- Email: [email protected]
Breast cancer
COMMON CANCERS
disease (5-year survival rates: 81% <45 years, 86% >65 years). Other risk factors include early menarche, late menopause, parity, breastfeeding and prolonged use of exogenous hormones, obesity, lack of exercise and alcohol consumption. Fewer than 5% of breast cancers are genetic. Patients with proven gene mutations (BRCA1/BRCA2) have an estimated lifetime risk of developing breast cancer of 40e85%. Breast cancer clearly poses a significant economic burden on an already struggling National Health Service (NHS). The cost of the NHS Breast Screening programme alone is £75 million (£37.50 per woman invited and £45.50 per woman screened). The cost of treating early breast cancer is poorly documented in the literature, but a recent publication estimated the total population cost of treating metastatic breast cancer at £26 million/year.2 With new technologies and targeted therapies it is inevitable that these costs will increase, putting more pressure on the economy.
Breast cancer Eleri Lloyd Davies
Abstract Breast cancer is the most common cancer to affect women, with a recent estimate of lifetime risk being one in eight. The number of women found to have breast cancer in the UK has risen to 52,250 in 2011 with the highest rise being in the 50e69-years age group. This is probably attributable to several lifestyle factors such as diet, alcohol consumption, lack of exercise and late pregnancies. Because of earlier diagnosis and major treatment advances, survival rates have gradually improved over the last 20 years, with 80% of patients with early breast cancer now surviving 10 years after diagnosis. Recent advances in surgical management include the use of oncoplastic techniques for breast conservation and also advances in breast reconstruction following mastectomy. The current controversial area is the management of the positive axilla. The majority of patients will be offered adjuvant treatment such as radiotherapy, hormones, chemotherapy and biological agents, which aim to reduce local recurrence and improve survival. Novel developments include the use of biological markers to predict outcome and response to chemotherapy. This overview discusses the up-to-date management of breast cancer and recent developments in this field.
Pathology The majority of breast cancers (70e80%) are ductal, with several special subtypes (medullary, papillary, tubular, mucinous). Lobular cancers account for the remaining 20%. The tumour/ node/metastasis (TNM) classification looks at size, nodal status and distant metastasis. A simplified version is shown in Table 1. When considering nodal status, the presence of individual tumour cells is classed as node-negative, whereas micrometastasis (>0.2e2 mm) is classed as node-positive. The American Joint Committee on Cancer staging system provides a strategy for grouping patients with respect to prognosis (Table 2). Other variables that affect survival are oestrogen receptor (ER) and human epidermal growth receptor-2 (HER2) receptor status. The development of microarray-based gene expression profiling has shown breast cancer to be heterogeneous e it can be subclassified into five distinct subtypes: luminal A, luminal B, HER2overexpressing, basal-like and normal-like. These subtypes have very different prognoses and responses to adjuvant therapies.3
Keywords adjuvant therapy; biological markers; breast cancer; oncoplastic; sentinel node biopsy; trastuzumab
Terminology Breast cancer is caused by the presence of malignant cells in the breast. Cancer cells are characterized by uncontrolled division, leading to abnormal growth (in situ carcinoma) and the ability to invade normal tissue locally (invasive cancer). Depending on whether the glandular or ductal units of the breast are involved enables pathologists to subclassify breast cancer into types. The primary tumour begins in the breast but, once it becomes invasive, may progress to the regional (axillary/internal mammary) lymph nodes and it then has the ability to metastasize. The commonest sites of systemic involvement are the lung, bones, liver, skin and soft tissue. The presence of and number of regional lymph nodes containing cancer remains the single best indicator of whether or not the cancer has metastasized.
Diagnosis Patients present with symptoms or are detected through the NHS breast screening programme. National Institute for Health and Care Excellence (NICE) guidance4 states that both symptomatic and screen-detected patients should be referred to a specialist breast clinic for triple assessment (clinical, radiological, pathological). These assessments are now being performed more frequently in one-stop clinics as shown in Figure 1. Clinical assessment includes a history and an examination by a specialist breast surgeon or clinician. All patients over the age of 35 years will have a two-view mammogram with or without tomosynthesis. Any areas of clinical or mammographic concern are then examined by ultrasound scanning. If there is a discrete lesion to biopsy, a core biopsy is performed. A scoring system is used, ranging from 1 (benign) to 5 (malignant) for each component of the triple assessment. All patients are finally discussed at multidisciplinary team meeting to confirm a diagnosis and treatment plan.
Epidemiology Each year, breast cancer is diagnosed in 1.3 million women worldwide and 465,000 deaths result from the disease. It occurs very infrequently in men (300/year in UK) compared with women.1 The incidence increases with age, 80% occurring in women over the age of 50 years. It occurs less commonly in younger women, but they tend to display more aggressive
Investigations Eleri Lloyd Davies MB BCh FRCS(Eng) is an Oncoplastic Breast Surgeon Working at The Breast Centre, University Hospital Llandough, Cardiff, UK. Competing interests: none declared.
MEDICINE --:-
Histological investigations e as well as confirming the diagnosis (type, grade), these provide useful information
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
useful for accurate sizing of the cancer in very dense breasts.
Simplified tumour/node/metastasis (TNM) classification of breast cancer
Management
Tumour stage T1 Tumour <2 cm T2 Tumour 2e5 cm T3 Tumour 5 cm T4 Tumour fixed chest wall/skin or inflammatory Nodal stage Clinical Pathological pN Negative of individual tumour N0 No nodes cells (ITC) 1e3 micro- or N1 Mobile regional nodes macrometastasis 4e9 nodes N2 Fixed regional or internal mammary nodes N3 Supraclavicular nodes >10 nodes, axillary and internal mammary or supraclavicular nodes Distant metastasis M0 No distant metastasis M1 Distant metastasis
Multidisciplinary team (MDT) meeting Therapeutic decisions are made according to tumour size, lymph node status, ER, PR and HER2 status, and general health of the patient. A number of tools (e.g. Adjuvant! Online, Predict and NICE guidelines) are used to aid decision-making. In addition, the use of commercially available kits (e.g. Oncotype DXÒ, MammaPrintÔ), which characterize expression of a subset of genes within the breast cancer tissue, are increasingly being employed to estimate the likelihood of disease recurrence and/or response to chemotherapy in certain breast cancer subtypes7,8 (see Cytotoxic Chemotherapy: Clinical Aspects and Adjuvant Therapy on pages xxx and pages 00 respectively of this issue). Surgery Traditionally, the aim of surgery was to completely remove the primary breast lesion and axillary lymph nodes. Most patients were offered wide local excision (WLE) followed by postoperative radiotherapy or mastectomy. With increasing interest in oncoplastic breast surgery, a wide selection of breastconserving approaches e therapeutic mammoplasty, circumareolar incisions with dermoglandular flaps and several miniflaps e are now being offered, which achieve better cosmetic outcomes. In addition, in those 25e30% of patients who require a mastectomy, more women are being offered immediate or delayed reconstruction. Skin- and nipple-sparing mastectomy with reconstruction offers an excellent final cosmetic result for suitable patients. There is an increased interest in the use of various tissue matrices (i.e. StratticeÔ and AlloDermÒ), as well as an increasing use of microvascular surgery to improve cosmetic results. Other advances include lipofilling/lipomodulation, which involves the use of autologous fat transplantation techniques to improve breast-volume defects following breast conservation or reconstruction.9 Historically, axillary surgery involved an axillary node clearance (ANC). With only 25e30% of patients being node-positive, the remaining node-negative patients were subjected to a risk of lymphoedema, shoulder stiffness and paraesthesia without benefit. Sentinel node biopsy (SNB) allows accurate staging of the axilla using a minimally invasive surgical procedure with reduced morbidity. The sentinel lymph node (SLN) is identified by using a combination of radioactive colloid suspension and blue dye (Figure 3) (see Diagnostic and Therapeutic Imaging in Oncology on page xxx in this issue). If the SLN is negative on histological examination, the patient is classed as node-negative. However, the disadvantage of SNB is that women with positive nodes traditionally required a second operation to complete axillary surgery. This has triggered an interest in intraoperative assessment of the SLN, followed by immediate axillary surgery if the node is positive. Several techniques have been introduced, including frozen section, touch imprint cytology and reverse transcription polymerase chain reaction.10 Recent publication of the Z11 clinical trial11 comparing axillary dissection with no axillary treatment in women with
Table 1
about oestrogen (ER), progesterone (progesterone receptor (PR)) and HER2 status. Radiological staging (computed tomography of the thorax, abdomen and pelvis, and bone scanning) e these are performed only if there is a high suspicion of metastasis (i.e. bone pain or locally advanced disease, lymph nodes discovered postoperatively or recurrent disease). Magnetic resonance imaging (MRI) is currently used in limited situations in breast cancer patients because a large multicentre trial (COMICE) demonstrated an increased incidence of overtreatment when MRI was used preoperatively in breast cancer.5 The current indications are lobular breast cancer, multifocal disease, dense breast (where estimation of cancer size is an issue) and assessment of implant integrity. In lobular cancers there is a high incidence of bilateral disease and multifocality, and MRI has proved beneficial in surgical planning for these patients.6 In addition, Figure 2 illustrates how MRI can be
AJCC staging system for breast cancer Stage
TNM classification
5-year survival
I IIa IIb IIIa IIIb IIIc IV
T1N0M0 T1N1M0 or T2N0M0 T2N1M0 or T3N0M0 T2N2M0 or T3N1M0 or T3N2M0 T4N0M0 or T4N1M0 or T4N2M0 Any TN3M0 Any T, ANY N, M1
90% 80% 65% 45% 40% 30% 14%
AJCC, American Joint Committee on Cancer; TNM, tumour/node/metastasis.
Table 2
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2
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
action is achieved through suppression of ovarian function, by surgical means, using ovarian ablation, or by the use of luteinizing hormone-releasing hormone agonists such as goserelin. Alternatively, the use the selective oestrogen receptor modulators, such as tamoxifen, has been shown to reduce recurrence by 47% and death by 26%14 (see Hormonal Therapy for Cancer on page xx in this issue). However, most breast cancers occur in postmenopausal women and approximately 80% of these will be ER-positive. In these women the ovaries no longer produce oestrogen; instead, small quantities of oestrogens are synthesized in non-ovarian tissues such as the liver, adrenal glands and, importantly, breast tissue itself. Traditionally, the oestrogenic stimulation of breast cancer was suppressed through the use of tamoxifen. Aromatase inhibitors (AIs) target oestrogen production by blocking the conversion of androgens to oestrogen through inhibition of the aromatase enzyme. Clinical data demonstrate that AIs are superior to tamoxifen15 and have replaced it as a first-line therapy in postmenopausal women with breast cancer. The optimal duration of treatment is still uncertain but it is currently given for at least 5 years. Many patients experience adverse effects that include hot flushes, venous thromboembolism and endometrial cancer (tamoxifen), arthralgia and osteoporosis (AIs).
Algorithm of the triple assessment process Screening
Symptomatic
Triple assessment < 35 years
> 35 years
Clinical and USS Normal
Lump
Reassure
Biopsy
Clinical and mammography Normal Reassure
Lump/ abnormality Ultrasound biopsy
MDT Benign Reassure
Malignant Treatment options
MDT, multidisciplinary team; USS, ultrasound scanning. Figure 1
Chemotherapy: adjuvant chemotherapy has been shown to reduce local recurrence by 30% and death by 20%.14 Chemotherapy is usually used in combination regimens to reduce toxicity and resistance, and increase efficacy. Anthracycline regimens are considered the ‘gold standard’. Patients are offered chemotherapy only if they have high-risk disease (premenopausal, ER/PR-negative, HER2 overexpression, large tumours and node-positive disease) to avoid toxicity and the use of expensive drugs in those who will not benefit. Adverse effects of treatment include myelosuppression, alopecia, nausea, diarrhoea and infertility. Anthracyclines are cardiotoxic. There is also increasing interest in and use of neoadjuvant chemotherapy (NACT) in a subgroup of patients. The benefits of NACT are multifold and include down-staging the disease to allow advanced of inflammatory cancers to become operable. However, there is also a role for NACT in operable cancer to allow down-staging of disease to allow breast conservation, down-staging of nodal disease and time to assess the response to chemotherapy.
invasive breast cancer and positive SNB has caused much controversy regarding the correct treatment of the axilla in this group of patients. In the UK there is no consensus of opinion. The POSNOC trial has been launched to try and answer this specific question. Adjuvant therapy The aim is to reduce the risk of loco-regional and distant recurrence and improve overall survival by targeting microscopic tumour foci in residual breast tissue, regional lymph nodes or the bloodstream. Radiotherapy: radiotherapy after WLE reduces the 5-year local recurrence rate from 26% to 7% and has been shown to be equivalent to mastectomy. Recent evidence suggests an overall absolute survival benefit of about 5% for postoperative adjuvant radiotherapy.12 The majority of mastectomy patients do not require radiotherapy, but those at increased risk of recurrence (T3/T4 tumours, lymphovascular invasion, four or more positive lymph nodes) will benefit from chest wall and supraclavicular fossa irradiation. Recent evidence has supported the use of radiotherapy in intermediate and high-grade ductal carcinoma in situ. Trials of the use of axillary radiotherapy in SLN-positive patients (AMAROS trial) have demonstrated that ANC and axillary radiotherapy after a positive SNB provide excellent and comparable regional control. Radiotherapy had a lower risk of short-term and long-term lymphoedema compared with surgery. Clinical trials are currently assessing the role of intraoperative partial breast irradiation.13
Biological therapy and novel agents: trastuzumab, a monoclonal antibody used in the treatment of HER2-positive patients, reduces recurrence by 50% and prolongs survival by 30% when used in combination with chemotherapy.16 It is now included in NICE guidelines. Its main toxicity is cardiac failure, and use in combination with anthracyclines should be avoided. Other novel drugs include the oral tyrosine kinase inhibitor lapatinib, and the anti-angiogenic drug bevacizumab. Both have demonstrated efficacy following trastuzumab failure and are licensed for use, but are only available by application on a named-patient basis because of their cost. Early clinical trials have shown that nuclear enzyme poly (ADP-ribose) polymerase inhibitors, controlling DNA repair and apoptosis, are of particular benefit with BRCA mutations and in basal-like and triple-negative (ER/PR/HER2) patients.
Endocrine therapy: oestrogens play a crucial role in breast cancer; by binding to target receptors they promote proliferation of breast cancer cells. The majority of breast cancers (w70%) are ER-positive. In premenopausal women, circulating oestrogens are produced primarily by the ovaries. Inhibition of oestrogen
MEDICINE --:-
3
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
Figure 2 (a) Right mammogram showing very dense breast tissue. (b) Magnetic resonance imaging scan in the same patient demonstrating a 4.1-cm lobular cancer not visible on the initial mammograms.
Follow-up There is current controversy over the most appropriate follow-up procedure. NICE guidelines (2009) suggest annual mammograms for 5 years and clinical follow-up until adjuvant therapies have been completed.4 The ideal interval for mammographic followup is controversial and the Mammo50 trial is assessing this further. Follow-up procedures are usually agreed at a local level and many are run by nurses with extended roles. Issues to consider are management of the adverse effects of adjuvant hormones and, in particular, bone health.
Metastatic disease Metastatic breast cancer will be covered only briefly in this paper. Treatment focuses on palliating symptoms to maintain quality of life and to extend life where possible. The treatments offered are as follows: endocrine therapy e in ER-positive patients as first line chemotherapy e reserved for patients who are ER-negative or hormone-resistant trastuzumab e for HER2-positive patients, even if they were given it at initial treatment
Figure 3 (a) A sentinel node, which has been dyed blue, with a blue lymphatic draining into it. (b) Measuring the signal from the technetium 99m in a lymph node using a probe.
MEDICINE --:-
4
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
radiotherapy e in those with bony metastases (to improve pain control), cord compression and, in addition, superior vena caval obstruction, fungating chest wall disease and brain metastases bisphosphonates e to reduce risk of pathological fractures and improve pain control. A
8 Menta R, Jain RK, Badve S. Personalized medicine: the road ahead. Clin Breast Cancer 2011; 11: 20e6. 9 Elfadl D, Gavimella V, Mahapatra TK, McManus PL, Drew PJ. Lipomodelling of the breast: a review. Breast 2010; 19: 202e9. 10 Chen JJ, Yang BC, Zhang JX. A prospective comparison of molecular assay and touch imprint cytology for intraoperative evaluation of sentinel lymph nodes. Clin Med J (Engl) 2011; 124: 491e7. 11 Guiliano A, Hunt KK, Ballman KC, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. J Am Med Assoc 2011; 305: 569e75. 12 Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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 2005; 366: 2087e106. 13 Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intra-operative radiotherapy versus breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, noninferiority phase 3 trial. Lancet 2010; 376: 91e102. 14 Early Breast Cancer Trials’ Collaborative Group (EBCTG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of randomised control trials. Lancet 2005; 365: 1687e717. 15 Cuzick J, Sestak I, Baum M, et al. Effect of anastrazole and tamoxifen as adjuvant treatment for early stage breast cancer: 10 year analysis of ATAC trial. Lancet Oncol 2010; 11: 1135e41. 16 Piccart-Gebhart MJ, Procter M, Leyland-Jones B. Trastuzumab after adjuvant chemotherapy in Her2 positive patients. N Engl J Med 2005; 353: 1659e72.
REFERENCES 1 Office for National Statistics. Cancer Statistics Regulations, England (Series MB1). http://www.ons.gov.uk/ons/rel/vsob1/cancerstatistics-registrationseenglandeseries-mb1-/index.html. 2 Ramak E, Brazil L. Cost of managing women presenting with stage 1V breast cancer in the United Kingdom. Br J Cancer 2004; 91: 77e83. 3 Dowsett M, Dunbler AK. Emerging biomarkers and new understanding of traditional markers in personalized therapy for breast cancer. Clin Cancer Res 2008; 14: 8019e26. 4 National Institute for Health and Care Excellence. Guidance on breast cancer (early and locally advanced): diagnosis and treatment. 2009. London: NICE. Also available at: http://guidance.nice. org/CG80. 5 Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised control trial. Lancet 2010; 355: 563e71. 6 Boetes C, Veltman J, van Die L, Bult P, Wobber T, Barentsz JO. The role of MRI in invasive lobular carcinoma. Breast Cancer Res Treat 2004; 86: 31e7. 7 Kaufman M, Puztai L, Biedenkopf Expert Panel Members, et al. Use of standard markers and incorporation of molecular markers in breast cancer therapy: consensus recommendation from an international expert panel. Cancer 2011; 117: 1575e82.
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5
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Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
disease (5-year survival rates: 81% <45 years, 86% >65 years). Other risk factors include early menarche, late menopause, parity, breastfeeding and prolonged use of exogenous hormones, obesity, lack of exercise and alcohol consumption. Fewer than 5% of breast cancers are genetic. Patients with proven gene mutations (BRCA1/BRCA2) have an estimated lifetime risk of developing breast cancer of 40e85%. Breast cancer clearly poses a significant economic burden on an already struggling National Health Service (NHS). The cost of the NHS Breast Screening programme alone is £75 million (£37.50 per woman invited and £45.50 per woman screened). The cost of treating early breast cancer is poorly documented in the literature, but a recent publication estimated the total population cost of treating metastatic breast cancer at £26 million/year.2 With new technologies and targeted therapies it is inevitable that these costs will increase, putting more pressure on the economy.
Breast cancer Eleri Lloyd Davies
Abstract Breast cancer is the most common cancer to affect women, with a recent estimate of lifetime risk being one in eight. The number of women found to have breast cancer in the UK has risen to 52,250 in 2011 with the highest rise being in the 50e69-years age group. This is probably attributable to several lifestyle factors such as diet, alcohol consumption, lack of exercise and late pregnancies. Because of earlier diagnosis and major treatment advances, survival rates have gradually improved over the last 20 years, with 80% of patients with early breast cancer now surviving 10 years after diagnosis. Recent advances in surgical management include the use of oncoplastic techniques for breast conservation and also advances in breast reconstruction following mastectomy. The current controversial area is the management of the positive axilla. The majority of patients will be offered adjuvant treatment such as radiotherapy, hormones, chemotherapy and biological agents, which aim to reduce local recurrence and improve survival. Novel developments include the use of biological markers to predict outcome and response to chemotherapy. This overview discusses the up-to-date management of breast cancer and recent developments in this field.
Pathology The majority of breast cancers (70e80%) are ductal, with several special subtypes (medullary, papillary, tubular, mucinous). Lobular cancers account for the remaining 20%. The tumour/ node/metastasis (TNM) classification looks at size, nodal status and distant metastasis. A simplified version is shown in Table 1. When considering nodal status, the presence of individual tumour cells is classed as node-negative, whereas micrometastasis (>0.2e2 mm) is classed as node-positive. The American Joint Committee on Cancer staging system provides a strategy for grouping patients with respect to prognosis (Table 2). Other variables that affect survival are oestrogen receptor (ER) and human epidermal growth receptor-2 (HER2) receptor status. The development of microarray-based gene expression profiling has shown breast cancer to be heterogeneous e it can be subclassified into five distinct subtypes: luminal A, luminal B, HER2overexpressing, basal-like and normal-like. These subtypes have very different prognoses and responses to adjuvant therapies.3
Keywords adjuvant therapy; biological markers; breast cancer; oncoplastic; sentinel node biopsy; trastuzumab
Terminology Breast cancer is caused by the presence of malignant cells in the breast. Cancer cells are characterized by uncontrolled division, leading to abnormal growth (in situ carcinoma) and the ability to invade normal tissue locally (invasive cancer). Depending on whether the glandular or ductal units of the breast are involved enables pathologists to subclassify breast cancer into types. The primary tumour begins in the breast but, once it becomes invasive, may progress to the regional (axillary/internal mammary) lymph nodes and it then has the ability to metastasize. The commonest sites of systemic involvement are the lung, bones, liver, skin and soft tissue. The presence of and number of regional lymph nodes containing cancer remains the single best indicator of whether or not the cancer has metastasized.
Diagnosis Patients present with symptoms or are detected through the NHS breast screening programme. National Institute for Health and Care Excellence (NICE) guidance4 states that both symptomatic and screen-detected patients should be referred to a specialist breast clinic for triple assessment (clinical, radiological, pathological). These assessments are now being performed more frequently in one-stop clinics as shown in Figure 1. Clinical assessment includes a history and an examination by a specialist breast surgeon or clinician. All patients over the age of 35 years will have a two-view mammogram with or without tomosynthesis. Any areas of clinical or mammographic concern are then examined by ultrasound scanning. If there is a discrete lesion to biopsy, a core biopsy is performed. A scoring system is used, ranging from 1 (benign) to 5 (malignant) for each component of the triple assessment. All patients are finally discussed at multidisciplinary team meeting to confirm a diagnosis and treatment plan.
Epidemiology Each year, breast cancer is diagnosed in 1.3 million women worldwide and 465,000 deaths result from the disease. It occurs very infrequently in men (300/year in UK) compared with women.1 The incidence increases with age, 80% occurring in women over the age of 50 years. It occurs less commonly in younger women, but they tend to display more aggressive
Investigations Eleri Lloyd Davies MB BCh FRCS(Eng) is an Oncoplastic Breast Surgeon Working at The Breast Centre, University Hospital Llandough, Cardiff, UK. Competing interests: none declared.
MEDICINE --:-
Histological investigations e as well as confirming the diagnosis (type, grade), these provide useful information
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
useful for accurate sizing of the cancer in very dense breasts.
Simplified tumour/node/metastasis (TNM) classification of breast cancer
Management
Tumour stage T1 Tumour <2 cm T2 Tumour 2e5 cm T3 Tumour 5 cm T4 Tumour fixed chest wall/skin or inflammatory Nodal stage Clinical Pathological pN Negative of individual tumour N0 No nodes cells (ITC) 1e3 micro- or N1 Mobile regional nodes macrometastasis 4e9 nodes N2 Fixed regional or internal mammary nodes N3 Supraclavicular nodes >10 nodes, axillary and internal mammary or supraclavicular nodes Distant metastasis M0 No distant metastasis M1 Distant metastasis
Multidisciplinary team (MDT) meeting Therapeutic decisions are made according to tumour size, lymph node status, ER, PR and HER2 status, and general health of the patient. A number of tools (e.g. Adjuvant! Online, Predict and NICE guidelines) are used to aid decision-making. In addition, the use of commercially available kits (e.g. Oncotype DXÒ, MammaPrintÔ), which characterize expression of a subset of genes within the breast cancer tissue, are increasingly being employed to estimate the likelihood of disease recurrence and/or response to chemotherapy in certain breast cancer subtypes7,8 (see Cytotoxic Chemotherapy: Clinical Aspects and Adjuvant Therapy on pages xxx and pages 00 respectively of this issue). Surgery Traditionally, the aim of surgery was to completely remove the primary breast lesion and axillary lymph nodes. Most patients were offered wide local excision (WLE) followed by postoperative radiotherapy or mastectomy. With increasing interest in oncoplastic breast surgery, a wide selection of breastconserving approaches e therapeutic mammoplasty, circumareolar incisions with dermoglandular flaps and several miniflaps e are now being offered, which achieve better cosmetic outcomes. In addition, in those 25e30% of patients who require a mastectomy, more women are being offered immediate or delayed reconstruction. Skin- and nipple-sparing mastectomy with reconstruction offers an excellent final cosmetic result for suitable patients. There is an increased interest in the use of various tissue matrices (i.e. StratticeÔ and AlloDermÒ), as well as an increasing use of microvascular surgery to improve cosmetic results. Other advances include lipofilling/lipomodulation, which involves the use of autologous fat transplantation techniques to improve breast-volume defects following breast conservation or reconstruction.9 Historically, axillary surgery involved an axillary node clearance (ANC). With only 25e30% of patients being node-positive, the remaining node-negative patients were subjected to a risk of lymphoedema, shoulder stiffness and paraesthesia without benefit. Sentinel node biopsy (SNB) allows accurate staging of the axilla using a minimally invasive surgical procedure with reduced morbidity. The sentinel lymph node (SLN) is identified by using a combination of radioactive colloid suspension and blue dye (Figure 3) (see Diagnostic and Therapeutic Imaging in Oncology on page xxx in this issue). If the SLN is negative on histological examination, the patient is classed as node-negative. However, the disadvantage of SNB is that women with positive nodes traditionally required a second operation to complete axillary surgery. This has triggered an interest in intraoperative assessment of the SLN, followed by immediate axillary surgery if the node is positive. Several techniques have been introduced, including frozen section, touch imprint cytology and reverse transcription polymerase chain reaction.10 Recent publication of the Z11 clinical trial11 comparing axillary dissection with no axillary treatment in women with
Table 1
about oestrogen (ER), progesterone (progesterone receptor (PR)) and HER2 status. Radiological staging (computed tomography of the thorax, abdomen and pelvis, and bone scanning) e these are performed only if there is a high suspicion of metastasis (i.e. bone pain or locally advanced disease, lymph nodes discovered postoperatively or recurrent disease). Magnetic resonance imaging (MRI) is currently used in limited situations in breast cancer patients because a large multicentre trial (COMICE) demonstrated an increased incidence of overtreatment when MRI was used preoperatively in breast cancer.5 The current indications are lobular breast cancer, multifocal disease, dense breast (where estimation of cancer size is an issue) and assessment of implant integrity. In lobular cancers there is a high incidence of bilateral disease and multifocality, and MRI has proved beneficial in surgical planning for these patients.6 In addition, Figure 2 illustrates how MRI can be
AJCC staging system for breast cancer Stage
TNM classification
5-year survival
I IIa IIb IIIa IIIb IIIc IV
T1N0M0 T1N1M0 or T2N0M0 T2N1M0 or T3N0M0 T2N2M0 or T3N1M0 or T3N2M0 T4N0M0 or T4N1M0 or T4N2M0 Any TN3M0 Any T, ANY N, M1
90% 80% 65% 45% 40% 30% 14%
AJCC, American Joint Committee on Cancer; TNM, tumour/node/metastasis.
Table 2
MEDICINE --:-
2
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002
COMMON CANCERS
action is achieved through suppression of ovarian function, by surgical means, using ovarian ablation, or by the use of luteinizing hormone-releasing hormone agonists such as goserelin. Alternatively, the use the selective oestrogen receptor modulators, such as tamoxifen, has been shown to reduce recurrence by 47% and death by 26%14 (see Hormonal Therapy for Cancer on page xx in this issue). However, most breast cancers occur in postmenopausal women and approximately 80% of these will be ER-positive. In these women the ovaries no longer produce oestrogen; instead, small quantities of oestrogens are synthesized in non-ovarian tissues such as the liver, adrenal glands and, importantly, breast tissue itself. Traditionally, the oestrogenic stimulation of breast cancer was suppressed through the use of tamoxifen. Aromatase inhibitors (AIs) target oestrogen production by blocking the conversion of androgens to oestrogen through inhibition of the aromatase enzyme. Clinical data demonstrate that AIs are superior to tamoxifen15 and have replaced it as a first-line therapy in postmenopausal women with breast cancer. The optimal duration of treatment is still uncertain but it is currently given for at least 5 years. Many patients experience adverse effects that include hot flushes, venous thromboembolism and endometrial cancer (tamoxifen), arthralgia and osteoporosis (AIs).
Algorithm of the triple assessment process Screening
Symptomatic
Triple assessment < 35 years
> 35 years
Clinical and USS Normal
Lump
Reassure
Biopsy
Clinical and mammography Normal Reassure
Lump/ abnormality Ultrasound biopsy
MDT Benign Reassure
Malignant Treatment options
MDT, multidisciplinary team; USS, ultrasound scanning. Figure 1
Chemotherapy: adjuvant chemotherapy has been shown to reduce local recurrence by 30% and death by 20%.14 Chemotherapy is usually used in combination regimens to reduce toxicity and resistance, and increase efficacy. Anthracycline regimens are considered the ‘gold standard’. Patients are offered chemotherapy only if they have high-risk disease (premenopausal, ER/PR-negative, HER2 overexpression, large tumours and node-positive disease) to avoid toxicity and the use of expensive drugs in those who will not benefit. Adverse effects of treatment include myelosuppression, alopecia, nausea, diarrhoea and infertility. Anthracyclines are cardiotoxic. There is also increasing interest in and use of neoadjuvant chemotherapy (NACT) in a subgroup of patients. The benefits of NACT are multifold and include down-staging the disease to allow advanced of inflammatory cancers to become operable. However, there is also a role for NACT in operable cancer to allow down-staging of disease to allow breast conservation, down-staging of nodal disease and time to assess the response to chemotherapy.
invasive breast cancer and positive SNB has caused much controversy regarding the correct treatment of the axilla in this group of patients. In the UK there is no consensus of opinion. The POSNOC trial has been launched to try and answer this specific question. Adjuvant therapy The aim is to reduce the risk of loco-regional and distant recurrence and improve overall survival by targeting microscopic tumour foci in residual breast tissue, regional lymph nodes or the bloodstream. Radiotherapy: radiotherapy after WLE reduces the 5-year local recurrence rate from 26% to 7% and has been shown to be equivalent to mastectomy. Recent evidence suggests an overall absolute survival benefit of about 5% for postoperative adjuvant radiotherapy.12 The majority of mastectomy patients do not require radiotherapy, but those at increased risk of recurrence (T3/T4 tumours, lymphovascular invasion, four or more positive lymph nodes) will benefit from chest wall and supraclavicular fossa irradiation. Recent evidence has supported the use of radiotherapy in intermediate and high-grade ductal carcinoma in situ. Trials of the use of axillary radiotherapy in SLN-positive patients (AMAROS trial) have demonstrated that ANC and axillary radiotherapy after a positive SNB provide excellent and comparable regional control. Radiotherapy had a lower risk of short-term and long-term lymphoedema compared with surgery. Clinical trials are currently assessing the role of intraoperative partial breast irradiation.13
Biological therapy and novel agents: trastuzumab, a monoclonal antibody used in the treatment of HER2-positive patients, reduces recurrence by 50% and prolongs survival by 30% when used in combination with chemotherapy.16 It is now included in NICE guidelines. Its main toxicity is cardiac failure, and use in combination with anthracyclines should be avoided. Other novel drugs include the oral tyrosine kinase inhibitor lapatinib, and the anti-angiogenic drug bevacizumab. Both have demonstrated efficacy following trastuzumab failure and are licensed for use, but are only available by application on a named-patient basis because of their cost. Early clinical trials have shown that nuclear enzyme poly (ADP-ribose) polymerase inhibitors, controlling DNA repair and apoptosis, are of particular benefit with BRCA mutations and in basal-like and triple-negative (ER/PR/HER2) patients.
Endocrine therapy: oestrogens play a crucial role in breast cancer; by binding to target receptors they promote proliferation of breast cancer cells. The majority of breast cancers (w70%) are ER-positive. In premenopausal women, circulating oestrogens are produced primarily by the ovaries. Inhibition of oestrogen
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COMMON CANCERS
Figure 2 (a) Right mammogram showing very dense breast tissue. (b) Magnetic resonance imaging scan in the same patient demonstrating a 4.1-cm lobular cancer not visible on the initial mammograms.
Follow-up There is current controversy over the most appropriate follow-up procedure. NICE guidelines (2009) suggest annual mammograms for 5 years and clinical follow-up until adjuvant therapies have been completed.4 The ideal interval for mammographic followup is controversial and the Mammo50 trial is assessing this further. Follow-up procedures are usually agreed at a local level and many are run by nurses with extended roles. Issues to consider are management of the adverse effects of adjuvant hormones and, in particular, bone health.
Metastatic disease Metastatic breast cancer will be covered only briefly in this paper. Treatment focuses on palliating symptoms to maintain quality of life and to extend life where possible. The treatments offered are as follows: endocrine therapy e in ER-positive patients as first line chemotherapy e reserved for patients who are ER-negative or hormone-resistant trastuzumab e for HER2-positive patients, even if they were given it at initial treatment
Figure 3 (a) A sentinel node, which has been dyed blue, with a blue lymphatic draining into it. (b) Measuring the signal from the technetium 99m in a lymph node using a probe.
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COMMON CANCERS
radiotherapy e in those with bony metastases (to improve pain control), cord compression and, in addition, superior vena caval obstruction, fungating chest wall disease and brain metastases bisphosphonates e to reduce risk of pathological fractures and improve pain control. A
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Please cite this article in press as: Davies EL, Breast cancer, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.002