Neoadjuvant chemotherapy for locally advanced breast cancer: A review of the literature and future directions

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EJSO 35 (2009) 113e122

www.ejso.com

Review

Neoadjuvant chemotherapy for locally advanced breast cancer: A review of the literature and future directions J. Mathew a,*, K.S. Asgeirsson a, K.L. Cheung a, S. Chan b, A. Dahda b, J.F.R. Robertson a a

Professorial Unit of Surgery, Nottingham University Hospital (City hospital Campus), Hucknall Road, Nottingham NG5 1PB, UK b Department of Clinical Oncology, Nottingham University Hospital (City hospital Campus), Nottingham, UK Accepted 28 March 2008 Available online 23 May 2008

Abstract Background: Most patients with locally advanced primary breast cancer have micrometastases at the time of presentation. Randomised trials on the use of neoadjuvant chemotherapy have not been carried out specifically in a population of breast cancer patients with locally advanced disease (LAPC). Despite this, its use for cytoreduction in these patients is an established option which may facilitate excision of the primary tumour and local lymph node metastasis for local control. Significant improvements in local disease control have been seen with recent advances in systemic chemotherapy regimens although thus far this has not shown in randomised trials to translate into overall survival benefits. Methods: In this review, all studies where a large proportion (approximately 70%) of included patients with LAPC, were selected. A search of Medline and PubMed databases was performed. Specifically, the different chemotherapy regimens and their relation to oncological outcomes was assessed. Results and conclusion: The studies assessed were heterogeneous with regard to patient selection and chemotherapy regimens used. A complete pathological response is the strongest predictor of disease-free and overall survival. Recent studies on the use of targeted biological therapies in addition to chemotherapy suggest that rates of complete pathological response may be significantly increased when compared to chemotherapy alone. Furthermore, improvements in localisation and imaging techniques, used in conjunction with the increasing use of oncoplastic breast-conserving techniques, highlight the possibility that a subgroup of these patients may safely be treated with breast conservation. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Locally advanced primary breast cancer; Neoadjuvant chemotherapy; Clinical response; Pathological response; Oncoplastic conservation surgery

Introduction Patients presenting with locally advanced primary breast cancer (LAPC) are a heterogeneous group with variable outcomes with regard to local recurrence rates and survival. There is no standard or international agreement on the definition of this type of breast cancer, but one commonly used clinical staging includes patients with large primary tumours greater than 5 cm (T3) or with fixed skin or chest involvement (T4), and/or fixed axillary (N2) or ipsilateral internal mammary lymph node involvement.1,2 According * Corresponding author. Tel.: þ44 115 926 8993. E-mail address: [email protected] (J. Mathew). 0748-7983/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2008.03.015

to TNM staging system proposed by the American Joint Committee on Cancer (AJCC), all of stage III disease is therefore considered locally advanced, as is a subset of stage IIB (T3N0). In addition, inflammatory breast cancer (T4d), with its distinct clinical presentation and worse prognosis, is included within the scope of locally advanced disease. Although the TNM system is not as widely used in the UK, it is generally accepted that locally advanced breast cancers represent those cancers that are difficult to resect with primary surgery either because of their size or extension to chest wall or skin or involvement of regional axillary lymph nodes. Compared to patients with operable primary breast cancer, patients with LAPC are at significantly higher risk of local recurrence and distant metastases

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and have a worse overall survival; UK figures show that patients with stage II disease have a 10-year survival rate of just under 60%, whereas this is approximately 30% for patients with stage III disease.3 With the widespread use of breast cancer screening, breast cancers are increasingly being diagnosed at an earlier stage. Because of this, patients with locally advanced breast cancer are less commonly seen than before. Nevertheless, there remains a group of patients who either because they do not seek advice earlier or because the tumour is more aggressive, present with locally advanced disease. Data from the American National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program show that 7% of all breast cancer patients have stage III disease at diagnosis, although this percentage is less than 5% in the screening population.4 Despite this, patients with LAPC still present a significant clinical problem and exemplify a subgroup of patients where a multidisciplinary approach is particularly important to outcome. Initially, an aggressive single modality, local therapy approach, was commonly advocated for the treatment of patients with LAPC, either in the form of radical surgery or radiotherapy. This often provided temporary local control, although on follow-up of these patients, the morbidity and recurrence rates were high and survival poor.5 Further modalities were introduced in subsequent studies and the sequence of these modalities did not seem to have an impact on the outcome.6e9 Multimodal approach is now an established option in most patients with LAPC, especially oestrogen receptor (ER) negative tumours or aggressive ER positive tumours (e.g. some inflammatory cancers). This includes the combination of surgery and radiotherapy for local control and systemic therapy, usually chemotherapy þ/ hormone therapy. For others, such as those with strongly hormone receptor positive tumours, local treatments (i.e. surgery þ/ radiotherapy) plus endocrine therapy or even primary endocrine therapy may be appropriate options. This may for example be the case in many elderly patients, some of who are medically unfit for surgery. Neo-adjuvant chemotherapy was first described in patients with LAPC and published by De Lena et al in the late 1970s.10 Since then a large number of studies have assessed the use of neoadjuvant chemotherapy in operable primary breast cancer. Although the results in operable breast cancers suggest that the breast conserving rates can be increased, survival is no different when compared to post-operative adjuvant chemotherapy.11 However, patients with LAPC often have inoperable disease at diagnosis and the main goal of neoadjuvant treatment is to achieve resectability, either in the form of standard mastectomy or breast-conserving surgery. Furthermore, the clinical and histological response to neoadjuvant chemotherapy has been shown to be important predictors of recurrence and survival in studies of operable breast cancer. In this paper, we systemically review the literature on the use of neoadjuvant chemotherapy specifically in

LAPC, analyse factors important in the prediction of outcome, and discuss the possible role of breast conservation in these patients. Selection of studies A search of Medline and PubMed databases of studies on neoadjuvant chemotherapy was performed. Key words used were neoadjuvant chemotherapy in locally advanced primary breast cancer, primary chemotherapy in locally advanced primary breast cancer, and preoperative chemotherapy in locally advanced primary breast cancer. Following this search, only trials and case series where approximately 70% of the patients with tumours larger than 5 cm or defined as locally advanced breast cancers according to the TNM classification were selected. Furthermore, only studies with surgery as the primary modality for local control of disease after chemotherapy were included. Even given these broad criteria, the number of randomised controlled trials is very small. The studies are listed in Table 1. Response to chemotherapy Type of chemotherapy As shown in Table 1, the majority of chemotherapy regimens included an anthracycline regimen and clinical complete response (cCR) ranged from 4% to 62% and pathological complete response (pCR) rates ranged from 3% to 46%.8,12e34 In the EORTC-NCIC-SAKK multicenter study,14 the possible benefit of dose intensified anthracycline regimen versus a standard regimen was assessed. In this randomised controlled trial with 217 patients in one arm and 220 patients in the other, all of which were patients with tumours more than 5 cm, no significant difference in cCR rate or pCR rate was seen between the treatment arms. In three phase 2 studies, which included a taxane in addition to anthracycline regimen, cCR ranged from 20% to 31% and a pCR ranged from 7% to 18%.17e19 One randomised controlled trial in which around 60% of patients had tumours more than 5 cm compared an anthracycline regimen to an anthracycline plus taxane.12 In this study the cCR increased from 34% to 62% and the pCR response increased from 16% to 34% in favour of the combination of anthracycline and taxane. Only patients who showed response to the initial anthracycline combination were included in this trial, which may explain the high pCR. A similar increase in response (cCR and pCR) has been noted in operable breast cancers in National surgical adjuvant breast and bowel project B27.35,36 However in this study of 2411 patients, despite the pCR rate doubling from 13.7% to 26.1% the breast conservation rate did not increase (61.65% vs. 63.7%) nor did the overall survival.36 Recent studies to significantly improve the rates of pCR have shown promise. Minckwitz et al., in a phase 3 randomised trial (GEPARDUO) of 913 women with operable

Table 1 Studies on neoadjuvant chemotherapy Trial

Patients

T >5 cm (%)/S (%)

Type of chemo

c CR (%)

Tan et al., 20018

RCT RCT

Thomas et al., 200413

RCT

79 64 59, N2e13 60, N2e6 84

Therasse et al., 200314

RCT

Semiglazov et al., 200715

RCT

Ezzat et al., 200416 Matteis et al., 200217 Lebowitz et al., 200418 Espinosa et al., 200419 Kao et al., 200520 Tham, 200521 Gradishar et al., 200522 Kuerer, 199923 Clark et al., 199824 Shen et al., 200425 Huang et al., 200526 Baldini et al., 200427 Erol et al., 200528 Kim et al., 200429 McIntosh et al., 200330 Favret et al., 200131 Agoglu et al., 200532 Colozza M et al 199633 Gajdos et al., 200234

Phase Phase Phase Phase Phase Phase Phase Pros Pros Pros Retro Retro Retro Retro Retro Retro Retro Retro Retro

217 220 118 121 126 q 29 50 16 51 45 372 34 33 542 68 74 25 166 64 28 30 139

100 100 >70 >70 88 80 70 100 100 73 100 89 100 100 84 100 100 100 73 100 100 (TNM-LAPC) 100 76

MMM Endocrine treatment CVAPþCVAP CVAPþT CVAP Randomisation post op CEF ECþFulgrastin DþP Endocrine treatment PC ET TþCapAC ET PVino Taxane Taxane FAC A A/CMF/other FAC/VACP/AT FAC/FEC CMF FAC/FEC/AC/Vino/T/CF CVAP FAC FAC CisAC Cytoxan MF/ A

9

Heys et al., 200212

56 52 50 47 200

2 2 2 2 2 2 2

pCR (%)

BCS (%)

Median FU (M)

DFS (%)

OS/Alive (%)

52

NR

45

34 62 18

16 34 12

48 67 5

36 36 166

77 90 51% at 5 yrs

84 97 60% at 5 yrs

31 27

14 10

53% at 5 yrs 51% at 5 yrs

16 13 7 18 46 11 7 12 21 12 NR 3 19 NR 15 NR 3 7 13

66 66 36 36 38 NR NR 22 22 28 67 58 30 91 70 120 62 NR 62 51 52 72 52

34 months 34 months

28 20 31 20 NR 27 7 NR NR 30 14 NR 15 4 21 45 11 7 8

NR NR 24 33 29 17 59 12 NR 9 6 29 44 100 NR NR 4 NR 25 6 100 NR 10

71 NR NR 82 31 NR NR 72 77% 3 yrs 70% at 5 yrs NR 26 52% at 5 yrs NR NR 58% at 5 yrs NR 28 51 at 5 yrs

87 NR NR 90 56% at 4 yrs 77 80% at 5 yrs 76 88% at 3 yrs 78 at 5 yrs NR 40 79% at 5 yrs 69% at 5yrs NR 75% at 5 yrs 66% at 5 yrs 29 62 at 5 yrs

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Authors

NR, not reported; PVino, paclitaxel  vinorelbine; T >5 cm (%), % of patients with tumour >5 cm; S%, percentage of patients with stage IIB, III and T4d. CisAC, cisplatin, doxorubicin, cyclophosphamide; MMM, mitoxantrone, methotrexate, mitomycin; CVAP, cyclophosphamide, vincristine, doxorubicin, prednisone; CEF, cyclophosphamide, epirubicin, fluorouracil; PC, paclitaxel, cyclophosphamide; TþCapAC, docetaxel þ capecitabine  doxorubicin and cyclophosphamide. cCR, complete clinical response; pCR, complete pathological response; BCS, breast conservation surgery; DFS, disease-free survival; OS, overall survival.

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breast cancers, looked into whether sequencing anthracycline and taxanes as opposed to dose-dense regimen would improve outcome.37 This study reported that sequential therapy with doxorubicin þ cyclophosphamide followed by docetaxel is more effective in inducing pCR than a dose-dense doxorubicin and docetaxel regimen (14.3% vs. 7%; odds ratio 2.22, 90% CI 1.52e3.24; p < 0.001). Another trial by Minckwitz (GEPARTRIO) in operable breast cancer patients reported that early response to two cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) reliably identify patients with high chance of achieving a pCR. In this study on 285 patients, 73% (208 patients) achieved clinical objective response (CR/PR) and went on to receive an additional four cycles of TAC preoperative chemotherapy.38 Patients who did not respond received either an additional four cycles of the same treatment (TAC) or vinorelbine and capecitabine (NX) chemotherapy. Responding patients following two cycles achieved a pCR of 22.6% compared to 7.3% in patients receiving additional TAC in the non-responding group and 3.1% in the non-responding NX group. Gianni and colleagues have looked into combining neoadjuvant chemotherapy with Trastuzumab in HER-2 positive patients diagnosed preoperatively on core biopsy.39 In this phase 3 randomised trial involving 228 HER 2þ locally advanced primary breast cancers receiving 3 cycles of doxorubicin-paclitaxel, 4 cycles of paclitaxel and 3 cycles of CMF chemotherapy with or without herceptin, a significant increase in the pCR rate was shown in favour of patients receiving herceptin (43% vs. 23%; P ¼ 0.002). Similarly in a study by Buzdar and colleagues in HER-2 positive patients, a higher pCR was noted in patients receiving chemotherapy and herceptin.40 In 45 patients receiving Paclitaxel, FEC and Trastuzumab, a pCR was seen in 60% of cases compared to 26% in 19 patients receiving Paclitaxel and FEC chemotherapy alone. Thus Trastuzumab should be considered for patients with Her2/neu positive disease who are receiving neoadjuvant chemotherapy. While the concomitant use of trastuzumab with anthracycline is best restricted to clinical trials, trantuzumab and epirubicin appeared to be well tolerated in the above trial. Recent studies have shown vascular endothelial growth factor (VEGF) as a potential target in breast cancer treatment,41 and the use of bevacizumab (recombinant humanized monoclonal antibody to VEGF) in the neoadjuvant setting is being evaluated in clinical trials.42 Patients with insufficient clinical response, especially with progressive disease, benefit little from continuing treatment and an alternative treatment should be considered so as to spare the toxicity. However, if we can predict the response to treatment even before the start of chemotherapy it could be more advantageous. Patients whose tumour expresses marker of good response to chemotherapy include low or absent hormone receptor status, high-grade, non-lobular invasive histology, high Ki67 and luminal B.43 These tumour types have a higher chance of response and should be considered for neoadjuvant chemotherapy. In contrast,

tumours which show low response to chemotherapy (e.g. lobular type, low Ki67) should be considered for alternative approaches (e.g. neoadjuvant endocrine therapy or mastectomy as initial treatment). Gene-expression profiling is another area under investigation which could predict response. Sorlie et al., in their study on gene expression in 78 breast cancers, 3 fibroadenomas and 4 normal breast tissue samples, have identified three subgroups for the luminal/ERþ subtype along with previously described basal-like subtype, ERBB2þ subtype, and normal breast like type.44 Univariate survival analysis comparing subtypes showed basal-like and ERBB2þ subtypes having poor survival. Basal-like subtype showed high frequency of TP53 mutations, which has been considered a predictor of poor prognosis and poor response to systemic therapy. In addition, another interesting finding in this study was the sub-classification of luminal/ERþ tumours into A, B and C, and luminal B and C representing a group with a worse clinical course as opposed to luminal A. While these reports are interesting, their relevance to selecting patients with LAPC for neoadjuvant chemotherapy as opposed to other treatment options is unresolved at this time. Hormone sensitivity Studies suggest that oestrogen receptor (ER)-positive tumours respond less well to chemotherapy than ER-negative tumours.45,46 Semiglazov et al., in a randomised control trial, looked into the efficacy of chemotherapeutic agents versus endocrine agents in the neoadjuvant setting in achieving an objective response and breast conservation in ER-positive breast cancer patients who were ineligible for breast conservation surgery from the onset. Eligible patients were randomly assigned 1:1 to receive endocrine therapy (Anastrazole, 61 patients or Exemestane, 60 patients) versus neoadjuvant chemotherapy (Doxorubicin and Paclitaxel, 118 patients, 4 cycles).15 At 3 months assessment, there was no statistically significant difference in overall objective response between the groups (Anastrazole 62%; Exemestane 67%; chemotherapy 63%; p > 0.5). More patients in the endocrine group were suitable for breast conservation compared to the chemotherapy group although this was not statistically significant (33% vs. 24%; p ¼ 0.058). After a median follow-up of 36 months, there was no significant difference in the incidence of local recurrence between the two groups (endocrine 3.3% vs. chemotherapy 3.4%). In a series reported by Mathieu et al., the clinical response rate following neoadjuvant chemotherapy for lobular cancer (91% ER positive) was 26% versus 58% for ductal carcinoma with 68% ER-positive tumours ( p < 0.001).47 There were no cCR or pCR in patients with lobular carcinoma. Similarly, in a study by Cistofenelli et al. of over 1000 patients treated by neoadjuvant chemotherapy, patients with invasive lobular cancer (92%

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ER-positive) were significantly less likely to have pCR (3% vs. 15%; p < 0.001) when compared to patients with invasive ductal cancer (62% ER-positive).48 Neoadjuvant hormone therapy can be a consideration over chemotherapy in ER-positive cancers. Association between response and outcome In operable disease, the National Surgical Adjuvant Breast and Bowel Project B-18 trial (NSABP B-18), reported no difference in survival between neoadjuvant and adjuvant chemotherapy. However, an association between the category of clinical response and survival was seen.11 Of the 682 patients in the study group, 247 (36%) had complete clinical response and 88 (13%) had complete pathological response. At 9 years of follow-up, the rates of disease-free survival was 64% in patients with complete clinical response compared to 46% in non-responders (stable disease and progressive disease; p ¼ 0.0008). The overall survival was similarly better; 75% vs. 65% ( p ¼ 0.005). In this study it was shown that the histological response might be a better predictor of outcome. At 9 years, the disease-free survival in patients who achieved complete pathological response was 75% compared to 58% for incomplete responders ( p ¼ 0.0005). For overall survival the rates were 85% and 73% (0.00008). Similar findings have been reported in locally advanced breast cancers. In a randomised controlled trial by Heys et al. in patients with locally advanced breast cancers, the group with better clinical and pathological response was found to have a significant increase in disease-free survival at 3 years; 90% vs. 77% ( p ¼ 0.03).12 Similarly overall survival rates were 97% and 84% respectively ( p ¼ 0.05). More recently these data have been updated and presented at the 2003 San Antonio Breast cancer Symposium and at a median follow-up of 65 months, the anthracycline þ docetaxel group with better cCR and pCR reported an overall survival rate of 95% compared to 78% in the anthracycline alone group ( p ¼ 0.04).49 In a study by Thomas et al. of 200 patients with locally advanced breast cancers, 17.6% of the patients had cCR and 12.2% had pCR.13 The rates of recurrence-free and overall survival for the complete clinical responders were 79% and 85%, respectively compared to 40% and 52%, respectively for the incomplete clinical responders ( p ¼ 0.0001). Similarly the recurrencefree and overall survival in the pCR group were both 86% compared to 52% and 59% in the group who did not achieve pCR ( p ¼ 0.0001). A phase 2 study by Ezzat et al. on 126 women with locally advanced breast cancers undergoing neoadjuvant chemotherapy with paclitaxel and cisplatin followed by surgery and postoperative chemo- (FAC) and radiotherapy, showed that following multivariate analysis clinical response of the primary tumour, pathological response of the primary tumour and the pathological nodal status were independent prognostic indicators of disease-free

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survival.16 It failed to identify independent prognostic factors for overall survival. In a prospective study by Kuerer and colleagues on 372 patients with locally advanced breast cancers receiving FAC neoadjuvant chemotherapy, a pCR of 12% achieved, and 5-year disease-free survival and overall survival of this group was 87% and 89%, respectively compared to 58% and 64%, respectively in non-responders ( p < 0.01).23 The presence of axillary lymph node involvement in breast cancer is a well-established prognostic factor.50,51 Following neoadjuvant chemotherapy, residual disease in the axilla has also been associated with poor outcome.52e54 In a study by Rouzier et al. in 152 patients with T1eT3 tumours with cytologically proven metastasis in the axilla, complete pathological response was seen in 23% in the axilla compared to 13% at the primary site, suggesting a higher rate of response in the axilla to chemotherapy than the primary tumour itself.53 This can also be explained in terms of tumour size, i.e. primary tumours are usually larger than the corresponding lymph node metastasis. Following multivariate analysis the study concluded that in node-positive patients a complete pathological response in the breast could be considered as a marker of pathological axillary conversion following chemotherapy rather than a predictor of survival by itself, and conversion of positive to negative nodes was a strong predictor of survival ( p < 0.01). Fourteen of the 20 patients with pCR of the primary tumour had complete axillary down-staging ( p < 0.001), suggesting an association between pathological response in the primary site and the axilla. In summary, these studies suggest an association between clinical and pathological complete response and good outcome, and residual pathological nodal involvement seems to be an important predictor of outcome. However, comparison of outcomes between trials and individual series is difficult because of the heterogeneity of the study populations. Breast conservation in LAPC The role of breast conservation surgery in LAPC is not well established. In operable disease, several studies have highlighted some important clinical and pathological findings. In the NSABP B-18 trial, surgeons were required to disclose the intended surgical procedure (i.e. lumpectomy or mastectomy) before randomisation to pre- or postoperative chemotherapy.11 In the neoadjuvant group, a statistically significantly higher rate of ipsilateral breast tumour recurrences (IBTR) occurred in patients treated by breast conservation, but not deemed suitable for it before chemotherapy (11/69, 15.9%), compared to those suitable for breast conservation to begin with (43/434, 9.9%; p < 0.04). In another randomised control trial by Van der Hage and colleagues on 698 operable breast cancers randomised to pre- and postoperative chemotherapy, the rate of breast conservation surgery was higher in the

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preoperative chemotherapy group compared to the postoperative therapy group.55 Twenty-three percent of the preoperative group who were initially planned to have mastectomy underwent breast-conservation surgery. These patients had a significantly worse overall survival when compared with patients who were initially planned to receive breast-conservation therapy ( p < 0.04). As the type of surgery in these studies was not randomised and assessing suitability for breast conservation surgery can be subjective, selection bias is easily introduced which may have a significant impact on the results. In a more recent larger study (National Surgical Adjuvant Breast and Bowel Project B27), 2411 patients with operable breast cancer were randomised to an anthracycline þ/ a taxane. Despite a doubling of pCR rate from 13.7% to 26.1% the breast conservation rate did not increase (61.65 vs. 63.7%) nor did the overall survival.36 However, in operable breast cancer there has been a recent meta-analyses of 11 studies involving over 5000 patients, which has looked into breast conservation and locoregional recurrence in those receiving neoadjuvant chemotherapy versus adjuvant chemotherapy.56 Overall there was a significant decrease in mastectomy in favour of neoadjuvant chemotherapy, although significantly more patients in the neoadjuvant group developed local recurrence compared to those on adjuvant treatment. However, when three studies which comprised more than one-third of patients receiving only radiotherapy for local control and no surgery after complete response were excluded, there was no significant difference between the two groups with regard to local recurrence (HR 1.12; 95% CI 0.92e1.37). The maximum median follow-up of studies included in this analyses was 10 years and a longer follow-up may be required to categorically ascertain this clinical outcome. In LAPC, a study involving 97 patients, addition of docetaxel to CVAP as opposed to further CVAP as neoadjuvant agents resulted in better complete clinical and pathological response and this did translate into a higher breast conservation rate (67% vs. 48%).12 This study was not statistically powered to detect differences in survival. In the small Phase II trial by Lebowitz et al. in LAPC (n ¼ 29), after neoadjuvant chemotherapy, 59% of the patients underwent breast-conservation surgery, whereas only 13% were thought to be suitable for it initially.18 Neither local recurrence rates nor survival were reported. There are a few papers that have included patients with locally advanced primary breast cancers which have reported low recurrence rates and good survival following neoadjuvant chemotherapy and breast conservation surgery when compared to neoadjuvant chemotherapy and mastectomy. In a prospective review by Kuerer and colleagues involving 372 women, 89% of which had tumours larger than 5 cm receiving neoadjuvant chemotherapy, patients undergoing breast conservation surgery (29%) had a significantly better disease-free and overall survival (73% and 82%) compared to those patients undergoing mastectomy (57%

and 66%; p < 0.01).23 However the results might be explained simply by selection bias. In the first instance, patients were more likely to have conservative surgery rather than mastectomy if they presented with earlier stage disease (IIA, IIB, IIIA; 73% vs. IIIB and IV; 27%). Secondly, patients who had a good response would be more likely to have a smaller tumour suitable for breast-conserving surgery while at the same time the fact that they had had a good response placed them in a better group with regard to survival when compared to patients that didn’t respond well. McIntosh et al. reported in locally advanced breast cancers (T > 4 cm) a locoregional recurrence rate of 2% in 44 patients undergoing breast conservation surgery compared to 7% in 122 patients undergoing mastectomy after a median follow-up of 62 months.30 However, all 44 patients undergoing breast conservation surgery were responders and 18 (41%) patients had complete clinical response. Of the 122 patients who had mastectomy, only 71 patients (67%) were responders and 17 (14%) patients had complete clinical response. Survival was not reported in this study. This study too suffers from the same selection bias as that reported by Kuerer and colleagues. In another study, on a selected group of 33 women with stage IIIB and IIIC tumours with good clinical response following neoadjuvant chemotherapy, Shen et al. reported an actuarial ipsilateral breast cancer recurrence of 6% at 5 years following breast conservation surgery.25 The disease-free and overall survivals were 75% and 78%, respectively at 5 years. In a small series by Clark et al., in 15 of the total of 34 patients (44%) undergoing breast conservation surgery, only one developed regional recurrence at a median follow-up of 30 months.24 The actuarial 3-year disease-free and overall survival was 77% and 88%, respectively. In another retrospective study which included 28 patients with stage IIB and stage III breast cancers, undergoing breast conservation surgery following FAC chemotherapy, Asoglu and colleagues reported clear margins in all patients and an incidence of locoregional recurrence of 4 (14%) with an overall survival of 66% at 5 years.32 There are problems associated with offering breast conservation to patients with LAPC. Pathological studies have shown that chemotherapy may not produce a uniform response of the cancer, but rather a honeycomb or multifocal type pattern, leaving clusters of viable tumours cells at a distance from the central residual tumour site.52,55 Veronesi et al. reported a study of 226 patients with tumours more than 3 cm (197 patients or 87% had tumours between 3e5 cm) who underwent neoadjuvant chemotherapy with various chemotherapy regimens (including CMF with and without anthracyclines) followed by surgery. In this study the histopathology showed multifocality in the primary tumour in 37 patients (16.3%) and complete pathological response was seen in only 8 patients (3.5%).52 In a retrospective study by Clouth et al., 101 patients with LAPC (identified as T2, T3, N0 or N1,M0) underwent

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neoadjuvant chemotherapy (four cycles of doxorubicin and cyclophosphamide), with addition of four cycles of Paclitaxel (n-91).57 Twenty-five patients (25%) achieved a complete clinical and radiological response and were subjected to multiple core biopsies, centrally and at all four quadrants. Sixteen patients had negative core biopsies (pCR) and were followed up without further treatment, and those who had residual disease underwent breast conservation (1 patient) or mastectomy (8 patients) depending on extent of residual disease. Thus most patients with residual disease had a tumour in more than one quadrant (8/9) in spite of achieving complete clinical and radiological response following neoadjuvant chemotherapy. In a randomised controlled trial by Van der Hage and colleagues, comparing the outcome of preoperative and postoperative chemotherapy (fluorouracil, epirubicin and cyclophosphamide), 120 of 350 patients underwent breast conservation surgery from the preoperative group.55 Sixty-three of these (group 1) were deemed suitable for breast conservation from the onset (before neoadjuvant chemotherapy treatment) and the remaining 57 (group 2) were initially planned to have mastectomy. In both groups, no statistical difference was seen in clinical (before neoadjuvant chemotherapy) or pathological tumour size. In group 1, 22% had a clinical size more than 2 cm, whereas on histology 21% were noted to be of this size. In group 2, the respective percentages were 23% and 25%. A comparison between clinical tumour size after preoperative chemotherapy and pathological tumour size was not made in this group nor did they comment on multifocality. However, a cCR was seen in 23 of 350 patients (6.6%), and a pCR in 13 (3.7%), six of whom showed a cCR. Although the rates of both cCR and pCR in this study seem low, it highlights and supports other studies, which have shown a great discrepancy between cCR and pCR.23,58e67 These studies might be interpreted to suggest that the extent of surgery should not be based on estimated size or the subjective assessment of clinical response following chemotherapy. These observations may at least in part explain why the down-staging effect, as judged by the ability to convert from mastectomy to breast conservation surgery by neoadjuvant chemotherapy in operable disease, has not been as effective in the long run as initially anticipated.11 Breast conservation may be carried out in a selected group of patients, especially those that show a pCR response following neoadjuvant treatment and, while being avoided in patients with multicentric disease. Further investigation to assess the oncological safety of breast conservation needs to be addressed in prospective randomised trials. Oncoplastic breast surgery No studies, and certainly no randomised controlled trials, have specifically looked at the role of oncoplastic breast-conserving surgery in LAPC, although the principles of these techniques seem potentially applicable in this

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setting. Individual case series have shown that these techniques can be used in the resection of large operable tumours.68 In general, these techniques involve breastreshaping or volume replacement and frequently include contralateral surgery. They allow for large excisions, including overlying skin where appropriate, thereby potentially reducing the incidence of margin involvement and hence local recurrence without compromising the cosmetic outcome.69 Tumour localisation In addition to the difficulties in deciding on the extent of surgery, localising the tumour following neoadjuvant chemotherapy can be difficult, especially in the subgroup of patients showing a complete clinical response. Edeiken and colleagues have shown the advantage of ultrasoundguided implantation of metallic markers for localisation of the tumour bed in anticipation of complete or near complete response following neoadjuvant chemotherapy.70 Of the 49 patients they looked into, in 23 (47%) patients the metallic marker was the only remaining evidence of original tumour site following chemotherapy. The study also showed that there was no evidence of migration of metallic markers as comparisons were made on mammograms after implantation and shortly before surgery. This was also confirmed on histopathology on the basis of their position adjacent to fibrosis or scar characteristic of post-chemotherapy changes. Veronesi and colleagues have highlighted the use of skin tattoo to identify the tumour site following neoadjuvant chemotherapy.52 They looked into 226 patients with tumours more than 3 cm who were initial candidates for mastectomy and underwent neoadjuvant chemotherapy followed by surgery. Before the start of chemotherapy the position of the tumour was marked on the surface by tattoo and surgical incision was guided by the tattoo marks. Two hundred and three patients (90%) were treated by breast conservation surgery and after a mean follow-up of 36 months, the local recurrence was 5.9% (12/203, 2% per annum) compared to 21.7% (5/23, 7.2% per annum) in the remaining patients who had mastectomy. Although tattoos may be useful in the identification of tumours as suggested in this paper, with the availability of modern imaging techniques and the use of metallic markers for tumour localisation, it has become less commonly used among surgeons. Imaging of tumours In operable breast cancer, MRI imaging has shown promise and can accurately identify additional residual disease, and has been shown to alter the planned local treatment in 10e16% of cases.71,72 It has been shown to make a superior differentiation between chemotherapy-induced fibrosis from residual tumour compared to the conventional methods of assessment including clinical

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examination, mammography and ultrasonography. In a study by Partridge and colleagues on 52 patients undergoing neoadjuvant chemotherapy, MRI imaging was done before and after chemotherapy.73 Following histopathology, MR imaging identified all cases of residual disease, whereas clinical assessment resulted in five false-negative interpretations in 52 treated patients. However, of the eight pathological responders only three were assessed as complete responders on MR and the rest were suggested to have residual disease (high false positive rate). In another study by Garimella and colleagues, of the 186 patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy, 76 patients (46%) were found to be suitable for breast conservation following MRI.74 Eight patients (10.5%) were found to have pathologically more extensive disease than seen on MRI scan and had to undergo further surgery. Overall, this study suggested that MRI had an accuracy of 90% in predicting the extent of disease following neoadjuvant chemotherapy. However, the rate of recurrence in these 68 patients treated by breast conservation was high. After a short median follow-up of 30 months, 7 (10%, 4% per annum) developed local recurrence, 9 (13%, 5.4% per annum) regional recurrence and 17 (25%, 10% per annum) distant metastases. There have also been reports on the use of PET scans as predictors of pathological response, but these studies are small and require further validation.75 These studies therefore suggest that newer imaging modalities may improve the selection of LAPC patients truly suitable for breast conservation after neoadjuvant chemotherapy. However, whether this can be achieved with acceptable rates of local recurrence remains to be seen. Larger studies with longer follow-up may provide some further information but there is clearly a need for well-designed, prospective randomised trials to address this issue. Summary The multimodal approach is an established option for most patients with LAPC, especially oestrogen receptor (ER)-negative tumours or aggressive ER-positive tumours (e.g. some inflammatory cancers). Various different chemotherapy regimens can result in high rates of resectability and local control. Recent studies have shown that with the combination of taxanes and anthracyclines and the increasing use of biological response modulators, high rates of pCR can be achieved which in turn may have a surrogate value on long-term outcome. The potential value of breast conservation surgery following neoadjuvant chemotherapy in LAPC is unproven, as there are very few randomised controlled trials looking specifically at this subgroup of patients and much of the evidence comes from retrospective studies and phase II trials. Locally advanced breast cancer is one area of breast cancer where there has been a relative paucity of prospective randomised trials. Many of the issues discussed in this

review should be addressed in well-designed, prospective randomised clinical trials. Conflict of interest The authors state that they have no conflicts of interest.

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