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Recent advances and future developments in breast cancer surgery.

Introduction

There has been a resurgence in understanding the importance of local treatments in the care of breast cancer. The pendulum has now swung back following years of predeterminism and surgical nihilism. This followed the decline of Halstedian concepts of stepwise progression of breast cancer with the Fisher model of a disease 'systemic from origin'. Spectrum models [1] recognise the importance of both local and systemic treatments for successful outcome, and state that generally breast cancers develop from small lesions of low metastatic potential that can be successfully treated by local therapies, to larger, more aggressive lesions where systemic therapies are of more importance.

This shift in attitudes towards local therapies, and in particular surgery, has been supported by various lines of evidence. The 2005 Oxford overview of randomised trials of radiotherapy and the extent of surgery [2] and the Overgaard data of post-mastectomy radiotherapy [3] confirm the importance of local therapies in reducing the risk of distant disease and improving overall survival. In the Oxford overview, radiotherapy following breast-conserving surgery reduced the risk of local recurrence from 26% to 7%, with a 5.4% mortality reduction; approximately one death avoided for every four local recurrences prevented. When taken together with data on the importance of attention to surgical detail, such as the achievement of clear surgical margins for minimising recurrence rates, the importance of accurate and scrupulous surgical technique becomes self-apparent. For example, margin width is an important determinant of local control in ductal carcinoma in situ [4] and adjuvant therapies do not obviate the need to obtain clear surgical margins [5]. Moreover, this general oncological principle is not unique to breast cancer and has been demonstrated for other solid tumour types such as for accurate total mesorectal excision in rectal cancer [6]. This suggests that whilst local recurrence may be an indicator of aggressive tumour biology, it may also act as a source of tumour re-seeding, particularly in the context of suboptimal local treatment.

Further data on the importance of surgical treatment is supplied by meta-analyses of neoadjuvant therapies. A higher local recurrence rate was observed in trials where more patients in the neoadjuvant, compared to the adjuvant arm received radiotherapy without surgery [7], further indicating that systemic therapy or radiotherapy cannot compensate for a lack of, or inadequate, surgery. Finally, there has been data from retrospective analyses suggesting the possibility that local therapy might influence outcome, even in the context of systemic disease [8]. These provide compelling evidence on the crucial role played by accurate and high-quality surgery in optimising outcome.

Oncoplastic surgery

This increasing rediscovery of the oncological importance of surgery has occurred in parallel with developments in minimising the cosmetic sequelae of local treatments. Oncoplastic surgery has been defined as, 'seamless specialist breast cancer surgery in which ablation of the cancer is merged with reconstruction as an integrated whole' [9]. The aim is, as, stated to merge the oncological aspects of resectional breast surgery with plastic surgical principles and techniques to maximise oncological benefit and minimise morbidity. In its simplest form, oncoplastic surgery includes accurate cosmetically designed scar placement for mastectomy and wide local excision. Defects created following resection can then be filled by tissue displacement or replacement (Figures 1 and 2). Simple wide excision defects, for example, can be filled by mobilising adjacent breast tissue [10]. This can be more formally achieved through performing a wide excision through a breast reduction technique, often with contralateral matching reduction--an 'oncoplastic mammoplasty' [11,12]. Techniques have evolved to deal with tumours in any part of the breast, either through the various standard breast-reduction techniques or through modifications of them [13].

If there is insufficient volume to enable tissue displacement techniques, or if volume reduction is not desirable (for example, if the consequence might be the requirement for contralateral reduction to achieve symmetry, which some patients may not wish to undergo) then tissue replacement may be used. This can take the form of partial breast reconstruction with miniflaps [14] or fasciocutaneous flaps [15]. Some of these strategies may also be used to correct secondary deformities following breast-conserving surgery [16]. When used in the immediate setting as part of breast-conserving surgery, these techniques increase the scope of breast-conserving surgery and reduce the mastectomy rate, but all require radiotherapy as they leave breast tissue behind. It is possible that in the future they might be combined with advances in intra-operative radiotherapy [17].

[FIGURE 1 OMITTED]

Despite advances in partial breast reconstruction, increases in the scope of breast-conserving surgery and earlier diagnosis through expanded screening programmes, mastectomy will still be required due, for example, to tumour multifocality. Paradoxically, it may be that conditions such as widespread ductal carcinoma in situ (DCIS) are treated more aggressively surgically than high-grade tumours with lymph node metastases, where systemic therapies assume more importance, and this is not inconsistent with the spectrum model of disease progression. The ultimate expression of this line of thinking is risk-reducing surgery, both in gene carriers and those at high risk due to family history, and in those with contralateral cancers. This has been reviewed in a previous edition of this publication [18,19].

Breast reconstruction requires a skin envelope and tissue volume. Minimal access techniques such as skin-sparing mastectomy or endoscopic mastectomy enable one to minimise loss of the natural skin envelope but in early-stage breast cancer do not lead to inferior oncological outcome [10,20]. The skin envelope can be adjusted as required by incorporating skin from flaps, by tissue-expander techniques or by performing a mastectomy through one of a range of breast-reduction incisions with or without a contralateral symmetrisation procedure. Volume can be from an implant, either as a tissue-expander-type procedure or from autologous tissue. Autologous tissue can be from a pedicled flap such as the latissimus dorsi, or free flaps such as the deep inferior epigastric (DIEP). Data is now available to demonstrate the safety of implants [21] but many large series of implant-based reconstructions demonstrate an inevitable implant revision rate [22].

[FIGURE 2 OMITTED]

Further developments in oncoplastic surgery continue apace, and it is likely that ever more ingenious methods of amalgamating plastic surgery techniques with oncological resectional surgery will be devised. For example, the use of alloderm [23] or skin-sparing reduction mastectomy in immediate reconstruction [24] allows immediate tissue coverage between skin and implants. Autologous fat transfer is likely to achieve more widespread use to correct wide excision defects, correct reconstruction deformities and even, in some cases, for cosmetic augmentation [25]. This technique involves liposuction from various donor sites and regrafting back through injection into the required area. Preliminary results have been encouraging and there is even some evidence that the technique may improve tissue and skin quality following radiotherapy. Initial concerns regarding calcification secondary to fat necrosis and interference with surveillance radiology do not appear to be justified. The challenge for oncoplastic surgery in the future will be to produce collaborative trials and datasets large enough to demonstrate beyond doubt oncological safety, and optimal integration of these techniques with treatments such as radiotherapy.

Axillary surgery

The traditional roles of axillary surgery to both stage and treat the axilla are being increasingly separated. Sentinel node biopsy has enabled staging of the axilla whilst reducing morbidity [26]. Long-term data is now available to demonstrate the oncological safety of this technique and to confirm that axillary dissection is not required in sentinel node-negative patients [27]. One important issue is the management of the axilla in sentinel node-positive patients. Further treatment may be important for two reasons: firstly to increase the accuracy of staging, because if the axilla is positive, additional prognostic information will be gained by determining the number of positive axillary nodes following a clearance; secondly, if the axilla is positive, treatment should reduce the local recurrence rate. There are nomograms to predict possibility of involvement of other nodes within the axilla; the clinical significance of micrometastases within sentinel nodes is becoming clearer [28]; and the AMAROS trial should provide further information on the utility of radiotherapy in treatment of the sentinel node-positive axilla.

In general, however, in the presence of a positive axillary sentinel node, further treatment usually involves an axillary dissection. Approximately 30% of patients undergoing sentinel node biopsy have an involved sentinel node [29] and so require further surgery. In most cases this involves a further visit to the operating theatre. Techniques have therefore evolved to accurately stage the axilla intra-operatively, to enable those that are node positive to progress to an immediate axillary dissection at the same operation. Pathological techniques such as touch-imprint cytology and frozen section have a high specificity but even in the best hands have a more limited sensitivity when compared to routine histopathology [30]. Emergent molecular techniques for intra-operative sentinel node analysis as exemplified by the GeneSearch[TM] BLN Assay (Veridex, LLC) and the OSNA assay (Sysmex, Kobe, Japan) detect cytokeratin 19, and also in the case of GeneSearch, mammaglobin in sentinel nodes to determine if metastases are present. These assays have a much higher sensitivity than frozen section or touch-imprint cytology, and may even theoretically have higher sensitivity than standard histopathology. It is inevitable that such techniques will become more widespread in the near future, both for economic reasons, as they avoid a second procedure, and because they improve the quality of care by reducing potentially hazardous repeat surgery and possible delays in adjuvant therapies.

Future surgical developments

Advances in breast surgery in the future are likely to continue to be driven by advances in technology, including advances in imaging and molecular imaging, chemotherapeutic agents and targeted therapies, changes in society and epidemiological make-up, and finally changes in service delivery and economic pressures. In general, advances in technology, and in particular imaging and screening, may lead to earlier diagnosis of disease and increased controversy as to the clinical significance of early disease detected. This has already been seen in breast screening with debates in the national press regarding possible overtreatment of screen-detected lesions [31]. Similar debate is also under way regarding magnetic resonance imaging for breast-conserving therapy, with retrospective trials demonstrating increased disease detection [32] but failing to show benefit in terms of clinical outcome [33].

Along with increases in breast screening due to initiatives such as age extension in the United Kingdom, there will be an increase in image-guided surgery and percutaneous excision, for example, by ultrasound-guided vacuum-assisted biopsy and excision. Whilst, in general, technology is expensive and likely to be limited by economic pressures, surgery is, in general, cheap in comparison to advances in molecular-targeted therapeutics. The uptake of surgical advances, however, is often limited by constraints of the technology availability. For example, the uptake of breast-conserving surgery in the United Kingdom was dependent on the availability of radiotherapy. It is likely that availability of technologies such as intracavity radiotherapy and CT planning for radiotherapy play a role in the rate at which surgical changes brought about by these changes are adopted. Economic pressures will inevitably demand streamlining of processes to increase efficiency, and any advances and innovations will need to pass both effectiveness and cost-effectiveness tests. Whilst surgery is generally cost-effective, demonstration of cost-effectiveness for innovations such as intra-operative molecular sentinel node analysis will be crucial to their uptake. It is likely that specialist oncoplastic surgery will become more centralised, especially given the likelihood of a wider range of adjuvant and neoadjuvant treatments. Economic pressures will increasingly lead to an increase in ambulatory 24-hour breast surgical procedures.

Advances in biological targeted therapies, such as monoclonal antibodies or small-molecule kinase inhibitors, will mean that in many cases breast cancer is treated more like a chronic disease with various therapeutic options. Molecular biomarkers or gene expression pattern evaluation will lead to selection of targeted therapies on a personalised basis for appropriate patients. As disease recurs and the cancer escapes from these targeted therapies, further profiling and molecular analysis will identify further strategies. In many cases surgery will be seen more as one in a sequence of treatments, for example, following neoadjuvant therapy with early or metabolic imaging, gauging the benefit of treatments and a switch to surgery occurring at an appropriate point within the sequence. Again, in many cases this will increase the requirement for image guidance and the requirement for smaller and more precise, and possibly technically challenging, surgery.

Whilst in colorectal cancer, liver resection of isolated metastasis is recognised to be of benefit, imaging will lead to earlier identification of isolated breast metastases, and increased requirement for surgical rather than palliative treatment for them. The evidence in terms of improved outcome for surgery to the primary tumour in cases of metastatic disease has already been discussed; but surgical treatment of recurrent disease and salvage surgery--possibly with flaps if required--as tumours escape control of designer therapies, will always be an important therapeutic option. Following sentinel node biopsy with further future developments to accurately stage the axilla, there are likely to be fewer axillary procedures, but these are likely to be more technically challenging and salvage cases. It is therefore unlikely that surgical reduction of tumour burden will cease to be an important component of the treatment armamentarium.

Changes in society, both in terms of altered population demographics and expectations, will drive further change. An increasingly elderly population will increase the incidence of breast cancer whilst earlier diagnosis, through screening programmes and increased awareness coupled with improved therapeutics, will lead to an increased prevalence of breast cancer and increased diagnostic workload. Expectations on speed of service will increase to demand instant access to diagnostic services, as seen by the UK Government target that no patient referred with breast symptoms should wait for more than 2 weeks for assessment.

Overall surgical treatment of smaller earlier lesions with, for example, image-guided techniques, and treatment of more complex recurrent disease following previous breast-conserving surgery including radiotherapy, will become more common. Those patients detected by the UK breast screening programme, with cancers in the excellent and good prognosis groups of the Nottingham Prognostic Index, already have overall survival as good as that of the general population. Political pressures and societal expectations will also shape service in the future. The UK National Mastectomy Audit has demonstrated an increase in the uptake of immediate breast reconstruction from 11% to 21% over the course of the audit, highlighting demand and public expectation.

Service delivery pressures will inevitably lead to increased specialisation since surgical treatments will become more complex, either through earlier diagnosis or more surgically complex recurrent disease. Specialisation in breast surgery does appear to improve outcome [34]; and increased public scrutiny, and professional requirements for revalidation and reaccreditation, will lead to a requirement for better information technology to accurately record outcome for quality assurance and audit purposes, particularly with respect to symptomatic disease. Since, as discussed, diagnostic workload will increase, the inevitable questions will arise as to how this will be dealt with. The heavy outpatient workload may lead to an increase in breast physicians or specialist nurses with appropriate skills to assist with this workload. Patient and political demand for greater choice may lead to an increase in competition between providers for the diagnostic and follow-up work traditionally performed by surgeons.

Conclusions

Surgical advances in the future will be integrated into a range of technological advances that include more powerful imaging and possibly molecular imaging to allow earlier diagnosis, and molecular diagnostics and profiling to predict responsiveness to new systemic biological and targeted therapies. This will be coupled with extended treatments, including multiple biological and local treatments, and an increased understanding of the importance of sequencing of these treatments, including that of surgery, will be required. Surgical treatments will be geared towards maintaining maximal oncological benefit whilst minimising cosmetic impact by a combination of oncoplastic and reconstructive techniques with earlier diagnosis and neoadjuvant strategies. Axillary surgery will be further streamlined in the short term with intra-operative molecular sentinel node analysis. Adaptability will be required for surgical services to respond to future technological advances, whilst continuing to serve changing service and patient needs.

References

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Correspondence to: Ramsey I Cutress

Cancer Research UK Clinical Centre

Somers Cancer Research Building MP824

Southampton General Hospital

Southampton SO16 6YD, UK

(email: r.i.cutress@soton.ac.uk)

Ramsey I Cutress

Southampton General Hospital, UK
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Title Annotation:Feature Article
Author:Cutress, Ramsey I.
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Dec 1, 2009
Words:3620
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