Invited review

Surgical treatment of primary breast cancer in the neoadjuvant setting S. Kümmel1 , J. Holtschmidt1 and S. Loibl2,3 1 Kliniken Essen Mitte, Klinik für Senologie, Essen, 2 German Breast Group, Neu-Isenburg, and 3 Sana Klinikum Offenbach, Offenbach, Germany Correspondence to: Professor S. Loibl, German Breast Group, GBG Forschungs GmbH, Martin-Behaim-Strasse 12, 63263 Neu-Isenburg, Germany (e-mail: [email protected])

Background: Neoadjuvant chemotherapy (NACT) is a standard treatment option for primary operable

breast cancer when adjuvant chemotherapy is indicated. Methods: This article reviews the use of NACT in breast cancer treatment. Results: Pathological complete response (pCR) rates of up to 60 per cent have been reached for

certain breast cancer subgroups. Patients achieving a pCR have a lower locoregional recurrence rate. Nevertheless, the rate of breast-conserving surgery seems to be stable at around 65–70 per cent, although more than 80 per cent of patients respond to NACT. The risk of local relapse does not appear to be higher after NACT, which supports the recommendation to operate within the new margins, as long as there is no tumour in the inked area of the surgical specimen. However, tumours do not shrink concentrically and the re-excision rate is higher after NACT. Mastectomy rates for lobular carcinomas remain high irrespective of tumour response. The role of sentinel lymph node biopsy (SLNB) in the context of NACT has been studied in recent years, and it is not yet completely clear which type of axillary staging is the most suitable. SLNB before NACT in clinically node-negative patients has been the preferred option. However, this practice is currently changing, and it seems advisable to have the SLNB after NACT to reduce the risk of a false-negative SLNB. Conclusion: Overall, patients do benefit from NACT, especially those with human epidermal growth factor receptor 2-positive and triple-negative breast cancer, but surgical/local procedures need to be adapted. Paper accepted 2 April 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9545

Introduction

Neoadjuvant therapy has become a standard option in the treatment of primary operable and locally advanced breast cancer1 . Initially developed for use in locally advanced tumours, the concept of neoadjuvant chemotherapy (NACT) has now also been adopted in the setting of early breast cancer. The evolution of modern chemotherapy regimens has led to a steady rise in pathological complete response (pCR) rates over recent decades in patients with early breast cancer. Tailored systemic therapy can be administered according to the tumour subtype and nodal status, and the effectiveness monitored using the primary lesion as an in vivo chemosensitivity test (Fig. 1). The safe use and advantages of NACT, in downstaging disease within the breast and axilla, have long been described. As shown by the National Surgical Adjuvant Breast and Bowel Project (NASBP) B-18 trial2,3 , a significantly higher rate of breast-conserving surgery (BCS) and © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

downstaging of axillary involvement can be achieved without jeopardizing disease-free (DFS) and overall (OS) survival at a follow-up of 15 years. These results date from a time when the concomitant use of taxanes and biologicals had not yet been implemented. Nowadays, pCR rates of 20–25 per cent can be achieved by NACT alone. A combination of NACT with targeted agents, such as trastuzumab, two agents targeted against human epidermal growth factor receptor (HER) 2 or bevacizumab, has led to pCR rates of up to 40–80 per cent, especially in HER2-positive and triple-negative breast cancer4 – 10 . Although NACT regimens have been refined, leading to high pCR rates, the rate of BCS has remained stable (Tables 1–3)11 – 33 . Follow-up results from earlier studies imply that the use of BCS after NACT is safe in terms of local control as rates of locoregional recurrence (LRR) are low following NACT and surgery30,34 . Surgery in new BJS

S. Kümmel, J. Holtschmidt and S. Loibl

Adjuvant treatment

Neoadjuvant treatment

Breast cancer diagnosis

Breast cancer diagnosis

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Surgery

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No clinical response

Change regimen

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Tumour typing and staging

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Surgery

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Adjuvant therapy

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Use of chemotherapy in breast cancer treatment. Boxes indicate points at which tumour samples can be collected to monitor effects

Fig. 1

margins adjusted for the tumour response after NACT hence seems feasible, and is recommended1 . However, several questions remain to be addressed in future studies. Can clinical assessment with magnetic resonance imaging (MRI) or jet biopsy be used to predict a pCR reliably? Is a further reduction in surgical radicality for disease within the breast safe, analogous to the trend towards conservative axillary surgery? What is the prognostic impact of such a change in the trend of breast cancer treatment?

Pathological complete response: a good prognostic factor

Historically, breast cancer was understood to be a localized disease that requires radical surgery to achieve a cure. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

Since the time of radical mastectomy as postulated by Halsted in 1894, a tremendous amount of information has been gathered, leading to a different understanding of the disease. Breast cancer is nowadays regarded as a systemic disease with broad biological heterogeneity. The implementation of systemic therapies in addition to the crude resection of affected tissue has long been shown to improve the prognosis as measured by DFS and OS35,36 . If adjuvant systemic therapy is capable of eradicating minimal residual/disseminated disease after resection of the primary lesion, clinically occult dissemination of tumour cells must already have taken place before surgery. The pCR is a strong prognostic marker for superior DFS and OS, especially in the hormone receptornegative subgroups (either HER2-positive or -negative) www.bjs.co.uk

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Surgical treatment of primary breast cancer in the neoadjuvant setting

Table 1 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and breast-conserving surgery rates: neoadjuvant trials and trials comparing preoperative versus postoperative administration Trial GeparDo11 * GeparDuo12 * GeparTrio pilot13 * GeparTrio14,15 *

GeparQuattro10,16 * HER2-negative

HER2-positive AGO-117 * PREPARE18 * SWOG 001219 MDACC20 CALGB 4060321

Older trials comparing preop. and postop. administration NSABP B-183 ABCSG-0722 EORTC 1090223

Preoperative therapy

n

ypT0/Tis ypN0 (%)

BCS (%)

dd A Doc × 4 dd A Doc × 4 + Tam dd A Doc + Tam A C × 4 then Doc + Tam TAC × 6 TAC × 2 then 4 × N X TAC × 6 TAC × 8

126 122 453 454 252 33 1085 686

9⋅5 5⋅7 10⋅2 19⋅2 19⋅0 6 18⋅7 29⋅0

TAC × 2 then N X × 4

301

6⋅9

69 69 66 75 n.a. n.a. 68 69 responders 57 non-responders 60

E C × 4 then Doc × 4 E C × 4 then Doc + X × 4 E C × 4 then Doc × 4 then X × 4 CHT + H for HER2-positive E Pac × 4 dd E × 3 then dd Pac × 4 E C × 4 then Pac × 4 dd E × 3 then dd Pac × 3 then CMF × 3 A C × 5 every 3 weeks then Pac × 12 A × 15 weekly + C daily then Pac × 12 FAC × 4 dd FAC × 4 Pac × 12 then dd A C × 4 + Bev × 9 every 2 weeks + Cb × 6 every 3 weeks + Cb + Bev

343 345 362 445 335 333 370 363 179 177 100 99 108 110 113 112

18⋅7 16⋅5 19⋅1 41⋅3 6⋅6 13⋅2 14⋅6 20⋅4 20⋅7 24⋅3 9⋅0 13 39⋅0 43⋅0 49⋅0 60⋅0

A C×4 Primary surgery CMF × 3 Primary surgery FEC × 4 Primary surgery

747 759 203 195 350 348

5⋅9 bpCR 4⋅0

68* 67 64 58 67 65 n.a. n.a n.a.

67 60 66 60 35 22

*Numbers are based on original data used for meta-analysis; data in study publication may be different. ypT or N, pathological tumour or node category after chemotherapy; BCS, breast-conserving surgery; dd, dose dense; A, doxorubicin; Doc, docetaxel; Tam, tamoxifen; C, cyclophosphamide; TAC, docetaxel–doxorubicin–cyclophosphamide; n.a., not available; N, vinorelbine; X, capecitabine; E, epirubicin; HER, human epidermal growth factor receptor; CHT, chemotherapy; H, trastuzumab; AGO, Arbeitsgemeinschaft für Gynäkologische Onkologie; Pac, paclitaxel; PREPARE, Preoperative Epirubicin Paclitaxel Aranesp Study; CMF, cyclophosphamide–methotrexate–5-fluorouracil; SWOG, Southwest Oncology Group; MDACC, MD Anderson Cancer Center; FAC, 5-fluorouracil–doxorubicin–cyclophosphamide; CALGB, Cancer and Leukemia Group B; Bev, bevacizumab; Cb, carboplatin; NSABP, National Surgical Adjuvant Breast and Bowel Project; ABCSG, Austrian Breast and Colorectal Cancer Study Group; bpCR, breast pathological complete response; EORTC, European Organization for Research and Treatment of Cancer; FEC, 5-fluorouracil–epirubicin– cyclophosphamide.

as the correlation with survival is best in these groups. It has therefore been used as the primary endpoint for many trials of neoadjuvant therapy37 – 41 . The introduction of targeted therapies such as trastuzumab has had further impact on pCR rates and outcome27 . For patients with HER2-overexpressing tumours a further improvement in the efficacy of NACT is conceivable based on the results of the NeoSphere8 and TRYPHAENA4,5 trials. A significant increase in pCR, defined as the absence of invasive neoplastic cells in the breast (pathological status after neoadjuvant therapy

(yp) T0/Tis), was observed in the NeoSphere trial8 by addition of neoadjuvant pertuzumab to trastuzumab and docetaxel. The TRYPHAENA trial4 evaluated cardiac safety and reported pCR (ypT0/Tis) rates above 60 per cent. These results led to the US Food and Drug Administration (FDA) approval of pertuzumab for the neoadjuvant treatment of breast cancer42 . In the past, new chemotherapeutic agents had to be tested in the adjuvant setting before approval. Adjuvant studies require years of follow-up of clinical outcome and are therefore protracted and costly.

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S. Kümmel, J. Holtschmidt and S. Loibl

Table 2 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and breast-conserving surgery rates: targeted therapy trials Trial Buzdar et

al.24

NSABP B-4125

CHER-LOB26

NOAH27,28

Neo ALTTO6

TRYPHAENA4

NeoSphere8

TECHNO9 * GeparQuinto5,29 * HER2-positive HER2-negative NSABP B-407

Preoperative therapy

n

ypT0/Tis ypN0 (%)

BCS (%)

Pac × 4 then FEC × 4 Pac × 4 then FEC × 4 + H × 24 weekly

19 23 (164 planned)

26 65

53 57

177 171 171

49⋅4 47⋅4 60⋅2

n.a. n.a. n.a.

36 39 46

25 26 47

67 58 69

99 118 117 154 149 152 73 75 77 107 107 107 96 217

16 19⋅0 38⋅0 24⋅7 29⋅5 51⋅3 56 55 64 21⋅5 39⋅3 11⋅2 18 39⋅0

n.a. 13 23 43 39 41 n.a. n.a. n.a. n.a. n.a. n.a. n.a. 64

309 311 956 969 392 393 390

44⋅6 30⋅2 21⋅7 18⋅3 25⋅8 23⋅2 26⋅9 23⋅0 with Bev 27⋅6 no Bev

64 59 62 62 46 43 50 n.a.

A C × 4 then Pac × 12 + H weekly +L + H weekly + L Pac × 12 then FEC × 4 + H weekly +L + H+L A + Pac × 3 then Pac × 4 then CMF × 3 HER2-negative HER2-positive HER2-positive + H × 11 every 3 weeks 6 weeks L then 12 × Pac + L 6 weeks H then 12 × Pac + H 6 weeks L + H then 12 × P + H + L FEC + H + P × 3 then Doc + H + P × 3 FEC × 3 then Doc + H + P × 3 Doc + Cb + H + P × 6 Doc × 4 + H every 3 weeks Doc × 4 + H + P every 3 weeks H + P every 3 weeks Doc + P every 3 weeks E C × 4 then Pac + H × 4 E C × 4 then Doc × 4 + H E C × 4 then Doc × 4 + L E C × 4 then Doc × 4 + Bev E C × 4 then Doc × 4 Doc × 4 then A C × 4 Doc × 4 + X then A C × 4 Doc × 4 + Gem then AC × 4 Bev × 6 for half of all patients

*Numbers are based on original data used for meta-analysis; data in study publication may be different . ypT or N, pathological tumour or node category after chemotherapy; BCS, breast-conserving surgery; Pac, paclitaxel; FEC, 5-fluorouracil–epirubicin–cyclophosphamide; H, trastuzumab; NSABP, National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; C, cyclophosphamide; n.a., not available; L, lapatinib; CHER-LOB, Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer; NOAH, NeOAdjuvant Herceptin; CMF, cyclophosphamide– methotrexate–5-fluorouracil; HER, human epidermal growth factor receptor; Neo ALTTO, Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization; P, pertuzumab; Doc, docetaxel; Cb, carboplatin; TECHNO, Taxol Epirubicin Cyclophosphamide Herceptin Neoadjuvant; E, epirubicin; Bev, bevacizumab; X, capecitabine; Gem, gemcitabine.

Pertuzumab was the first drug for which an accelerated approval was granted based on the results of a NACT study. In May 2012 the FDA published draft guidance to alter this procedure of approval43 . The objective of this draft was the regulation for use of pCR as an endpoint in study design to predict and confirm clinical benefit, and the establishment of a homogeneous definition of pCR. Thus, the availability of new therapies for patients with high-risk early breast cancer can be accelerated, while the confirmation of approval is still pending. Recently, Sikov and colleagues21 presented preliminary results of the Cancer and Leukemia Group B (CALGB)

40603 trial (NCT00861705) in which neoadjuvant carboplatin with or without bevacizumab was added to conventional taxane and anthracycline-containing NACT. The addition of carboplatin led to a significant increase in pCR (ypT0/is, N0), but the increase observed with addition of bevacizumab did not reach significance.

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Pathological complete response and breast-conserving surgery rates

Despite increasing pCR rates, the rate of BCS has remained stable, irrespective of the tumour subtype (Tables 1–3). Too BJS

Surgical treatment of primary breast cancer in the neoadjuvant setting

Table 3 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and breast-conserving surgery rates: trials investigating taxane regimens Trial NSABP

B-272,30

Aberdeen31

Diéras et al.32 ACCOG33

Preoperative therapy

n

ypT0/Tis ypN0 (%)

BCS (%)

A C×4 A C × 4 then Doc × 4 CVAP × 4 then CVAP × 4 CVAP × 4 then Doc × 4 CVAP × 4 (no clinical response) then Doc × 4 A Pac × 4 A C×4 A C×6 A Doc × 6

1606 805 52 52 55 133 67 180 183

11⋅5 21⋅8 15 bpCR 31 bpCR 2 bpCR 16⋅0 10 16⋅0 12⋅0

62 64 67 48 n.a. 58 45 20 20

ypT or N, pathological tumour or node category after chemotherapy; BCS, breast-conserving surgery; NSABP, National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; C, cyclophosphamide; Doc, docetaxel; CVAP, cyclophosphamide–vincristine–doxorubicin–prednisone; bpCR, breast pathological complete response; n.a., not available; Pac, paclitaxel; ACCOG, Anglo-Celtic Cooperative Oncology Group.

many women still undergo mastectomy, even when a pCR is obtained. This problem is particularly evident among patients with lobular carcinoma, in whom a pCR is less likely, but long-term outcome is superior to that in patients with ductal carcinoma44 . The described high rate of elective mastectomy might be due to the poorer response to NACT. Smaller retrospective studies45,46 have addressed the question of whether rates of negative resection margins achieved by BCS following NACT are comparable to those after upfront BCS. Positive margin rates were not influenced by NACT, and the rate of detection of residual tumour in re-excision specimens was not significantly different. An overall association between lobular subtype and margin involvement was described; yet, the administration of NACT itself before surgery for lobular carcinoma did not have an impact on the probability of residual tumour in resection margins45 . A study47 concerning the influence of resection margin width during BCS in the adjuvant setting on LRR rates has been published recently. Data from 535 triple-negative tumours were analysed retrospectively according to margin width. For patients with triple-negative tumours and an increased risk of LRR, no significant influence of margin width on local recurrence, LRR or distant recurrence was observed. The local recurrence rate was 4⋅7 per cent if resection margins were 2 mm or less compared with 3⋅7 per cent for margins greater than 2 mm after a follow-up of 60 months. All patients received adjuvant whole-breast irradiation (WBI) and 80 per cent were allocated to adjuvant chemotherapy, which might have contributed to local control. No data are available from prospective trials regarding margin width and oncological safety following NACT. A subgroup analysis of the neoadjuvant Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) 1 study48 showed superior DFS after a median follow-up of 69 months for

patients who had BCS compared with those who had mastectomy after NACT. The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 201349 confirmed the minimal acceptable margin as no tumour on the inked area of the specimen and stated that, if BCS is desired, the only absolute contraindications are inability to achieve clear margins after multiple resections and inability to deliver adjuvant breast radiotherapy (RT). Bearing in mind the trend towards increasing pCR rates and the reduction in local therapy, the reasons for the continuing high mastectomy rates after NACT are unclear. Thorough preoperative clinical assessment is needed in the planning of breast surgery. The extension of resection should be adapted to the clinical tumour response, and obstacles that hinder BCS should be identified. For instance, the tumour site should be marked adequately. With rising pCR rates, clip placement at the beginning of NACT is of paramount importance. Patients with locally advanced breast cancer, who are scheduled primarily for mastectomy after NACT, should be spared a mutilating procedure when BCS with the new post-NACT margins seams feasible. In the case of clinical complete remission, the possibility of BCS is jeopardized if no clip is placed. This approach is in accordance with the current guidelines of the German gynaeco-oncological association50 . One problem seems to be the accurate description of lesion size after NACT. The amount of residual non-invasive tumour tissue is comparatively greater in patients with HER2-positive disease than in those with HER-2-negative tumours51 . MRI can be used to assess actual tumour size following NACT. In a meta-analysis52 of preoperative MRI after NACT, only a slight overestimation of tumour size was found, but levels of agreement between measured tumour size and pathological tumour size were still wide. Moreover, preoperative ultrasound assessment performed comparably, but was not compared

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directly with MRI12 . To the authors’ knowledge, there are still no available data showing a positive influence of preoperative use of MRI on BCS rates. The accurate prediction of tumour response, especially the reliable detection of residual tumour, could be used to guide surgery and avoid unnecessary mastectomy and reoperations for positive margins, especially in patients with lobular carcinoma53 . Further studies aiming to determine the best clinical assessment of pathological tumour response to NACT are required. This would allow the improvements in NACT that have resulted in higher pCR rates to be translated into a higher BCS rate and improved cosmetic outcome. Surgical complications following neoadjuvant chemotherapy

An aspect of NACT that has not yet been investigated thoroughly is the effect of preoperative treatment on surgical complications. The influence of new agents such as biologicals and dose-dense therapies on postoperative wound healing, wound infection, haematoma formation and the need for reoperation has still scarcely been studied. In a recent retrospective analysis54 , data were collected from 44 533 patients after breast surgery. A multivariable regression analysis was performed to identify predictors of postoperative wound complications; 2006 patients had received NACT before surgery. Wound complication rates were generally low and comparable in the neoadjuvant treatment and primary surgery groups (3⋅4 versus 3⋅1 per cent). It was concluded that NACT does not influence postoperative wound healing, although there was a trend towards a higher rate of wound complications (4⋅0 per cent) among patients who had mastectomy and immediate reconstruction after NACT. However, these rates may be an underestimate as postoperative complications requiring reoperation were excluded. It is understandable that mastectomies with immediate or delayed reconstruction have higher postoperative complication rates than BCS55 . In smaller series56 – 58 of immediate breast reconstruction following NACT, complication rates after mastectomy and immediate autologous or expander/implant reconstruction with or without preceding NACT were compared, and reported to be similar. Bearing in mind the small sample sizes, NACT did not, however, seem to affect postoperative complication rates. Some reports have raised doubt about whether the use of preoperative bevacizumab is safe59 . Bevacizumab in addition to chemotherapy increases the pCR rate5,7 . The GeparQuinto study60 reported a non-significant increase in overall surgical complications after preoperative addition of bevacizumab (11 versus 15⋅3 per cent; P = 0⋅12), but © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

revealed an increased risk for patients who required two or more operations to achieve clear margins for BCS61 . Bear and colleagues40 documented a significant increase in non-infectious wound healing complications when bevacizumab was administered before and after surgery according to the NSABP B-40 protocol (overall non-infectious wound complication rate 10⋅6 and 4⋅3 per cent with and without bevacizumab). Complication rates doubled in patients who had mastectomy and reconstruction. In both studies surgery was allowed no earlier than 4 weeks after the last administration of bevacizumab. The additional adjuvant administration of ten cycles of bevacizumab in the NSABP B-40 protocol might be a plausible explantion for the reported increase in wound healing problems. Golshan and colleagues62 reported an increased complication rate when performing immediate breast reconstruction using expanders. In a single-arm study, with only 51 patients enrolled, that evaluated neoadjuvant cisplatinum plus bevacizumab, no significant increases in wound healing complications following BCS were observed compared with the results of a previous study in which cisplatinum was given without bevacizumab. Nevertheless, loss of the reconstruction (implant or expander) was reported in four of eight patients. A further study63 reported no difference in overall surgical complication rate among patients treated with neoadjuvant doxorubicin–cyclophosphamide–paclitaxel with or without bevacizumab. Patients in the two cohorts undergoing mastectomy with or without reconstruction (autologous tissue or implant/expander) were compared. Again, the rate of complications was higher when implants/expanders were used for immediate reconstruction following administration of bevacizumab in a cohort of 119 patients. Locoregional recurrence after neoadjuvant chemotherapy

In a meta-analysis64 of nine randomized clinical trials, the clinical outcome of 3861 patients receiving the same systemic therapy either before or after surgery was compared. No significant difference in cancer-related death, disease progression or distant disease recurrence was reported. A significant increase in LRR rate was observed in the neoadjuvant treatment arm (relative risk 1⋅22; P = 0⋅015). Four of the nine studies included in this meta-analysis allowed RT alone, without any breast surgery, when a complete clinical response was achieved. The NACT regimens administered in those studies are not comparable with those of the current standard of care, and clinical response was assessed by palpation and X-ray mammography. Imaging systems have since been refined (breast MRI). In addition, complete www.bjs.co.uk

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Surgical treatment of primary breast cancer in the neoadjuvant setting

response was not proven histologically by biopsy before the decision to omit surgery was taken. Thus an increase in LRR in the neoadjuvant arm is understandable. Long-term follow-up results of the NSABP B-18 and B-27 trials have been published recently30 . These two studies included a total of 3088 patients undergoing NACT or adjuvant chemotherapy. All underwent surgery in the course of treatment. RT was limited to WBI following BCS. Chest wall RT following mastectomy or RT of regional lymph nodes was not allowed in the trial protocols, so an influence of unstandardized RT on locoregional control was avoided. The 10-year cumulative LRR rate after NACT was 12⋅3 per cent for patients who had a mastectomy and 10⋅3 per cent for those treated with BCS and consecutive WBI. Clinical tumour size greater than 5 cm in patients who had a mastectomy and age below 50 years in the BCS group had a significant impact on the risk of LRR by 10 years. Clinically node-positive (cN+) disease before NACT and pathological nodal involvement after NACT were independent predictors of LRR, irrespective of type of surgical therapy. Patients who failed to achieve downstaging of the axilla (cN + to ypN0) and breast pCR were at higher risk of LRR. Unfortunately, data concerning hormone receptor and HER2 status were not available, and it not could not therefore be determined whether certain subgroups may benefit more, or may be at increased risk of LRR after NACT. Moreover, the direct comparison of LRR rates between the two groups in NSABP B-18, which received the same type of chemotherapy (1 group before and 1 after surgery), was not reported. If subgroups at increased risk of LRR could be identified, this knowledge could be included when deciding on surgical treatment. In a recent meta-analysis65 of 12 592 patients with breast cancer treated with initial surgery (BCS or mastectomy) it was stated that the risk of LRR may vary between tumour subtypes. Patients with triple-negative breast cancer or a HER2-positive phenotype have a higher risk of LRR than patients with luminal tumours. Lowery and co-workers65 reported a LRR rate of 7⋅1 per cent for BCS and 9⋅0 per cent for mastectomy at a median follow-up of 57 months for patients with HER2-positive breast cancer, these patients showing the highest risk of LRR. Keeping in mind that these data were collected before the era of trastuzumab and that all NACT was excluded, these rates may not apply to modern NACT regimens. All patients who had BCS underwent adjuvant RT, and 44 per cent of those having a mastectomy received chest wall RT. Adjuvant chemotherapy was administered to 48 per cent of all patients. Young age is also a risk factor for increased risk of local recurrence. However, it seems that this is especially true for

young patients without a pCR. In one study66 , of women who did not achieve a pCR, the LRR rate among those aged 35 years or less was significantly higher than that among women aged 36–50 years (P = 0⋅024). However, there was no age-related difference among women who achieved a pCR. Is it possible that microscopic residual tumour is left behind when BCS is performed within new margins? It could be speculated that such resistant residual tumour could increase the overall risk of LRR. The main target of NACT is shifting from merely downstaging to monitoring tumour response, and tailoring therapy and predicting clinical outcome. At the San Antonio Breast Cancer Symposium 2011, the German Breast Group presented data from a meta-analysis34 of seven prospective neoadjuvant trials with a total of 6377 patients. LRR rates were analysed according to initial tumour stage, intrinsic tumour subtype, type of surgery, pCR rate and nodal status. At a median follow-up of 46⋅2 months, 485 patients had experienced LRR. LRR rates for BCS were significantly lower than those for mastectomy. Not surprisingly, the percentage of women undergoing BCS declined with increasing initial clincial tumour (cT) category (ranging from 77⋅7 per cent for cT1 to 19⋅1 per cent for cT4d), and LRR rate rose with increasing tumour size after NACT (from 4⋅7 per cent for ypT0 to 31⋅2 per cent for ypT4d). The LRR rate was higher among patients with non-invasive residual disease (9⋅9 versus 3⋅7 per cent). Comparing tumour subtypes, despite achieving a pCR, luminal B/HER2-positive tumours had a higher LRR rate (8⋅1 per cent) than all other subtypes. Among patients who did not achieve a pCR, triple-negative and non-luminal-like HER2-positive tumours both displayed an extraordinary LRR rate of about 18 per cent. Weksberg and colleagues67 investigated the prognostic outcome of salvage therapy in patients with local recurrence after NACT and BCS. Data were analysed retrospectively for 1589 patients, of whom 448 had undergone surgery after NACT. Among these, 2⋅6 per cent of patients initially treated with BCS, and 5⋅8 per cent treated with NACT and subsequent BCS, experienced LRR at a median follow-up of 91 months. Higher nuclear grade, higher tumour stage and larger number of involved lymph nodes in the NACT group may account for the difference in LRR rate itself. No significant differences in DFS, OS and locoregional control were detected in the two groups following salvage treatment for isolated LRR. Therefore, resection within new margins after NACT is safe and should be offered to more patients, enabling translation of the increasing pCR rates into higher BCS rates and avoidance of unnecessary mastectomies.

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Treatment of the axilla in the era of neoadjuvant chemotherapy

Before the NSABP B-04 trial, axillary lymph node dissection (ALND) had been a standard procedure in the surgical treatment of breast cancer for many years68 . The current standard for axillary staging is sentinel lymph node biopsy (SLNB). The false-negative rate (FNR) in most studies is below 10 per cent69 . Given these results, clinically node-negative patients can be spared ALND, avoiding postoperative morbidity such as lymphoedema and arm movement impairment. In particular, patients with no metastatic lymph nodes found on ALND can avoid a non-beneficial procedure. Moreover, based on results from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial70 in 2010, ALND can be omitted under certain preconditions (tumour smaller than 5 cm, cN0, M0, planned WBI for BCS) in patients with affected sentinel lymph nodes (SLNs) without altering LRR significantly. In this randomized trial, initial BCS and SLNB was performed. Additional axillary metastases were detected by ALND in 27 per cent of the patients who had a positive SLNB. Adjuvant opposing tangential field WBI and adjuvant systemic therapy was mandatory in that setting. At median follow-up of 6⋅3 years, possible undetected remaining axillary disease in these patients did not translate into a significant difference in local recurrence or OS rate. These conclusions apply to breast cancer in an adjuvant treatment plan, but are they exportable to the neoadjuvant setting? Is SLNB similarly safe when performed after NACT? Is SLNB a reasonable surgical procedure for patients who present with a clinically downstaged axilla? Are SLN detection rates, sensitivity and FNRs reliable after NACT? Is a second SLNB feasible after NACT for patients who already had one before neoadjuvant treatment? This would allow patients whose axillary lymph nodes were cleared of tumour cells to be identified and avoid ALND. Two recent prospective multicentre trials have addressed some of these questions. The ACOSOG Z1071 trial71 enrolled 701 patients with non-metastatic breast cancer of any T category and confirmed axillary involvement. Patients underwent SLNB followed by immediate ALND after completion of NACT. The objective was to assess the FNR of SLNB following NACT. At least one SLN was detected in 92⋅7 per cent, and a FNR of 12⋅6 per cent was reported (39 patients with a negative SLN among 310 with residual axillary disease). This was slightly above the predefined goal of a FNR below 10 per cent, and applied only to patients in whom two or more SLNs were detected. If only one SLN was detected, © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

the FNR increased to 31 per cent (17 patients with a negative SLN among 54 with residual axillary disease). Even though dual-agent mapping (blue dye and radiotracer) was used in most patients, in only 80⋅9 per cent were two or more SLNs detected. If the system requires three or more sentinel nodes to be collected to achieve a FNR of less than 10 per cent, two questions arise. Is a secondary ALND necessary in 43⋅9 per cent of patients, if in only 57⋅1 per cent more than three SLNs are detected and the additional harvesting of some neighbouring lymph nodes is not validated? Is the initial idea of SLNB compromised if five or more SLNs are removed in over 20 per cent of patients? A possible influence could be related to the fact that all patients were eligible for SLNB after NACT, even those with clinical residual disease in the axilla. Low detection rates and a raised FNR might be due to remaining tumour burden in the desired lymph nodes. Therefore, the feasibility of SLNB following NACT remains uncertain based on these results. A second prospective multicentre study that evaluated the reliability of SLNB after NACT is the SENTINA study72 . A total of 2234 patients scheduled to receive NACT were enrolled in the trial and data from 1737 were used in the final analysis. Clinically node-negative patients (palpation and ultrasonography) were staged by SLNB before NACT (arm A + B) and clinically node-positive patients went straight to NACT (arm C + D). Patients who were node-negative, clinically and by SLNB, received no further axillary surgery (arm A). In those with a positive SLNB, a second SLNB and ALND were carried out after NACT (arm B). Re-SLNB (arm B) had the lowest detection rate (SLN detected in only 60⋅8 per cent) and proved to be false-negative in over 50 per cent. Patients who converted to clinically node-negative disease after NACT received SLNB plus immediate ALND (arm C), whereas those with persistent clinical axillary disease received ALND (arm D). The SLN detection rate was 80⋅1 per cent in arm C with an overall FNR of 14⋅2 per cent (24⋅3 per cent if 1 SLN removed, 18⋅5 per cent if 2 SLNs removed and less than 10 per cent if more than 2 SLNs removed). Interestingly, the FNR was only 8⋅6 per cent if combined mapping (blue dye and radiotracer) was used, although this was not significant compared with the rate when radiotracer alone was used. According to Kuehn and colleagues72 , a re-SLNB biopsy should not be done after NACT (arm B), because the detection rate and FNR are unfavourable after the initial lymphatic drainage of the tumour bed has been discontinued at primary surgery. In arm C, the lymph node detection rate after NACT was significantly lower than that in arm A + B (80⋅1 versus 99 per cent), possibly owing to the tissue reaction to NACT. Unfortunately, an additional arm www.bjs.co.uk

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Surgical treatment of primary breast cancer in the neoadjuvant setting

investigating SLNB in patients with cN0 disease only after NACT was not included in this study design. Therefore, a direct comparison between detection rates of SLNB in the cN0 situation before and after NACT cannot be made, and the best timing of SLNB in clinical practice remains unclear. What conclusions can be drawn based on the results of these two studies? Under certain preconditions (use of dual mapping) a SLN can be detected in about 90 per cent of patients having SLNB after NACT. An overall FNR above 10 per cent is to be expected, and a much higher FNR when only one SLN is harvested. However, whether these patients with undetected residual axillary disease are at increased risk of recurrence remains unclear. In the adjuvant setting, the results of the ACOSOG Z0011 trial suggest that possible undetected remaining axillary disease in 27 per cent of patients does not lead to a significant increase in local recurrence rate after 6⋅3 years of follow-up. This rate of undetected residual axillary tumour roughly equals the FNR if one SLN was resected in the SENTINA and ACOSOG Z1071 trials. Can residual tumour be left behind after NACT without altering the prognosis? In contrast to the patients who had SLNB after NACT, 58 per cent of patients in the ACOSOG Z0011 study received adjuvant chemotherapy and all were scheduled for adjuvant WBI. In the event of BCS, subgroups undergoing SLN alone and those having SLNB followed by ALND would both have WBI, which would presumably further reduce the tumour burden in the axilla. Patients undergoing mastectomy with a good tumour response but a false-negative SLNB after NACT might be at increased risk, because they would receive neither further chemotherapy nor adjuvant RT. Long-term data from these studies are needed to determine how many of the patients with a false-negative SLNB would develop LRR as first tumour recurrence and how this would affect OS. New studies addressing these issues are upcoming, such as the German Intergroup Sentinel Mamma (INSEMA) trial. So far it is unclear whether patients who convert from any node-positive disease before chemotherapy to ypN0 during NACT require further RT of the lymphatic basins. The ACOSOG Z1071 trial71 has reported that such a switch from cN + to ypN0 can be obtained in 41 per cent. Currently the NSABP B-51 trial (NCT01872975) is recruiting patients with T1–3, biopsy-proven node-positive breast cancer undergoing NACT, who have negative axillary nodes at the time of surgery (ypN0 verified by ALND or SLNB) (http://www.nsabp.pitt.edu/B-51.asp). Patients undergoing BCS are being randomized to WBI with or without regional nodal RT. Those receiving mastectomy

are being randomized to chest wall RT plus regional nodal RT or no RT at all. The protocol allows SLNB without ALND after NACT. In this study protocol, for patients with histologically proven axillary involvement before NACT, a broad spectrum of further multimodal therapy is envisaged.

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Conclusion

An increasing number of patients are being treated in the neoadjuvant setting. Knowledge on early response-guided therapy and the prognostic impact of pCR on survival has increased in recent years. With NACT regimens becoming more and more effective, the need for surgical therapies is beginning to be questioned. For example, the question of whether irradiation alone, without any surgical resection of the primary tumour, is an option following a pCR has been raised73 . No breast surgery at all for patients achieving a pCR is provocative, but might become an option in the future. Still, the crucial question remains: by what means can these patients be identified reliably among those with minimal residual tumour? Previous studies74,75 that have analysed this option retrospectively used palpation to assess for complete clinical response. The findings concerning DFS and OS after RT alone are interesting. Owing to small sample sizes, the prognostic impact did not reach statistical significance, and a substantial number of patients had to undergo salvage mastectomy. Before prospective trials investigating this matter can be undertaken, a reliable method for predicting pCR has to be evaluated. Promising additional post-neoadjuvant therapies for patients who fail to achieve a pCR are currently being investigated. For example, the KATHERINE study (NCT01772472) is recruiting patients with HER2-positive residual tumour after NACT who will be randomized to treatment with adjuvant standard trastuzumab versus adjuvant trastuzumab emtansine (http://clinicaltrials.gov/ct2/show/record/NCT0177 2472)76 . Based on available data, surgery within new margins seems to be safe, although not tested in a prospective randomized clinical trial, and should result in a higher BCS rate. However, many questions still remain and need to be addressed in future clinical trials.

Acknowledgements

The authors thank B. Lederer, German Breast Group headquarters, for editorial support. Disclosure: The authors declare no conflict of interest. BJS

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