Leading article
Lessons learned in breast cancer surgery I. S. Fentiman Research Oncology, Third Floor Bermondsey Wing, Guy’s Hospital, London SE1 9RT, UK (e-mail: [email protected])
Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9407
William Halsted1 reported the results of radical mastectomy 130 years ago. His achievement was to recognize that the only chance of controlling breast cancer was by complete excision. Less than radical operations resulted in early recurrence. His aim was to achieve local control and avoid fungating ulcers which, at that time, were the prelude to a grim death for many women. Breast conservation
Despite uncontrolled studies avoiding mastectomy, such as those of Geoffrey Keynes2 who used implanted radium needles, most surgeons regarded anything less than radical mastectomy as a breach of duty. Conservative surgery started very badly. The first randomized trial compared radical mastectomy with wide excision of the cancer3 . Both groups received 25–27 Gy to the supraclavicular fossa, internal mammary chain and axilla. Those treated by wide excision also received 35–38 Gy to the breast, so they had no axillary surgery and inadequate axillary radiotherapy. After 10 years, there were significantly more locoregional relapses in the wide excision group (25 versus 7 per cent), mostly in the axilla. For patients with clinical stage I tumours, overall survival at 10 years was 80 per cent in both groups, but for those with stage II disease, a wide excision meant significantly worse survival (30 versus 60 per cent). By 25 years, even those with stage I breast cancers treated by wide excision had a much higher death rate (57 versus 14 per cent)4 . Two lessons were learned: undertreatment of the 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
axilla increased both local recurrence and death from breast cancer; and the effect was not apparent with a short period of follow-up such as 5 years. Subsequent work, however, showed that outcomes in patients treated by either radical mastectomy or quadrantectomy, axillary clearance and radiotherapy were similar. Longterm results showed slightly more breast relapses in the conservation group but similar mortality in both arms5 . Breast-conserving surgery is now regarded as a safe oncological operation for patients with unifocal cancers measuring 40 mm or more. There is, however, a difference between conserving the breast and achieving a good cosmetic outcome. Excision of a 4-cm diameter mass may produce a major tissue deficit with poor cosmesis, and nowadays this can often be avoided by neoadjuvant therapy. This enables up to 80 per cent of patients with larger tumours to be downstaged and avoid mastectomy, as well as providing an opportunity for monitoring sensitivity to chemotherapy. The twin aims of oncoplastic surgery are to achieve good cosmesis and to resect the tumour with clear margins. If the breast is remodelled, margins will be moved and so intraoperative confirmation of tumour-free margins is essential. A variety of techniques have been developed to correct the residual deformity that exists in up to 30 per cent of patients undergoing wide excision6 . An atlas and guidelines that consider breast volume, density and tumour location are available to select the most
appropriate choice for the patient7 . If the resection comprises less than 20 per cent of breast volume, a step-bystep remodelling is possible, whereas a mammoplasty technique is needed for larger resections. Successful oncoplastic surgery not only requires the breast surgeon to be fully trained, but also necessitates an infrastructure that allows close collaboration with the histopathologist. Sentinel node biopsy
Sentinel node biopsy (SNB) is the simplest and least damaging method of confirming axillary nodal status, although not without a slight risk of lymphoedema, occurring in 1–7 per cent8,9 , as a result of overzealous harvesting of extra stained/hot nodes, postoperative infection or extension of the radiation field to the axilla. For those few patients with a falsenegative SNB, the situation is more complicated. In a Dutch multicentre study10 of 929 patients with a negative SNB, axillary recurrence occurred in 15 (1·6 per cent). Risk factors were young age and no radiotherapy. There was a significantly worse prognosis in those with axillary relapse. Although there is consensus that the presence of isolated tumour cells in the sentinel lymph node is not an indication for axillary clearance, controversy exists regarding management of micrometastasis (smaller than 0·2 mm) and single macrometastasis. Preliminary results from the American College of Surgeons Oncology Group Z0011 trial11 have prompted many surgeons to avoid axillary clearance. Only BJS 2014; 101: 145–147
146
with long-term follow-up will the effect of this strategy be determined. Breast reconstruction after mastectomy
Most clinicians would accept that immediate breast reconstruction should be discussed with all patients advised to have a mastectomy, except where significant co-morbidity or the need for adjuvant therapy precludes this option. The National Mastectomy and Breast Reconstruction Audit12 for 2009 in the UK, however, reported that only 18 per cent of women undergoing mastectomy had immediate reconstruction. Reconstructive options offered tend to be those that the breast surgeon has been trained to perform. Breast reconstruction has to be tailored to the needs and body habitus of the patient, and whenever possible performed at the same time as mastectomy to minimize the alteration in body image. Repeated procedures after suboptimal reconstruction are distressing for the patient, as well as time- and resource-consuming. Older women
Age alone is not a contraindication to effective systemic therapy and radiation. In a Cochrane analysis13 of seven trials comparing primary endocrine therapy (tamoxifen alone) with surgery, with or without adjuvant endocrine therapy, in women aged at least 70 years, progression-free survival was significantly worse in those who received tamoxifen alone. This approach should therefore be used only in those who are too frail or refuse surgery. Aromatase inhibitors might be more efficacious and avoid surgery for older women with operable breast cancer. It is possible that there will be a slightly longer period of control, but subsequent relapse in 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
I. S. Fentiman
an older and frailer patient with more aggressive disease. The time to give the most effective surgical treatment is at the time of diagnosis.
Glasgow than in other areas of Scotland. After MDT establishment in that city alone, breast cancer mortality was 18 per cent lower than elsewhere17 . Time spent in MDTs is worthwhile.
Ductal carcinoma in situ
Trials of breast conservation for ductal carcinoma in situ (DCIS) have shown that, after wide excision and radiotherapy, there was a halving in the rate of ipsilateral recurrence and progression to invasive disease compared with rates in patients who did not receive radiotherapy. Tamoxifen reduced recurrent DCIS by 30 per cent and contralateral cancers by 56 per cent, but with no effect on ipsilateral invasive disease. Radiotherapy was effective for all sizes and subtypes of DCIS, so histology does not identify patients who do not need postoperative radiotherapy. In the European Organization for Research and Treatment of Cancer trial (EORTC) 1085314 , after central review of specimens, there was evidence of margin involvement in 24 per cent. The risk of recurrence with margin involvement was higher than that when no radiotherapy was given. What these trials should have taught us is that clear margins and postoperative radiotherapy should be intrinsic aspects of breast-conserving treatment for DCIS. Multidisciplinary teams
Multidisciplinary team (MDT) working is accepted widely as an essential feature in the provision of high-quality care15 . Within this team, the surgeons’ breast cancer workload has been linked with outcome16 , with a 5-year survival rate of 60 per cent in the lowest- and 68 per cent in the highest-workload categories. There is accumulating evidence that MDTs can improve survival17 . Before the introduction of MDTs, breast cancer mortality was 11 per cent higher in www.bjs.co.uk
Tailoring the treatment
At present treatment is determined by patient characteristics such as menopausal status and co-morbidity together with tumour features including size, stage, grade, steroid receptor and human epidermal growth factor receptor 2 (HER2) status. Neoadjuvant or adjuvant systemic therapy may be modified by the need to protect fertility or when genetic testing will influence definitive surgery. Molecular profiling of tumours should enable more specific therapy for some patients and prevent others having unnecessary treatments. Sørlie and colleagues18 studied variations in gene expression in breast cancers using cDNA microarrays with hierarchical clustering. They were able to distinguish six subtypes: luminal A, luminal B, luminal C, HER2-rich, basal and normal breast-like. Subsequent work has shown that luminal A tumours carry a good prognosis, luminal B are more likely to relapse and neither subtype is sensitive to current adjuvant chemotherapies19 . Luminal C tumours have a high level of expression of genes of unknown function that are also found in HER2-rich and basal tumours19 . Both HER2 and basal types carry a worse prognosis. Molecular profiling of breast tumours by analysis of somatic copy number aberrations has confirmed the clinical impression that breast cancer is not a single disease. After analysing copy number and gene expression in both a discovery and a validation set of tumours, the Molecular Taxonomy of Breast Cancer International Consortium20 reported ten molecular subgroups with different prognoses. BJS 2014; 101: 145–147
Breast cancer surgery
As technology moves from research to diagnostic pathology, so future treatments will be based on specific tumour signatures, identifying those requiring more aggressive therapy and sparing others unnecessarily toxic interventions.
147
8
Disclosure
The author declares no conflict of interest.
9
References 1 Halsted WS. I. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Arch Surg 1894; 20: 497–501. 2 Keynes G. Conservative treatment of cancer of the breast. Br Med J 1937; 2: 643–666.3. 3 Atkins H, Hayward JL, Klugman DJ, Wayte AB. Treatment of early breast cancer: a report after ten years of a clinical trial. Br Med J 1972; 2: 423–429. 4 Fentiman IS. Long-term follow-up of the first breast conservation trial: Guy’s Wide Excision Study. Breast 2000; 9: 5–8. 5 Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A et al. Twenty-year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–1232. 6 Clough KB, Cuminet J, Fitoussi A, Nos C, Mosseri V. Cosmetic sequelae after conservative treatment for breast cancer: classification and results of surgical correction. Ann Plast Surg 1998; 41: 471–481. 7 Clough KB, Kaufman GJ, Nos C, Buccimazza I, Sarfati IM. Improving
2014 BJS Society Ltd Published by John Wiley & Sons Ltd
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11
12
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breast cancer surgery: a classification and quadrant per quadrant atlas for oncoplastic surgery. Ann Surg Oncol 2010; 17: 1375–1391. Schijven MP, Vingerhoets AJ, Rutten HJ, Nieuwenhuijzen GA, Roumen RM, van Bussel ME et al. Comparison of morbidity between axillary lymph node dissection and sentinel node biopsy. Eur J Surg Oncol 2003; 29: 341–350. Leidenius M, Leivonen M., Vironen J, von Smitten K. The consequences of long-time arm morbidity in node-negative breast cancer patients with sentinel node biopsy or axillary clearance. J Surg Oncol 2005; 92: 23–31. van Wely BJ, van den Wildenberg FJ, Gobardhan P, van Dalen T, Borel Rinkes IH, Theunissen EB et al. Axillary recurrences after sentinel lymph node biopsy: a multicentre analysis and follow-up of sentinel lymph node negative breast cancer patients. Eur J Surg Oncol 2012; 38: 925–931. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 30: 569–575. Clinical Effectiveness Unit, Royal College of Surgeons of England. National Mastectomy and Breast Reconstruction Audit 2009. A National Audit of Provision and Outcomes of Mastectomy and Breast Reconstruction Surgery for Women in England. Second Annual Report 2009. http://www. rcseng.ac.uk/surgeons/research/ surgical-research/docs/nationalmastectomy-and-breast-reconstruc tion-audit-second-report-2009 [accessed 29 November 2013]. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary
www.bjs.co.uk
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15
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endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2006; (1)CD004272. Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C et al. Risk factors for recurrence and metastasis after breastconserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001; 19: 2263–2271. Department of Health. The NHS Cancer Plan. Department of Health: London, 2000. Stefoski Mikeljevic J, Haward RA, Johnston C, Sainsbury R, Forman D. Surgeon workload and survival from breast cancer. Br J Cancer 2003; 89: 487–491. Kesson EM, Allardice GM, George WD, Burns HJ, Morrison DS. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women. BMJ 2012; 344: e2718. Sørlie T, Perou CM, Tibshirani R, Aas T, Geislar S, Johnsen H et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10 869–10 874. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13: 2329–2334. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 2012; 486: 346–352.
BJS 2014; 101: 145–147
Lessons learned in breast cancer surgery I. S. Fentiman Research Oncology, Third Floor Bermondsey Wing, Guy’s Hospital, London SE1 9RT, UK (e-mail: [email protected])
Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9407
William Halsted1 reported the results of radical mastectomy 130 years ago. His achievement was to recognize that the only chance of controlling breast cancer was by complete excision. Less than radical operations resulted in early recurrence. His aim was to achieve local control and avoid fungating ulcers which, at that time, were the prelude to a grim death for many women. Breast conservation
Despite uncontrolled studies avoiding mastectomy, such as those of Geoffrey Keynes2 who used implanted radium needles, most surgeons regarded anything less than radical mastectomy as a breach of duty. Conservative surgery started very badly. The first randomized trial compared radical mastectomy with wide excision of the cancer3 . Both groups received 25–27 Gy to the supraclavicular fossa, internal mammary chain and axilla. Those treated by wide excision also received 35–38 Gy to the breast, so they had no axillary surgery and inadequate axillary radiotherapy. After 10 years, there were significantly more locoregional relapses in the wide excision group (25 versus 7 per cent), mostly in the axilla. For patients with clinical stage I tumours, overall survival at 10 years was 80 per cent in both groups, but for those with stage II disease, a wide excision meant significantly worse survival (30 versus 60 per cent). By 25 years, even those with stage I breast cancers treated by wide excision had a much higher death rate (57 versus 14 per cent)4 . Two lessons were learned: undertreatment of the 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
axilla increased both local recurrence and death from breast cancer; and the effect was not apparent with a short period of follow-up such as 5 years. Subsequent work, however, showed that outcomes in patients treated by either radical mastectomy or quadrantectomy, axillary clearance and radiotherapy were similar. Longterm results showed slightly more breast relapses in the conservation group but similar mortality in both arms5 . Breast-conserving surgery is now regarded as a safe oncological operation for patients with unifocal cancers measuring 40 mm or more. There is, however, a difference between conserving the breast and achieving a good cosmetic outcome. Excision of a 4-cm diameter mass may produce a major tissue deficit with poor cosmesis, and nowadays this can often be avoided by neoadjuvant therapy. This enables up to 80 per cent of patients with larger tumours to be downstaged and avoid mastectomy, as well as providing an opportunity for monitoring sensitivity to chemotherapy. The twin aims of oncoplastic surgery are to achieve good cosmesis and to resect the tumour with clear margins. If the breast is remodelled, margins will be moved and so intraoperative confirmation of tumour-free margins is essential. A variety of techniques have been developed to correct the residual deformity that exists in up to 30 per cent of patients undergoing wide excision6 . An atlas and guidelines that consider breast volume, density and tumour location are available to select the most
appropriate choice for the patient7 . If the resection comprises less than 20 per cent of breast volume, a step-bystep remodelling is possible, whereas a mammoplasty technique is needed for larger resections. Successful oncoplastic surgery not only requires the breast surgeon to be fully trained, but also necessitates an infrastructure that allows close collaboration with the histopathologist. Sentinel node biopsy
Sentinel node biopsy (SNB) is the simplest and least damaging method of confirming axillary nodal status, although not without a slight risk of lymphoedema, occurring in 1–7 per cent8,9 , as a result of overzealous harvesting of extra stained/hot nodes, postoperative infection or extension of the radiation field to the axilla. For those few patients with a falsenegative SNB, the situation is more complicated. In a Dutch multicentre study10 of 929 patients with a negative SNB, axillary recurrence occurred in 15 (1·6 per cent). Risk factors were young age and no radiotherapy. There was a significantly worse prognosis in those with axillary relapse. Although there is consensus that the presence of isolated tumour cells in the sentinel lymph node is not an indication for axillary clearance, controversy exists regarding management of micrometastasis (smaller than 0·2 mm) and single macrometastasis. Preliminary results from the American College of Surgeons Oncology Group Z0011 trial11 have prompted many surgeons to avoid axillary clearance. Only BJS 2014; 101: 145–147
146
with long-term follow-up will the effect of this strategy be determined. Breast reconstruction after mastectomy
Most clinicians would accept that immediate breast reconstruction should be discussed with all patients advised to have a mastectomy, except where significant co-morbidity or the need for adjuvant therapy precludes this option. The National Mastectomy and Breast Reconstruction Audit12 for 2009 in the UK, however, reported that only 18 per cent of women undergoing mastectomy had immediate reconstruction. Reconstructive options offered tend to be those that the breast surgeon has been trained to perform. Breast reconstruction has to be tailored to the needs and body habitus of the patient, and whenever possible performed at the same time as mastectomy to minimize the alteration in body image. Repeated procedures after suboptimal reconstruction are distressing for the patient, as well as time- and resource-consuming. Older women
Age alone is not a contraindication to effective systemic therapy and radiation. In a Cochrane analysis13 of seven trials comparing primary endocrine therapy (tamoxifen alone) with surgery, with or without adjuvant endocrine therapy, in women aged at least 70 years, progression-free survival was significantly worse in those who received tamoxifen alone. This approach should therefore be used only in those who are too frail or refuse surgery. Aromatase inhibitors might be more efficacious and avoid surgery for older women with operable breast cancer. It is possible that there will be a slightly longer period of control, but subsequent relapse in 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
I. S. Fentiman
an older and frailer patient with more aggressive disease. The time to give the most effective surgical treatment is at the time of diagnosis.
Glasgow than in other areas of Scotland. After MDT establishment in that city alone, breast cancer mortality was 18 per cent lower than elsewhere17 . Time spent in MDTs is worthwhile.
Ductal carcinoma in situ
Trials of breast conservation for ductal carcinoma in situ (DCIS) have shown that, after wide excision and radiotherapy, there was a halving in the rate of ipsilateral recurrence and progression to invasive disease compared with rates in patients who did not receive radiotherapy. Tamoxifen reduced recurrent DCIS by 30 per cent and contralateral cancers by 56 per cent, but with no effect on ipsilateral invasive disease. Radiotherapy was effective for all sizes and subtypes of DCIS, so histology does not identify patients who do not need postoperative radiotherapy. In the European Organization for Research and Treatment of Cancer trial (EORTC) 1085314 , after central review of specimens, there was evidence of margin involvement in 24 per cent. The risk of recurrence with margin involvement was higher than that when no radiotherapy was given. What these trials should have taught us is that clear margins and postoperative radiotherapy should be intrinsic aspects of breast-conserving treatment for DCIS. Multidisciplinary teams
Multidisciplinary team (MDT) working is accepted widely as an essential feature in the provision of high-quality care15 . Within this team, the surgeons’ breast cancer workload has been linked with outcome16 , with a 5-year survival rate of 60 per cent in the lowest- and 68 per cent in the highest-workload categories. There is accumulating evidence that MDTs can improve survival17 . Before the introduction of MDTs, breast cancer mortality was 11 per cent higher in www.bjs.co.uk
Tailoring the treatment
At present treatment is determined by patient characteristics such as menopausal status and co-morbidity together with tumour features including size, stage, grade, steroid receptor and human epidermal growth factor receptor 2 (HER2) status. Neoadjuvant or adjuvant systemic therapy may be modified by the need to protect fertility or when genetic testing will influence definitive surgery. Molecular profiling of tumours should enable more specific therapy for some patients and prevent others having unnecessary treatments. Sørlie and colleagues18 studied variations in gene expression in breast cancers using cDNA microarrays with hierarchical clustering. They were able to distinguish six subtypes: luminal A, luminal B, luminal C, HER2-rich, basal and normal breast-like. Subsequent work has shown that luminal A tumours carry a good prognosis, luminal B are more likely to relapse and neither subtype is sensitive to current adjuvant chemotherapies19 . Luminal C tumours have a high level of expression of genes of unknown function that are also found in HER2-rich and basal tumours19 . Both HER2 and basal types carry a worse prognosis. Molecular profiling of breast tumours by analysis of somatic copy number aberrations has confirmed the clinical impression that breast cancer is not a single disease. After analysing copy number and gene expression in both a discovery and a validation set of tumours, the Molecular Taxonomy of Breast Cancer International Consortium20 reported ten molecular subgroups with different prognoses. BJS 2014; 101: 145–147
Breast cancer surgery
As technology moves from research to diagnostic pathology, so future treatments will be based on specific tumour signatures, identifying those requiring more aggressive therapy and sparing others unnecessarily toxic interventions.
147
8
Disclosure
The author declares no conflict of interest.
9
References 1 Halsted WS. I. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Arch Surg 1894; 20: 497–501. 2 Keynes G. Conservative treatment of cancer of the breast. Br Med J 1937; 2: 643–666.3. 3 Atkins H, Hayward JL, Klugman DJ, Wayte AB. Treatment of early breast cancer: a report after ten years of a clinical trial. Br Med J 1972; 2: 423–429. 4 Fentiman IS. Long-term follow-up of the first breast conservation trial: Guy’s Wide Excision Study. Breast 2000; 9: 5–8. 5 Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A et al. Twenty-year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–1232. 6 Clough KB, Cuminet J, Fitoussi A, Nos C, Mosseri V. Cosmetic sequelae after conservative treatment for breast cancer: classification and results of surgical correction. Ann Plast Surg 1998; 41: 471–481. 7 Clough KB, Kaufman GJ, Nos C, Buccimazza I, Sarfati IM. Improving
2014 BJS Society Ltd Published by John Wiley & Sons Ltd
10
11
12
13
breast cancer surgery: a classification and quadrant per quadrant atlas for oncoplastic surgery. Ann Surg Oncol 2010; 17: 1375–1391. Schijven MP, Vingerhoets AJ, Rutten HJ, Nieuwenhuijzen GA, Roumen RM, van Bussel ME et al. Comparison of morbidity between axillary lymph node dissection and sentinel node biopsy. Eur J Surg Oncol 2003; 29: 341–350. Leidenius M, Leivonen M., Vironen J, von Smitten K. The consequences of long-time arm morbidity in node-negative breast cancer patients with sentinel node biopsy or axillary clearance. J Surg Oncol 2005; 92: 23–31. van Wely BJ, van den Wildenberg FJ, Gobardhan P, van Dalen T, Borel Rinkes IH, Theunissen EB et al. Axillary recurrences after sentinel lymph node biopsy: a multicentre analysis and follow-up of sentinel lymph node negative breast cancer patients. Eur J Surg Oncol 2012; 38: 925–931. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 30: 569–575. Clinical Effectiveness Unit, Royal College of Surgeons of England. National Mastectomy and Breast Reconstruction Audit 2009. A National Audit of Provision and Outcomes of Mastectomy and Breast Reconstruction Surgery for Women in England. Second Annual Report 2009. http://www. rcseng.ac.uk/surgeons/research/ surgical-research/docs/nationalmastectomy-and-breast-reconstruc tion-audit-second-report-2009 [accessed 29 November 2013]. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary
www.bjs.co.uk
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15
16
17
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20
endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2006; (1)CD004272. Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C et al. Risk factors for recurrence and metastasis after breastconserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001; 19: 2263–2271. Department of Health. The NHS Cancer Plan. Department of Health: London, 2000. Stefoski Mikeljevic J, Haward RA, Johnston C, Sainsbury R, Forman D. Surgeon workload and survival from breast cancer. Br J Cancer 2003; 89: 487–491. Kesson EM, Allardice GM, George WD, Burns HJ, Morrison DS. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women. BMJ 2012; 344: e2718. Sørlie T, Perou CM, Tibshirani R, Aas T, Geislar S, Johnsen H et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10 869–10 874. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13: 2329–2334. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 2012; 486: 346–352.
BJS 2014; 101: 145–147
