Breast cancer is the most commonly diagnosed cancer in Ireland with over 3,000 new cases each year, accounting for 31% of all invasive cancers. It is the most common cause of cancer-related death in women worldwide.^1,2 The increasing incidence of breast cancer with its resultant social and economic burden has stimulated focused efforts to develop and provide appropriate, patient-specific treatment to reduce the morbidity and mortality of the disease. The development of an Irish Cancer Control Network with eight cancer centres, as outlined in ‘A Strategy for Cancer Control’, has been pivotal in addressing the increasing burden of cancer in Ireland.³

Recent decades have seen dramatic changes in breast cancer management including the development of new and effective adjuvant and targeted therapies that have resulted in significant decreases in breast cancer mortality.^4,5,6 Current treatment of breast cancer patients is an intricate multidisciplinary process with surgical management remaining at its core. Significant advances have been made in the surgical management of breast cancer, primarily as a result of a series of large, well designed and co-ordinated clinical trials that have shaped modern surgical practice. 

Evolving surgical techniques, combined with an improved understanding of tumour biology and increasing efficacy of adjuvant targeted therapies, have resulted in a shift towards increasingly conservative surgical approaches. The introduction of breast cancer screening has changed the profile of the disease at presentation and as surgical treatment continues to evolve, the new paradigm includes an emphasis on oncoplastic techniques and a growing awareness of the psychosocial needs of breast cancer patients. This review will provide an overview of the evidence-base that has guided the evolution to current practices in the surgical management of breast cancer. 

Diagnostics and breast cancer screening

Accurate pre-operative diagnosis and staging of breast cancer is critical to optimise therapeutic and surgical strategies. Mammography is the mainstay in diagnostic investigations for breast cancer. Diagnostic mammography is performed in symptomatic patients who present with a palpable mass or other symptoms of breast disease, a personal history of breast cancer or an abnormality detected on a breast screening mammography. Additional imaging studies, including ultrasonography and magnetic resonance imaging (MRI), are also used selectively to characterise breast lesions and aid in surgical planning. Mammography, however, is the only screening examination demonstrated to decrease breast cancer mortality in the general population.^7,8,9

The National Breast Cancer Screening Programme in Ireland commenced in 2000. Since 2008, it has provided a programme of two-yearly mammograms to women aged 50-64. The relative risk of breast cancer mortality for women in a breast screening programme compared to controls is estimated to be reduced by 20%.⁹ Breast cancer screening impacts significantly on the type of breast cancer being diagnosed; screen-detected cancers are generally smaller, lower grade, more hormone-sensitive, more node-negative and less invasive than symptomatic breast cancers.¹⁰

Additionally, since the introduction of breast screening there has been an increase in the detection rate of in situ breast cancers, now accounting for 21% of all screen detected breast cancers, a proportion of which will progress to invasive disease if left untreated. The specific tumour characteristics of screen-detected breast cancers have implications for surgical strategy, which has adapted to suit the needs of this population, including radiologically-guided localisation for both biopsy and excision of non-palpable mammographically detected lesions (see Figure 1).

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Prior to surgical intervention, confirmed abnormalities on diagnostic imaging studies require further evaluation with a biopsy. Surgical biopsy was the gold standard for diagnosis until the 1990s, when most breast cancers presented at the symptomatic stage. However, the widespread introduction of mammographic screening significantly increased the number of non-palpable breast lesions requiring diagnostic biopsy. Improved methods of obtaining tissue were developed including fine needle aspiration and core biopsy, which are significantly less invasive and can be performed in the outpatient setting. The European Society for Surgical Oncology guidelines recommended that the majority of breast cancers should receive a pre-operative diagnosis by fine needle aspiration or core biopsy.¹¹ More recently in the US, the National Accreditation Program for Breast Centers established “palpation-guided or image-guided needle biopsy as the initial diagnostic approach rather than open biopsy” as one of 19 clinical management standards by which breast centres are measured.^12,13

This reflects current practice in Ireland, where breast cancer care has been centralised into eight dedicated centres, which provide a multidisciplinary framework for the care of breast cancer patients. The National Cancer Control Programme and the Health Information and Quality Authority (HIQA) have developed key performance indicators (KPIs) to standardise care in line with international best practice. These KPIs include a recommendation that > 90% of breast cancers should be diagnosed without an operative procedure (open biopsy), with core biopsy being the diagnostic investigation of choice. The majority of breast core biopsies are now done under ultrasound guidance. This approach improves cancer treatment and minimises the number of surgical procedures to which the patient is subjected. 

From radical mastectomy to breast conservation

Surgery has always been the primary modality of breast cancer treatment. William Halsted first described the radical mastectomy in 1894.¹⁴ This procedure involved removal of the breast, pectoral muscles and regional lymph nodes, and remained the mainstay of breast cancer treatment until the 1970s despite its associated physical and psychosocial morbidity.¹⁵ The first steps towards less aggressive surgery to treat breast cancer were taken in the 1970s with the modified radical mastectomy which spared the pectoralis muscles. Subsequent evolution towards more conservative surgery followed as the result of large randomised clinical trials by pioneering investigators, which demonstrated comparable survival with less radical surgical approaches combined with adjuvant radiotherapy and systemic therapy. 

The National Surgical and Adjuvant Breast and Bowel Project (NSABP), founded in 1957, has conducted a number of landmark prospective, randomised controlled trials, giving rise to Level 1A evidence for breast cancer management. NSABP B-04 compared outcomes in patients who underwent radical mastectomy, total mastectomy or total mastectomy with regional radiotherapy, and demonstrated with 25-year follow-up that less aggressive surgery, with or without radiotherapy, would provide equivalent outcomes to radical mastectomy.¹⁶ The evidence from this practice-changing study brought about an end to Halsted’s radical mastectomy and signalled a paradigm shift in our approach to breast cancer treatment. Attempts to further reduce the radicality of breast cancer surgery led to the concept of breast conservation. A subsequent series of prospective randomised trials were designed to evaluate breast conserving surgery (BCS) or ‘lumpectomy’ in smaller tumours (see Table 1).^{17,18,19,20,21,22,23,24}

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Taken together, the data from these studies, some with follow-up of more than 20 years, has established that survival is equivalent for mastectomy and BCS followed by adjuvant radiotherapy. NSABP B-06, the only one of these trials which required negative resection margins, published 20-year follow-up of 1,851 patients, which concluded that lumpectomy followed by breast irradiation is an appropriate therapy provided that the margins of resected specimens are tumour free and an acceptable cosmetic result can be obtained.¹⁷

Importantly, although there was no difference in overall survival between the groups, those that underwent lumpectomy without radiation had a high recurrence rate of 39.2% at 20 years. This data established the acceptance of BCS and also confirmed the importance of radiation in this therapeutic strategy. Since these practice-changing trials were conducted, the rates of locoregional recurrence (LRR) have decreased further due to factors including improved imaging, increased attention to negative margins and advances in adjuvant and targeted therapy for breast cancer. The use of systemic chemotherapy, tamoxifen and trastuzumab have all been shown to significantly reduce the rate of locoregional or in-breast recurrence following BCS; recurrence rates of approximately 6% at 12 years follow-up are reported following breast conservation combined with contemporary adjuvant therapy.^25,26

The importance of disease-free margins of resection to minimise LRR is well recognised and there is consensus that negative margins, where there are no tumour cells adjacent to any edge of the resected specimen, is a requirement for BCS.²⁷ The anatomically complete resection of the tumour is not the only factor which impacts on LRR; there is an increasing recognition of the heterogeneity of breast cancer, and molecular sub typing has identified genetically distinct subtypes based on the expression of specific genes including oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor.²⁸ These subtypes have been shown to be predictive of outcomes including response to adjuvant therapy and LRR.²⁹ This highlights the importance of considering breast cancer biology in addition to the extent of surgical excision in adjuvant treatment decisions. 

Since there is no difference in overall survival between BCS and mastectomy, the primary aim of BCS is to adequately excise the breast tumour with oncologically acceptable outcomes while maintaining an optimal aesthetic outcome with minimal loss of breast tissue. Appropriate patient selection is crucial to the success of this approach and there remain some contraindications to BCS, including a history of prior therapeutic radiotherapy, persistently positive resection margins following repeated attempts at re-excision, multifocal disease or diffuse malignant calcifications. Large tumour size relative to breast size was previously considered to be a contra-indication to BCS, however, the increased use of neoadjuvant systemic therapy to downstage tumours pre-operatively has increased the cohort of patients for whom BCS may be indicated. Neoadjuvant systemic therapy has been shown to reduce the mastectomy rate by 16.6% while maintaining equivalent survival rates when compared to delivery of systemic therapy adjuvantly.^30,31

Oncoplastic breast preservation surgery 

Another development that has facilitated BCS for larger tumours is the new paradigm of oncoplastic breast preservation surgery, which combines oncologic principles with plastic surgery techniques to provide wide surgical margins while preserving the appearance and shape of the breast.³² Oncoplastic surgery by definition is a therapeutic procedure only undertaken on biopsy proven tumours. The specific goals of oncoplastic surgery are to remove the lesion with clear margins, to obtain excellent cosmesis and to perform one definitive surgery.³² To achieve these goals, surgical techniques employed by the oncoplastic surgeon include crescent, batwing, inframammary, periareolar and triangular incisions. Advancement flaps and the Benelli ‘round block’ mastopexy are also commonly performed.³³ The choice of technique is tailored to the individual patient and depends on factors including tumour size, tumour location within the breast, breast size and shape, and the need for a symmetrising procedure on the contralateral breast. Oncoplastic techniques have been shown to have comparable therapeutic outcomes when compared to BCS alone, with patients also being more satisfied with cosmetic outcomes.³⁴

Breast reconstructive surgery 

Despite advances in neoadjuvant systemic therapy and oncoplastic techniques, there remain patients for whom mastectomy is the optimal therapeutic surgical procedure (large multifocal tumours, inflammatory breast cancer, history of previous irradiation). Most patients requiring mastectomy are now offered reconstructive surgery³⁵ and it has been shown that breast reconstruction does not impact on the efficacy of adjuvant therapy or the ability to detect recurrence.³⁶ Immediate breast reconstruction has become increasingly popular, with patients undergoing oncologic mastectomy and reconstruction in a single procedure. With the increase in immediate reconstruction, skin-sparing mastectomy has developed as a technique to preserve the natural skin envelope at the time of mastectomy, which can then be used in the reconstructive surgery to improve cosmetic outcomes. Meta-analyses of prospective studies demonstrate that this approach provides equivalent oncologic outcomes to simple mastectomy.³⁷ A further development is nipple and areola-sparing mastectomy, which preserves the entire skin envelope including the areola and nipple. This approach is predominantly utilised for high-risk patients with BRCA 1 or 2 mutations undergoing risk-reducing surgery,³⁸ but has also been used in the treatment of highly selected tumours of small size and adequate distance from the nipple.³⁹ Retrospective series report that the oncologic outcomes are comparable to skin-sparing mastectomy.⁴⁰

Reconstruction methods frequently utilised in patients undergoing mastectomy include implants, with or without tissue expanders and/or autologous tissue flaps such as an extended latissimus dorsi flap or deep inferior epigastric perforators (DIEP) flap. Mammoplasty may also be undertaken on the contralateral breast, often in patients where large ipsilateral lesions have been resected (see Figures 2, 3 and 4).³²

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The principal advantage of BCS, skin- and nipple-sparing mastectomies with breast reconstructive techniques, compared to traditional mastectomy, is that of improved aesthetic outcome and reduced psychosocial morbidity while maintaining oncological safety.^41,42

Surgery of the axilla

Axillary nodal disease is a significant prognostic indicator for breast cancer overall survival and disease recurrence, with extent of positive nodes determining the pathological staging of the disease. As discussed previously, NSABP B-04 demonstrated that no survival advantage was conferred by undertaking axillary lymph node dissection (ALND) in addition to mastectomy for early breast cancers.¹⁶ Despite the absence of a survival advantage, surgical evaluation of the axilla remains valuable for disease staging, to inform decisions regarding adjuvant therapy and for locoregional control. Although these indications remain valid, ALND of disease-free axillary nodes may result in significant morbidity for patients including lymphoedema, axillary seroma, pain and shoulder problems such as brachial plexus injuries.^43,44

The development of sentinel lymph node biopsy (SLNB) represented a significant change in practice and has negated the need for extensive axillary dissection in clinically node-negative patients while still facilitating pathological tumour staging. The concept was initially described in 1960 by Gould et al, in the setting of a parotid gland neoplasm.^45,46 The technique is based on the theory that the first lymph node draining the primary tumour reflects the disease status of the regional lymph node basin. SLNB in breast cancer was firmly established in the 1990s by Morton, Giuliano et al, who used blue dye, injected subdermally into the breast, to identify the sentinel node.^47,48,49 In 1997, Veronesi et al utilised particles of albumin, labelled with a radioisotope, technetium-99m, as a tracer to identify the sentinel node. Following tracer injection the sentinel node was identified both pre-operatively and intra-operatively using scintigraphy and a hand-held gamma-ray detector probe. In patients where a sentinel node was identified, their method accurately determined nodal status in 98% of patients.⁵⁰

Following these early results, a number of prospective randomised controlled trials were published, with a total of more than 10,000 patients, demonstrating similarly high sentinel node detection rates and further confirming the role of SLNB (see Table 2).^{51,52,53,54,64} One such trial, NSABP B-32, conducted between 1999 and 2004, enrolled 5,611 patients and importantly demonstrated that in patients with clinically negative axillary nodes and pathologically negative SLNBs, no survival benefit was gained by performing completion ALND.⁵¹ Furthermore, the multicentre ALMANAC trial published in 2006 demonstrated significantly improved quality of life and reduced arm morbidity, at all measured time points up to one year, for patients randomised to SLNB rather than traditional ALND. They also observed reduced drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery.⁵⁴ SLNB following BCS is currently the standard of care for early stage breast cancers and has been a revolutionary advancement in breast cancer management, avoiding ALND in those with a positive SLNB.

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More recent debate has centred around the management of patients with a positive SLNB. Traditionally, completion ALND was advocated in this scenario. Disease in the SLN is classified according to the American Joint Committee on Cancer based on burden of tumour cells as follows (see Figures 5, 6 and 7):⁵⁵

• Isolated tumour cells (ITC) < 0.2mm of disease

• Micrometastases 0.2-2mm of disease

• Macrometastases > 2mm of disease.

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Low burden axillary metastatic disease (ITC and micrometastases) are frequently occult and only detected when additional, non-standard pathological investigations including immunohistochemistry are performed on the SLN. The clinical significance of micrometastatic disease in terms of overall survival has been examined by three large studies, concluding that the presence of occult/micrometastatic disease does not impact significantly on overall survival (see Table 3).^51,56,63 The data from these trials taken together strengthened the argument for no further axillary treatment in patients with micrometastatic disease, which is now the recommendation of the American Society of Clinical Oncology (ASCO).⁵⁷

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To address the question of macrometastatic axillary disease, the American College of Surgeons Oncology Group (ACOSOG) conducted the Z0011 trial, which randomised patients with a positive SLNB into two arms: ALND or no further surgery.⁵⁸ Both cohorts underwent BCS with adjuvant whole breast irradiation and hormonal and/or systemic chemotherapy. Results at six-year follow-up demonstrated no significant difference in overall survival or locoregional recurrence between the groups. The authors concluded that omission of ALND in low axillary disease burden (< 3 positive nodes) may be a reasonable management strategy in select patients only. There has been much debate on the applicability of these results to clinical practice, with critics citing the incomplete accrual of patients, non-significant differences in prognostic factors between the groups and questions regarding clarity of the radiotherapy fields as flaws of the study. Nonetheless, this trial has been practice changing; ASCO has this year revised its guidelines for SLNB, recommending that ALND can be omitted for selected patients with macrometastatic disease.⁵⁷

The concept that ALND is not necessary for all patients with SLN metastases has been further supported by recent data from the European Organisation for Research and Treatment of Cancer AMAROS trial.⁵⁹ This study demonstrated that, in select patients, adjuvant axillary radiotherapy provides comparable locoregional control of metastatic disease to ALND with a significantly reduced risk of lymphoedema; a further move towards conservation and reduced morbidity for breast cancer patients. 

Further clinical trials are ongoing to determine whether the change in practice effected by the Z0011 results can also be applied to patients with larger primary tumours, post-mastectomy, post partial breast irradiation, and in those undergoing neoadjuvant systemic therapy. However, until these data mature, there remain indications for ALND in select patients (see Table 4).

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While the surgical approach to the axilla has become increasingly conservative, there has been an increasing recognition of the importance of tumour biology in prognostication. Through gene expression profiling studies, we now have predictive tools which are increasingly used to guide adjuvant therapy decisions, for example Oncotype DX.⁶⁰ Ongoing trials are evaluating the potential for such tools to inform decision-making even in node-positive patients.^61,62

It is possible that in the future, node-positive patients may be spared chemotherapy based on a favourable biological profile. This is something that will need to be considered when planning axillary treatment and locoregional control as, to date, the evidence driving our new conservative approach has been based on patients treated with systemic therapy. The importance of multidisciplinary decision-making in this new era of conservative surgery coupled with increasingly tailored adjuvant therapeutic strategies cannot be underestimated. 

Conclusion

Surgery for breast cancer has evolved significantly over the past 50 years. The goal of contemporary breast cancer management is for individualised therapy. An increased recognition of the biological heterogeneity of the disease has greatly informed current management. 

While adjuvant therapy advances have moved towards targeted therapy, surgical advances, based on the results from well-designed randomised trials, have been aimed at minimising morbidity from extensive surgery. 

We have progressed from radical surgery to an era of conservation. Surgical management is now tailored for each individual patient and may include a variety of breast conserving techniques with SLNB and reconstruction methods that optimise both oncologic and psychosocial outcomes for patients. As the biological complexity of breast cancer is further uncovered and locoregional treatment strategies continue to evolve, the optimal setting for multimodality breast cancer treatment remains the multidisciplinary framework where therapeutic advances can be critically assessed and implemented for continued improvements in cancer outcomes.

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