enhanced breast surveillance. Women at moderately increased risk of breast cancer should be managed at secondary care level and referred for annual mammograms between the ages of 40 and 50 years. Women with a high risk of breast cancer because of their family history should be offered genetic counselling and testing, the key elements of which are as follows:

  • Construction of a three-generation pedigree with verification of cancer diagnoses

  • Clinical examination

  • Cancer risk assessment based on family history of cancer

  • Discussion of advantages and disadvantages of genetic testing

  • Discussion of psychological issues and offer of psychological support

  • Information about insurance implications

  • Discussion of confidentiality

  • Discussion of the genetic test result and its consequences for the affected individual and family members

  • Discussion of options for surveillance and risk reduction, with and without a genetic test

  • Information on costs of genetic testing and surveillance, and risk-reducing measures

Testing of high-risk genes offers the opportunity to identify the cause of breast cancers in the family, to offer testing to family members to clarify their breast cancer risk, and to help individuals at risk to make appropriate decisions regarding surveillance and risk-reducing options. Women who carry a BRCA1 or BRCA2 mutation have a lifetime risk of breast cancer of up to 85%; their lifetime risk of ovarian cancer is also increased by up to 50% in BRCA1 carriers and up to 30% in BRCA2 carriers. Men with a BRCA2 mutation have up to a 6% lifetime risk of breast cancer and an increased risk of prostate and other cancers.

Women at high risk of breast cancer because of their family history or a mutation in one of the breast cancer-associated genes should be offered digital mammograms and breast MRI. Prophylactic bilateral mastectomy has been shown to reduce the breast cancer risk by at least 90%, but reoperation rates of up to 30 to 49% have been reported.

At present there is no surveillance of proven benefit for women at high risk for ovarian cancer. There are ongoing trials designed to test the effectiveness of transvaginal ultrasonography and CA125 measurements for the early diagnosis of ovarian cancer. By contrast, prophylactic salpingo-oophorectomy has been proven to reduce the risk of ovarian cancer by up to 95%, and if performed before the menopause it also reduces the risk of breast cancer by up to 50%.

The future challenge is to a gain better understanding of the interaction of genetic and lifestyle/environmental factors in order to develop more effective surveillance and risk-reducing measures and treatments adapted to the biology of inherited cancers.

Clinical approach

Following a detailed history and clinical examination of both breasts, axillae, and supraclavicular regions, patients undergo imaging and cytology/core biopsy where indicated (triple assessment). Imaging is important in all aspects of the breast disease management pathway, with a key role in the early diagnosis of breast cancer through screening, the diagnostic assessment of breast symptoms and signs, the local and systemic staging of breast cancer, monitoring the response to treatment, and follow-up after treatment to detect recurrence.

Breast cancer screening

Population screening

Treatment of breast cancer at an early stage is more likely to prolong survival and may offer cure. Screening for breast cancer is an effective means of achieving early diagnosis, and provides the opportunity for reducing mortality. Randomized controlled trials indicate that X-ray mammography screening alone can be expected to reduce mortality by 30% in women aged 40 to 70 years who participate. The benefit is greatest in women aged 55 to 70 years (40%), with a lesser benefit in women aged 40 to 55 years (15%). Most developed countries offer mammographic breast screening to women aged 40 to 75 years every 1 to 3 years; this detects about 7 cancers per 1000 women screened, with 25% of these cancers being ductal carcinoma in situ (Fig. 13.8.3.1). To be effective, screening must be partnered with multidisciplinary assessment of screen-detected abnormalities and effective treatment of the cancers detected.

Fig. 13.8.3.1 Mediolateral view of mammogram showing malignant microcalcification characteristic of ductal carcinoma in situ.

Fig. 13.8.3.1
Mediolateral view of mammogram showing malignant microcalcification characteristic of ductal carcinoma in situ.

High-risk group screening

Breast cancerIn patients with a hereditary disposition, breast cancers usually develop at a much younger age and tend to be of a higher histological grade. The most effective management is prophylactic mastectomy, but early detection through screening is preferred by many women in this group. MRI is the most effective method for screening younger women (under age 40) at very high risk (e.g. BRCA1 and BRCA2 gene carriers).

Breast diagnosis

Diagnostic assessment of symptomatic breast problems and abnormalities detected at screening is best carried out by multidisciplinary teams following the principles of triple assessment. The primary imaging techniques used are X-ray mammography and ultrasonography (Figs. 13.8.3.2 and 13.8.3.3). MRI is used as a supplementary technique where there is diagnostic uncertainty. Ultrasound-guided core needle biopsy is the preferred method for sampling abnormalities. X-ray-guided core or vacuum-assisted mammotomy are used for impalpable abnormalities that are not visible on ultrasonography, these usually being microcalcifications detected at screening.

Fig. 13.8.3.2 Mediolateral view of mammogram showing a mass lesion characteristic of invasive carcinoma.

Fig. 13.8.3.2
Mediolateral view of mammogram showing a mass lesion characteristic of invasive carcinoma.

Fig. 13.8.3.3 Ultrasound scan showing characteristic appearance of invasive carcinoma with microcalcification.

Fig. 13.8.3.3
Ultrasound scan showing characteristic appearance of invasive carcinoma with microcalcification.

Results of the assessment process are discussed at prospective multidisciplinary meetings at which the clinical findings, imaging, and pathology are reviewed and clinical management decisions made before the treatment choices are discussed with the patient. This process ensures that patients with benign problems are provided with an accurate diagnosis and can be reassured rapidly, and those with breast cancer are provided with full information and advice on which to base their treatment choice.

Staging of breast cancer

Once the diagnosis has been made, further imaging is used to assess the extent of cancer in the breast and detect the spread of disease to the axilla. The extent of the disease is crucial for deciding if breast-conserving surgery is a viable option for treatment. Mammography provides an accurate assessment of disease extent in most cases, and axillary ultrasonography will detect around 40% of axillary node metastatic spread. For patients with dense breast tissue and those with invasive lobular carcinoma, MRI is the most reliable imaging technique for assessing the extent of disease and the presence of multifocality.

Axillary node involvement is a marker of possible spread of disease beyond the breast, and these patients may require additional staging. This involves skeletal scintigraphy to detect bone disease, and computed tomography of the chest and upper abdomen to detect lung, pleural, and visceral organ spread, prior to any further treatment.

Monitoring of treatment

Response to chemotherapy and hormone therapy, either primary or secondary, is best assessed with imaging. MRI provides the most accurate assessment of response in the breast, as it detects both anatomical and biological changes. To assess the response of systemic disease the imaging techniques used are the same as those used for staging.

Surveillance after treatment

Annual mammography is routine for the detection of ipsilateral breast recurrence and new primary malignancy in the opposite breast. Surveillance mammography is usually continued for 5 to 10 years after initial treatment, with the aim of reducing morbidity by earlier detection of recurrence of disease.

Histopathology of breast carcinoma

Ductal carcinoma in situ

Although it was previously believed that in some cases breast cancer arose in the ductules and in other cases in the lobules, it is now clear that this disease derives from the previously terminal duct lobular unit. However, two types of in situ carcinoma of the breast are conventionally described, ductal and lobular, and these have significant differences in morphology and clinical behaviour. Ductal carcinoma in situ (DCIS) is widely regarded as a true precursor of invasive breast cancer, but lobular carcinoma in situ is not generally accepted to be an invariable precursor of invasive disease. Histologically, DCIS can be recognized as a malignant proliferation of epithelial cells within the duct system, which has not breached the myoepithelial layer and basement membrane and therefore has not invaded into the breast stroma (Fig. 13.8.3.4). A variable number of ducts may be involved, but DCIS almost always involves a single duct system within the breast, although these vary significantly in size and distribution. As with invasive breast carcinoma, the microscopic appearance is highly variable, and DCIS is classified according to cytonuclear grade into high-, intermediate-, and low-grade forms, which are associated with differing risks of local recurrence and of harbouring an invasive tumour.

Fig. 13.8.3.4 Ductal carcinoma in situ. Low-power photomicrograph of sharply defined islands of malignant cells, with tumour retained within duct structures.

Fig. 13.8.3.4
Ductal carcinoma in situ. Low-power photomicrograph of sharply defined islands of malignant cells, with tumour retained within duct structures.

Invasive carcinoma

A large number of morphological variants of invasive breast carcinoma can be identified histologically, and it is clear that invasive breast carcinoma is a spectrum of disease with different appearances, protein profiles, and gene expression rather than a single entity. Despite recent interest in gene profiling of breast cancers, histological evaluation is clearly of importance as the inherent biological aggressiveness and likely clinical outcome can be predicted and influenced by selection of the most appropriate therapy based on these factors. According to national guidelines a minimum dataset of features provided in histological reports includes a number of factors. The most significant for prediction of prognosis remain histological examination of lymph node stage, histological grade, and histological assessment of tumour size, but evaluation of tumour type and the absence or presence of lymphovascular invasion provide additional information. Oestrogen receptor status and HER2 status are included as predictive markers for selection of therapy.

Lymph node stage must be determined by microscopic examination of the lymph nodes, as clinical and ultrasound assessment is not accurate. Histological grade is determined by assessing the amount of gland formation, the degree of nuclear pleomorphism, and the mitotic count of the tumour. Tumours are classified into three grades: grade 1 (equivalent to well differentiated) to grade 3 (poorly differentiated); 85% of patients with grade 1 tumours are alive 10 years after diagnosis, compared with 35% of patients with grade 3 tumours.

More than 50% of invasive breast carcinomas are classified as being of no special type (previously called ductal). These tumours are formed from cords and sheets of large malignant epithelial cells, which infiltrate in a disorganized fashion (Fig. 13.8.3.5). Infiltrating lobular carcinoma accounts for about 10 to 15% of invasive breast carcinomas, with linear cords of tumour cells classically infiltrating in a so-called targetoid or single-file pattern. Other forms of invasive carcinoma are less common, including medullary-like carcinoma, which is more commonly seen in women who have a BRCA1 gene mutation. Other special types of invasive breast carcinoma include tubular and mucinous forms, which are of significance as they tend to have a more indolent course and a better prognosis. Mixed forms of invasive cancer, with more than one histological pattern, are also quite common. Other types of invasive breast carcinoma, such as metaplastic/spindle-cell or squamous-cell carcinoma, are rare.

Fig. 13.8.3.5 Invasive breast cancer. Carcinoma of no special type (ductal), histological grade 3; the tumour is formed from sheets of large and pleomorphic malignant cells, with abundant mitoses present.

Fig. 13.8.3.5
Invasive breast cancer. Carcinoma of no special type (ductal), histological grade 3; the tumour is formed from sheets of large and pleomorphic malignant cells, with abundant mitoses present.

There is interest in subclassifying invasive carcinomas by the use of additional techniques such as immunohistochemistry panels and gene-array profiling. For example, the group of tumours categorized histologically as being of no special type can be further grouped with these techniques, and differing prognoses identified, e.g. some tumours express basal-type cytokeratins and appear, in general, to have a poorer outcome than those with luminal-type keratin expression. Based on variations in gene expression, it has been shown that cancers can be classified into basal and luminal groups, a group overexpressing ERBB2 (HER2), and a normal breast-like group. Furthermore, the luminal epithelial/oestrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. Survival analysis has shown significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two oestrogen receptor-positive groups.

Predictive markers

Alongside the increased use of targeted therapy there is a requirement for high-quality testing of markers that predict the value of a therapy for an individual patient. The oestrogen receptor competitor tamoxifen and aromatase inhibitors are frequently recommended for patients with tumours that express the oestrogen receptor. The degree of reactivity, in the form of the percentage and intensity of immunohistochemical staining (typically combined into a score from 0 to 8), approximates to the quantity of oestrogen receptor in the tumour-cell nucleus, and to the likelihood of a response to hormone therapy (Fig. 13.8.3.6).

Fig. 13.8.3.6 Oestrogen receptor-positive invasive breast carcinoma. Sheets of invasive carcinoma cells all show strong nuclear immunoreactivity for oestrogen receptors (Allred score 8; range 0–8).

Fig. 13.8.3.6
Oestrogen receptor-positive invasive breast carcinoma. Sheets of invasive carcinoma cells all show strong nuclear immunoreactivity for oestrogen receptors (Allred score 8; range 0–8).

HER2 (ERBB2) is a member of the human epidermal growth factor receptor family and is a transmembrane tyrosine kinase receptor. HER2 is expressed in approximately 15 to 20% of early invasive breast cancers and is associated with poorer patient outcome. Humanized monoclonal antibodies against the HER2 protein have proven invaluable in the treatment of the subgroup of patients who have cancers that overexpress HER2 or have amplification of the gene. For this reason, all invasive breast cancers are tested for the presence of excess protein on the cell surface by immunohistochemistry (scored 0 to 3) and/or for amplification of the gene by in situ hybridization (usually assessed as a ratio compared with chromosome 17 copy number) (Fig. 13.8.3.7).

Fig. 13.8.3.7 HER2-positive invasive breast carcinoma. Core biopsy of invasive breast cancer showing strong complete membrane reactivity for HER2; score 3+ (range 0–3).

Fig. 13.8.3.7
HER2-positive invasive breast carcinoma. Core biopsy of invasive breast cancer showing strong complete membrane reactivity for HER2; score 3+ (range 0–3).

Surgery

The surgical treatment of breast cancer has moved from radical to more conservative over the last century. Several randomized trials comparing different surgical procedures showed no difference in survival between radical mastectomy, modified radical mastectomy, and breast-conserving surgery with adjuvant radiotherapy.

Breast-screening programmes identify tumours at an earlier stage of disease, allowing locoregional treatment that, in some patients, results in complete cure. By contrast, patients with aggressive tumours or those who present late often have locally advanced tumours with nodal involvement and sometimes systemic disease.

Surgical treatment for breast cancer is designed to achieve locoregional control and staging of disease in order to plan adjuvant therapy.

Surgery to the breast

Broadly speaking, two main surgical options are available to treat breast cancer. These are modified radical mastectomy with or without immediate or delayed breast reconstruction, or breast-conserving surgery followed by adjuvant radiotherapy to the breast. The purpose of adopting breast-conserving surgery is to minimize the psychological morbidity associated with mastectomy, hence in addition to removing the tumour with an adequate margin of normal tissue it is important to achieve a good cosmetic outcome. This has to be balanced against ensuring an adequate clearance (there is no absolute consensus on what constitutes an adequate margin of excision) in order to minimize the risk of local recurrence.

There is general agreement on the criteria used to select patients for breast-conserving surgery, some of these being size and extent of tumour (relative to size of breast), unifocal disease, and patient preference. With the advent of neoadjuvant chemotherapy and endocrine therapy, and the consequent downstaging of tumour size, more patients are now able to undergo breast-conserving surgery. Furthermore, with modern techniques larger volumes of tissue may be removed, with oncoplastic procedures adopted to remodel the breast, thereby providing excellent cosmesis.

Following breast-conserving surgery and adjuvant radiotherapy, an acceptable 5-year actuarial rate of local recurrence is in the order of 5 to 10%. Factors influencing risk of local recurrence include close/involved margins, young age, high grade, extensive DCIS, and the presence of vascular invasion.

Patients undergoing mastectomy should be offered breast reconstruction if clinically indicated, the options including immediate versus delayed, and prosthetic versus autologous. The choices will depend primarily on comorbidities, previous abdominal surgery, the likelihood of postoperative adjuvant radiotherapy to the chest wall, and the patient’s wishes. Broadly speaking, autologous immediate reconstruction offers the patient the best long-term cosmetic outcome. Breast reconstruction does not impact on the detection of subsequent local or regional tumour recurrence.

Surgery to the axilla

Approximately 30 to 40% of early breast cancers have axillary nodal involvement, the management of which has been a hot topic of debate. Metastatic involvement of these nodes has been shown to be the best predictor of risk of recurrence and death, hence accurate assessment of axillary node status is important for staging, prognosis, and guiding adjuvant treatment selection.

Axillary lymph node dissection may be performed to one of three levels based on the anatomical relationship of the nodes to the pectoralis minor muscle. This procedure may be associated with physical morbidity that includes shoulder stiffness, numbness/paraesthesia along the distribution of the intercostobrachial nerve, and breast cancer-related lymphoedema. The latter develops in approximately 25% of patients at some time; it can be permanent and disfiguring and often interferes with manual dexterity. Because of this, two alternative procedures have been explored, namely four-node axillary sampling and sentinel lymph node biopsy.

Four-node axillary sampling involves the removal of a number of nodes (usually four) that are identified by palpation of the axillary nodal tissue, and is associated with less physical morbidity than standard axillary lymph node dissection in node-negative patients. It has been shown by some that the incidence of positive nodes identified by axillary sampling does not differ from that identified by axillary lymph node dissection, but others have found that 24% of patients undergoing axillary sampling are erroneously staged.

Breast cancerSentinel lymph node biopsy (Fig. 13.8.3.8) is a technique for identifying and then removing the first-draining lymph node (or nodes) of the breast. These so-called sentinel lymph node/s are then examined for the presence of tumour and, if metastases are present, the patient will require a completion axillary lymph node dissection. There are now three published prospective randomized controlled trials in Europe comparing axillary lymph node dissection and sentinel lymph node biopsy for a variety of different parameters such as physical and psychological morbidity. All have shown significant decreases in measures of physical and psychological morbidity with sentinel lymph node biopsy. Of particular relevance for breast cancer-related lymphoedema, rates of arm swelling have been shown to be decreased compared with axillary lymph node dissection. The rate of axillary recurrence after negative sentinel lymph node biopsy is comparable with that following axillary lymph node dissection. The recent Z0011 trial investigated the effect of complete axillary lymph node dissection in patients who had two nodes or fewer positive on sentinel node biopsy compared with no further surgery. This trial showed that there is no difference in survival (overall and disease-free) between the two groups. Although controversial, this trial does suggest that complete axillary lymph node dissection in the presence of positive sentinel node biopsy may be avoided in selected cases.

Fig. 13.8.3.8 Sentinel lymph node biopsy demonstrating lymphatics draining to the sentinel lymph node. A combined technique using isotope and patent blue dye is used.

Fig. 13.8.3.8
Sentinel lymph node biopsy demonstrating lymphatics draining to the sentinel lymph node. A combined technique using isotope and patent blue dye is used.

Radiotherapy

Radiotherapy is an established means of reducing the risk of locoregional recurrence following surgery for invasive breast cancer, and also improves survival. The prevention of four local tumour recurrences prevents one breast cancer death at 15 years.

Radiotherapy following breast-conserving surgery

Radiotherapy to the whole breast is recommended following breast-conserving surgery, in order to reduce the risk of local recurrence. Adjuvant radiotherapy reduces the risk of locoregional recurrence from 26% to 7% at 5 years, and decreases breast cancer and overall mortality at 15 years by 5.4% and 4.8%, respectively. Trials are assessing the use of partial breast irradiation in low-risk patients, but no group has as yet been identified in which breast-conserving surgery alone gives adequate local control. For patients at high risk of local recurrence (age <50 years, tumour grade 3, node-positive, large pT2 and T3 tumours, narrow excision margins, oestrogen receptor negative, presence of lymphovascular invasion) a boost to the tumour bed improves local control further. Three trials have shown that radiotherapy reduces the risk of recurrence following wide local excision of both high-grade and low-grade DCIS.

Postmastectomy radiotherapy

Postmastectomy radiotherapy to the chest wall, in combination with appropriate nodal irradiation (see below), has been demonstrated to improve locoregional control and survival in node-positive patients. Radiotherapy reduces the risk of locoregional recurrence from 23% to 6% at 5 years, and decreases breast cancer and overall mortality at 15 years by 6% and 3.5%, respectively. Patients with four or more involved lymph nodes get the most benefit from radiotherapy; the situation for those with one to three positive nodes is less clear, with current trials attempting to answer the question, particularly in the presence of more effective adjuvant systemic therapy. However, the 2005 Oxford overview of radiotherapy trials does show a decrease in local recurrence and breast cancer mortality in those with one to three positive nodes and those with four or more positive nodes.

Nodal irradiation following breast-conserving surgery or mastectomy

Axillary and supraclavicular fossa irradiation following a level 1 axillary node dissection or sentinel node biopsy

Following a negative sentinel node biopsy or level 1 axillary dissection, lymph node irradiation is unnecessary, as involvement of other nodes at higher levels is unlikely. If level 1 axillary nodes are involved and no further surgery is planned, irradiation may be given to the level 2 and 3 axillary and supraclavicular fossa nodes in order to reduce the risk of recurrence. The European Organisation for Research and Treatment of Cancer (EORTC) AMAROS trial is comparing complete axillary lymph node dissection with axillary radiotherapy in sentinel node-positive patients.

Axillary and supraclavicular fossa irradiation following level 3 axillary node dissection

Radiotherapy to the axilla is not recommended after a level 3 dissection as it is associated with a high incidence of lymphoedema. However, patients with four or more involved lymph nodes should be offered supraclavicular fossa irradiation because of the high risk of supraclavicular fossa nodal relapse (11% at 10 years).

Internal mammary nodes

Some of the radiotherapy trials that showed a survival advantage for postmastectomy irradiation (see above) irradiated both the supraclavicular fossa and internal mammary nodes. However, irradiating the internal mammary nodes increases the risk of cardiac toxicity, and trials (e.g. EORTC 22922) have evaluated the role of internal mammary irradiation. This is not currently recommended outside a clinical trial.

Practical issues

The most common fractionation schedule is 50 Gy in 25 fractions. A widely used fractionation regimen in the United Kingdom is 40 Gy in 15 fractions, and evidence from the START trial has shown its equivalence to 50 Gy in 25 fractions, both in terms of local control and cosmetic outcome.

Skin erythema and desquamation are common during radiotherapy and resolve within 4 weeks of completing treatment. Long term side effects are rare and include fibrosis, skin telangiectasia, lung fibrosis, rib fracture, ischaemic heart disease (left-sided tumours), and late malignancy (contralateral breast cancer, radiation-induced sarcoma, or lung cancer). They are uncommon in the first 5 years after treatment, but continue to occur 15 years or more after treatment. The excess mortality mainly results from heart disease and lung cancer.

Pregnancy, previous breast irradiation (including mantle irradiation for Hodgkin’s disease), significant pre-existing cardiac (for left-sided breast tumours) or lung disease, scleroderma, and limited shoulder mobility are contraindications for the use of radiotherapy.

Intensity-modulated radiotherapy (Fig. 13.8.3.9) can be used to optimize dose homogeneity and avoid unnecessary normal tissue irradiation. This will improve long-term cosmesis and reduce long-term side effects such as cardiac toxicity. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery is also under investigation.

Fig. 13.8.3.9 Example of three-dimensional breast radiotherapy planning. A, multiplanar view; B, transverse and C, sagittal section showing homogenous dose distribution throughout the breast. Surgical clips can be seen on the transverse section delineating the tumour bed, and are used to define the boost volume (light brown volume in multiplanar and beam’s-eye views [arrows]). D, beam’s-eye view.

Fig. 13.8.3.9
Example of three-dimensional breast radiotherapy planning. A, multiplanar view; B, transverse and C, sagittal section showing homogenous dose distribution throughout the breast. Surgical clips can be seen on the transverse section delineating the tumour bed, and are used to define the boost volume (light brown volume in multiplanar and beam’s-eye views [arrows]). D, beam’s-eye view.

Radiotherapy is useful for palliation, particularly of bone and brain metastases, both of which are common in breast cancer.

Systemic therapy

Considerable progress has been made in the management of breast cancer over the last two decades, with a marked decrease in recurrence and mortality. Endocrine therapy, chemotherapy, and, more recently, targeted therapy in both the early and advanced setting have all significantly contributed to this. Factors that profoundly affect decision-making in breast cancer include the hormone-receptor status (oestrogen receptor (ER) and progesterone receptor (PR)) and overexpression of the HER2 receptor. The following section describes the rationale for treatment in these settings.

Endocrine therapy

The value of oestrogen deprivation in the treatment of breast cancer was first established in 1899 when Beatson removed the ovaries of premenopausal women with advanced breast cancer and noted regression of the tumour. Since then a large number of hormone therapies have been developed with different mechanisms of action (Table 13.8.3.2), but the aim of hormone therapy in breast cancer is to prevent the growth-stimulatory effects of oestrogen signalling in breast cancer cells. This can be achieved either by reducing the production of oestrogen or by blocking its receptors. It is clear that such therapy is only of value in women in whom receptors have been identified by immunohistochemistry, and the stronger the ER/PR expression the greater the benefit.

Table 13.8.3.2 Hormone therapies in breast cancer

Hormone therapy

Route of administration

Indication

Main side effects

LHRH agonists

  • Goserelin

  • Leuprorelin

Subcutaneous, monthly/3 monthly

  • Premenopausal

  • Adjuvant, metastatic

Menopausal symptomsa

Selective oestrogen-receptor modulators

Tamoxifen

Oral, daily

Premenopausal

Endometrial cancer

Postmenopausal

Thromboembolism

Adjuvant, metastatic

Menopausal symptoms

Fulvestrant

Intramuscular, monthly

Postmenopausal

Menopausal symptoms

Metastatic

Osteoporosis

Aromatase inhibitors

Nonsteroidal

  • Anastrozole

  • Letrozole

Oral, daily

  • Postmenopausal

  • Adjuvantb

  • Osteoporosis

  • Joint aches, fractures

Steroidal

Exemestane

Oral

Primary medical therapy, metastatic

  • Osteoporosis

  • Joint aches, fractures

Progestogens

Megestrol acetate

Oral, daily

Premenopausal

Weight gain

Postmenopausal

Fluid retention

Metastatic

Thromboembolism

LHRH, luteinizing hormonereleasing hormone.

a Hot flushes, sweats mood changes, vaginal dryness, osteoporosis.

b National Institute for Clinical Excellence approval: TA112, 2006.

Premenopausal women

The main source of oestrogens in premenopausal women is the ovaries. A reduction in oestrogen levels can be achieved by preventing the ovaries from functioning, either medically with a luteinizing hormone-releasing hormone (LHRH) agonist or by oophorectomy (surgically or by radiotherapy). An alternative is to block the oestrogen receptors with a selective oestrogen-receptor modulator (SERM) such as tamoxifen, which is an antagonist with partial agonist activity, or one of the more selective anti-oestrogens (Table 13.8.3.2).

Postmenopausal women

In postmenopausal women the major source of oestrogen is peripheral aromatization of androgens synthesized by the adrenal glands. This process can be significantly reduced by a group of drugs called the aromatase inhibitors (Table 13.8.3.2). Tamoxifen is also widely used.

Side effects

In general terms these agents are relatively well tolerated. The commonly recognized toxicities are shown in Table 13.8.3.2.

Chemotherapy

Breast cancer is a disease which responds to cytoxic and other forms of chemotherapy, i.e. is ‘chemosensitive’, and there are a large number of cytotoxic drugs with different mechanisms of action available for its treatment (Table 13.8.3.3). Because of the heterogeneous nature of breast cancer some of the regimens are given in combination, whereby drugs from different classes are administered together to achieve maximum cell kill and reduce the risk of drug resistance.

Table 13.8.3.3 Chemotherapy in breast cancer

Chemotherapy

Indication

Class of cytotoxic

NICE approval

Doxorubicin

Adjuvant, PMT, metastatic

Anthracycline

Pre-NICE

Epirubicin

Adjuvant, PMT, metastatic

Anthracycline

Pre-NICE

Cyclophosphamide

Adjuvant, PMT, metastatic

Alkylating agent

Pre-NICE

5-Fluorouracil

Adjuvant, PMT, metastatic

Antimetabolite

Pre-NICE

Paclitaxel

Adjuvant, PMT, metastatic

Tubulin-binding

TA30, 2001 TA108, 2006

Docetaxel

Adjuvant, PMT, metastatic

Tublin-Binding

TA30, 2001 TA109, 2006

Capecitabine

Metastatic

Antimetabolite

TA62, 2003

Vinorelbine

Metastatic

Tubulin-binding

TA54, 2002

Gemcitabine

Metastatic

Antimetabolite

TA116, 2007

Carboplatin

Metastatic

Platinum

Pre-NICE

NICE, National Institute for Health and Clinical Excellence; PMT, primary medical therapy; TA, technology assessment and year of publication.

Side effects

Toxic effects associated with chemotherapeutic drugs cause significant short- and long-term clinical effects and even death. Short-term effects include nausea, vomiting, mucositis, alopecia, and myelosuppression with concomitant neutropenic sepsis. Long-term side effects include cardiotoxicity, infertility, and second malignancy. Every effort is made to reduce these side effects to a minimum, and all should be fully explained to the patient before treatment is started.

Biological therapy

Overexpression of HER2 occurs in approximately 15 to 20% of women with breast cancer, and is associated with a more aggressive clinical course and poor outcome. Trastuzumab is a humanized monoclonal antibody that has been created by inserting portions of the antigen-binding site of a mouse monoclonal antibody against HER2 into a human monoclonal antibody. This targeted agent is given intravenously on a 1- or 3-weekly basis, alone or in combination with chemotherapy, to patients whose tumours are strongly positive (3+ by immunocytochemistry or amplified by in situ hybridization). The major toxicity relates to cardiac dysfunction, hence close monitoring with regular assessment of ejection fraction is mandatory.

Lapatinib is an orally administered dual HER2 and EGFR (epidermal growth factor receptor; HER1) inhibitor that has shown significant activity in breast cancer, even in women who have progressed on trastuzumab. Bevacizumab is an intravenous vascular endothelial growth factor (VEGF) inhibitor that also has activity in breast cancer.

Systemic therapy in early breast cancer

Most women present with local disease confined to the breast, with or without axillary node involvement. The decision on the recommendation of adjuvant systemic therapy is based on the knowledge of various prognostic factors, which include the following: size and grade of the tumour, presence and number of axillary nodes habouring metastatic tumour, presence or absence of lympho-vascular invasion, hormone-receptor status, and HER2 overexpression. Other factors include menopausal status and comorbidities. Treatment guidelines are available to aid decision making. The National Institute of Health and Clinical Excellence has also produced guidelines to support recent developments in the use of many systemic therapies in the United Kingdom.

In general, women with hormone-nonresponsive (ER/PR-negative) disease should be offered chemotherapy. Those with hormone-responsive (ER/PR-positive) disease should be offered endocrine therapy, with the addition of chemotherapy to some intermediate-risk and all high-risk groups. Trastuzumab should be given to all women following chemotherapy if their tumours are HER2 positive.

Endocrine therapy

Tamoxifen has been the standard treatment of choice for many years for both pre- and postmenopausal women, with the recommendation that it is given for 5 years following surgery. In premenopausal women the uncertainty over whether ovarian function suppression provides additional benefit over and above endocrine therapy (with or without chemotherapy), is currently under investigation in large international randomized studies (SOFT, TEXT, PERCHE).

In postmenopausal women the third-generation aromatase inhibitors are playing an increasingly important role, and following the results of large randomized studies they are indicated either as initial therapy (ATAC, BIG 1–98) or after treatment with 2 to 3 years of tamoxifen (IES, BIG 1–98, ARNO) or following 5 years of tamoxifen (MA-17). The optimal timing and duration of aromatase inhibitor therapy has yet to be established. A disease-free survival advantage has been reported in all these trials, but an overall survival benefit only in the IES and MA-17 studies to date.

Chemotherapy

In general, all women with high-risk breast cancer will be offered chemotherapy, with the most benefit being gained in younger women and those with hormone-receptor negative tumours. Anthracycline-based chemotherapy is now standard of care. Treatment is given for six to eight courses in an outpatient setting, traditionally on a 3-weekly basis, but 2 weekly with growth-factor support is also possible. For patients with hormone-receptor positive tumours endocrine therapy is traditionally given after the chemotherapy.

Taxanes are increasingly being used in the adjuvant setting, particularly for women with high-risk, node-positive disease. This is based on a number of large randomized studies, such as CALGB 9344, BCIRG 001, and PACS01, with small but significant differences for both disease-free survival and overall survival compared with the control group. Further information will be available with longer follow-up and with the reporting of recently completed or ongoing trials.

There are a number of agents which are still being evaluated in the adjuvant setting, including gemcitabine, capecitabine and platinum compounds.

Biological therapy

Several trials have shown a significant benefit for the use of adjuvant trastuzumab in women whose tumours are HER2 positive. This is given for a period of a year following anthracycline-based chemotherapy, with several studies in progress to evaluate or report on a shorter (6 months, PERSEPHONE) or longer (2 years, HERA) duration. Lapatinib and bevacizumab are also being investigated in the adjuvant setting.

Systemic therapy as primary medical therapy

For women with locally advanced (operable and inoperable) large or inflammatory breast cancers, treatment with systemic therapy, in particular chemotherapy, is given as the initial treatment of choice. This approach can reduce the size of the tumour and render it operable. For more than a decade this approach has been extended to women with earlier stage tumours so that they can choose primary chemotherapy as initial treatment to increase the potential for breast-conserving surgery and thus avoid a mastectomy. Randomized studies have shown that this approach, followed by definitive surgery, radiotherapy, and additional systemic therapy (e.g. endocrine or trastuzumab) has a similar outcome. Additional benefits include the opportunity to determine whether the patient has a chemosensitive tumour, with the option of changing to a different non-cross-resistant regimen or stopping early if there is no response or the disease progresses. This approach also offers the unique opportunity to study the biology of early breast cancer using the tumour as a model, which will ultimately lead to tailored therapy for particular molecular subsets.

Standard treatment is usually with initial anthracycline-based chemotherapy followed by a taxane. This sequential scheduling has been shown to increase the rate of pathological complete remission, which is strongly correlated with survival.

Metastatic breast cancer

Despite the major advances outlined above, many women develop distant metastases and die of their disease. The median survival is about 3 years, but some women may have a very protracted course over many years. The most common sites and clinical scenarios associated with metastatic disease are shown in Table 13.8.3.4. Many of these can precipitate an acute medical emergency. If this is the first presentation of metastatic breast cancer the importance of taking a full medical history cannot be underestimated. Treatment is aimed at controlling symptoms, improving quality of life, and prolonging survival.

Table 13.8.3.4 Sites of metastatic disease and presentation

Site

Symptom/sign

Bone

Pain, fracture, hypercalcaemia, spinal cord compression

Soft tissue

Lymphadenopathy (with or without symptoms), skin nodules

Lung

Dyspnoea, cough, haemoptysis, pleural effusion(s), lung nodules, lymphangitis carcinomatosis

Liver

Anorexia, weight loss, abdominal pain, abdominal swelling, jaundice, ascites

Brain/CNS

Headaches, nausea, vomiting, visual disturbance, hemiparesis, carcinomatous meningitis

Heart

Dyspnoea, cardiac failure, pericardial effusion

Endocrine therapy

In the absence of rapidly progressive or life-threatening metastatic disease, endocrine therapy is the treatment of first choice providing the tumour is hormone-receptor positive. The options available are shown in Table 13.8.3.2 and will depend on the type of endocrine therapy given in the adjuvant setting and the time interval between stopping therapy and the development of recurrence. Treatment is given on a continuous basis, providing the patient responds or shows evidence of disease stabilization. The median duration of response or stabilization is 18 months. Once the patient has become resistant to a particular endocrine therapy then a change to an alternative is appropriate, e.g. from a nonsteroidal aromatase inhibitor to a steroidal aromatase inhibitor in postmenopausal women. In premenopausal women the treatment of first choice is a combination of an LHRH agonist with tamoxifen, with a change to an aromatase inhibitor on progression while maintaining complete ovarian blockade.

Chemotherapy

If the patient has exhausted all endocrine options, or has a hormone receptor-negative tumour, or rapidly progressive disease, then chemotherapy is the treatment of choice. The regimen will depend on the type given in the adjuvant therapy (Table 13.8.3.3). For example, as most women will have received an anthracycline in the adjuvant setting, then a taxane (docetaxel 3 weekly or weekly paclitaxel) would be advised. Treatment is usually given for 4 to 6 months, with regular objective assessments by clinical evaluation and CT scan after 2 to 3 courses to ensure that the patient is responding. The median duration of response is about 8 months. Should the patient not respond, progress while on treatment, or relapse on follow-up, then additional second-line chemotherapy would be considered, e.g. capecitabine.

Biological therapy

Trastuzumab should be considered in combination with nonanthracycline chemotherapy for those women who are HER2-positive. A major advance in the management of metastatic disease has been the improvement in survival in HER2-positive women receiving trastuzumab with paclitaxel, compared with paclitaxel alone. Trastuzumab is advocated in combination with other types of chemotherapy such as capecitabine and vinorelbine. Lapatinib and bevacizumab are currently being evaluated in a number of metastatic settings. There are also a number of other small molecules that are being investigated either as single agents or in combination with endocrine therapy or chemotherapy.

Adjunctive therapies

The prompt treatment of symptoms related to metastatic breast cancer is essential as an adjunct to the systemic therapy outlined in the previous sections. These include pain control with appropriate analgesia; draining ascites or pleural effusions; radiotherapy for bone pain, brain metastases, or spinal cord compression; and relief of obstructive jaundice by stenting.

A major step forward in the management of symptoms related to bone involvement has been the use of bisphosphonates. Currently, these agents (e.g. zoledronic acid, ibandronic acid) are indicated in patients who have evidence of bone involvement (radiographs, CT scan, or MRI), whether they have developed symptoms or not. They are usually given intravenously 3 to 4 weekly, initially for 6 to 12 months, and then orally (with newer compounds that are relatively well absorbed such as ibandronic acid). This has resulted in a reduction in a number of the common morbidities associated with bone involvement (fractures, hypercalcaemia, and pain).

Future developments

Although significant improvements have been made there remain a number of unresolved issues in the contemporary treatment of breast cancer. As many new genetic alterations involved in carcinogenesis are being unravelled and we gain greater understanding of previously identified molecular pathways, novel therapies are being introduced. Target-based therapies are widely considered to be the future of breast cancer treatment, and much attention has focused on developing agents directed against a number of pathways involving protein kinases, such as the EGFR–Ras–Raf–MEK–ERK–MAPK signalling pathway. A number of approaches have been employed in an attempt to target this and other pathways. These approaches include biological inhibitors (ribozymes, dominant-negative receptors, decoy receptors, peptides), antagonist antibodies, small-molecule inhibitors, and antisense inhibitors of expression.

Furthermore, as the cancer stem-cell hypothesis gains greater recognition, efforts have been made in an attempt to selectively target the cancer stem cell, believed to be resistant to conventional therapeutic approaches and to be responsible for local and systemic recurrence. A number of pathways involved in normal stem-cell regulation and believed to be disrupted in cancer have been the focus of attention, such as the Notch and Wnt signalling pathways. Table 13.8.3.5 summarizes and gives some examples of current and future attempts at target-based breast cancer treatment. These are all potentially useful, but trials in breast cancer are yet to be implemented for many.

Table 13.8.3.5 Current and future attempts at target-based breast cancer treatment

Pathway

Function

Disrupted/altered in

Current/potential future therapeutic agents

PI3K/Akt/mTOR

  • Proliferation survival

  • Growth

  • Mobility

Renal cell carcinoma Breast cancer Prostate cancer Mantle cell lymphoma

  • Sirolimus

  • Temsirolimus

  • VQD-002

  • Perifosine

  • GDC0941

  • Archexin

EGFR1–4

Growth Proliferation Survival Differentiation

  • Lung carcinoma Breast cancer

  • Head–neck

  • Gliomas

  • Lapatinib Gefitinib

  • Erlotinib

HGF/cMet

Epithelial–mesenchymal transition Growth Angiogenesis Survival Morphogenesis Adhesion

Head–neck cancers Breast cancer Hepatocellular carcinoma Pancreatic cancer

NK4 PHA665752 U1 ribozyme Antibody antagonists (5D5)

Notch

Stem-cell maintenance Proliferation Differentiation Apoptosis Angiogenesis

T-cell acute lymphoblastic leukaemia Breast cancer Renal carcinoma Pancreatic cancer Colorectal cancer

LY450139

Wnt/apc/catenin

Cell proliferation Differentiation Cell motility Apoptosis

Colorectal cancer Medulloblastoma Breast cancer Wilm’s tumour Prostate cancer Hepatocellular carcinoma

  • NSAIDs

  • Imatinib mesilate Endostatin β‎-catenin antisense nucleotides

  • Chimeric F-box protein

  • TCF-restricted replicating viruses

  • CGP049090

PLC/PKC

Cell proliferation Differentiation Apoptosis Angiogenesis

Breast cancer Pancreatic cancer Melanoma Haematological

Bryostatin 1 ISIS 3521 Enzastaurin

Ras/MEK

Cell proliferation Cell survival Differentiation

Colorectal cancer Pancreatic cancer Breast cancer Glioblastoma Papillary thyroid cancer

  • Antisense inhibitors of Raf expression LErafAON

  • AZD6244 CI-1040

NFκ‎B/Iκ‎Bα‎

  • Transcription Apoptosis

  • Cell cycle control

  • Cell transformation

  • Growth Differentiation

  • Breast cancer Colorectal cancer Hepatocellular carcinoma

  • Myeloma

Parthenolide BAY 11–7082 Antioxidants Nucleotides (antisense)

PDGFR

Embryonic development Cell proliferation Migration Angiogenesis

  • Gastrointestinal stromal tumours

  • Renal cancer

  • Small cell lung cancer

  • Pancreatic cancer

  • Sunitinib

  • Sorafenib Imatinib

CXCR/CCR7

Embryogenesis Angiogenesis Inflammation Cell migration

Breast cancer Ovarian cancer Prostate cancer Pancreatic cancer Melanoma

AMD3100 Bismacrocyclic analogues

VEGFR

Angiogenesis Increases vascular permeability

  • Colorectal cancer Renal cancer Prostate cancer

  • Lung cancer

  • Breast cancer

  • Bevacizumab Vatalanib

  • Sunitinib AZD-2171

NSAIDs, nonsteroidal anti-inflammatory drugs.

Resistance to drug therapy is frequently encountered, hence further understanding of the mechanisms involved and the development of novel modulators to overcome resistance and target molecular subsets will contribute to increasing the survival in this disease and enable advances in tailor-made therapy.

Further reading

Aetiology

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Collaborative Group on Hormonal Factors in Breast Cancer (1997). Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet, 350, 1047–59.Find this resource:

Cuzick J, et al. (2003). Overview of main outcomes in breast cancer prevention trials. Lancet, 361, 296–300.Find this resource:

Easton DF, et al. (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 447, 1087–93.Find this resource:

Ford D, Easton DF, Peto J (1995). Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet, 57, 1457–62.Find this resource:

Michels KB, et al. (2007). Diet and breast cancer: a review of the prospective observational studies. Cancer, 109 Suppl 12, 2712–49.Find this resource:

Rosman DS, Kaklamani V, Pasche B (2007). New insights into breast cancer genetics and impact on patient management. Curr Treat Options Oncol, 8, 61–73.Find this resource:

Vainio H, Bianchini F (2002). Breast cancer screening. IARC handbooks of cancer prevention, vol 7. IARC Press, Lyon, France.Find this resource:

    Walsh T, King MC (2007). Ten genes for inherited breast cancer. Cancer Cell, 11, 103–5.Find this resource:

    Wooster R, Stratton MR (1995). Breast cancer susceptibility: a complex disease unravels. Trends Genet, 11, 3–5.Find this resource:

    Yager JD, Davidson NE (2006). Mechanisms of disease. Estrogen carcinogenesis in breast cancer. N Engl J Med, 354, 270–82.Find this resource:

    Pathology

    Harvey JM, et al. (1999). Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol, 17, 1474–81.Find this resource:

    NHS Cancer Screening Programmes and The Royal College of Pathologists (2005). Pathology reporting of breast disease. http://www.cancerscreening.nhs.uk/breastscreen/publications/nhsbsp58.html.

    Sørlie T, et al. (2001). Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 98, 10869–74.Find this resource:

    Treatment

    Bartelink H, et al. (2007). Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 228811–0882 trial. J Clin Oncol, 25, 3259–65.Find this resource:

    Bijker N, et al. (2006). Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853—a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol, 24, 3381–87.Find this resource:

    Clarke M, et al. (2005). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet, 366, 2087–106.Find this resource:

    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 365, 1687–717.Find this resource:

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    Fisher B, et al. (2002). Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med, 347, 1233–41.Find this resource:

    Forrest AP, et al. (1995). The Edinburgh randomized trial of axillary sampling or clearance after mastectomy. Br J Surg, 82, 1504–8.Find this resource:

    Giuliano AE, et al. (2011). Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis. A randomized clinical trial. JAMA, 305, 569–75.Find this resource:

    Goldhirsch A, et al. (2007). Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol, 18, 1133–44.Find this resource:

    Kissin MW, et al. (1982). The inadequacy of axillary sampling in breast cancer. Lancet, 1, 1210–2.Find this resource:

    Lyman GH, et al. (2005). American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol, 23, 7703–20.Find this resource:

    Lynch MD, Cariati M, Purushotham AD. (2006). Breast cancer, stem cells and prospects for therapy. Breast Cancer Res, 8, 211.Find this resource:

    Veronesi U, et al. (2002). Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med, 347, 1227–32.Find this resource:

    Veronesi U, et al. (2005). Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery: experience with 590 cases. Ann Surg, 242, 101–6.Find this resource: