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Invited review

Surgical treatment of primary breast cancer in the

neoadjuvant setting

S. Kmmel1, J. Holtschmidt1 and S. Loibl2,3

1Kliniken Essen Mitte, Klinik fr 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 6570 per cent, although

more than 80 per cent of patients respond to NACT. The risk of local relapse doesnot 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 concentricallyand 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 benet from NACT, especially those with human epidermal growth fac-

tor receptor 2-positive and triple-negative breast cancer, but surgical/local procedures need to be adapted.

Cutting edge articles are invited by theBJSEditorial Team, and focus on how current research andinnovation will affect future clinical practice.

Paper accepted 2 April 2014

Published online 19 May 2014 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 withearly 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 dis-

ease 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 signicantly higher

rate of breast-conserving surgery (BCS) and downstagingof axillary involvement can be achieved without jeopar-dizing disease-free (DFS) and overall (OS) survival at a

follow-up of 15 years. These results date from a time whenthe concomitant use of taxanes and biologicals had not

yet been implemented. Nowadays, pCR rates of 2025per cent can be achieved by NACT alone. A combina-tion of NACT with targeted agents, such as trastuzumab,two agents targeted against human epidermal growth fac-

tor receptor (HER) 2 or bevacizumab, has led to pCR ratesof up to 4080 per cent, especially in HER2-positive andtriple-negative breast cancer4 10.

Although NACT regimens have been rened, leadingto high pCR rates, the rate of BCS has remained stable(Tables 13)1133. Follow-up results from earlier studies

imply that the use of BCS after NACT is safe in termsof local control as rates of locoregional recurrence (LRR)are low following NACT and surgery30,34. Surgery in new

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Surgical treatment of primary breast cancer in the neoadjuvant setting 913

Specim

en

Specim

en

Specim

en

Specim

en

Adjuvant

therapy

Adjuvant

therapy

Possibility to monitortreatment effect

YesNo Yes Partly

Breast cancer

diagnosis

Surgery

Neoadjuvant treatment

Breast cancer

diagnosis

Continue

same regimen

Change

regimen

Clinical response

Pathological

response

No clinical response

Tumour typing

and staging

Surgery

SurgerySurgery

Pathological

response

Pathological

response

Neoadjuvant treatmentAdjuvant treatment

Fig. 1Use of chemotherapy in breast cancer treatment. Boxes indicate points at which tumour samples can be collected to monitoreffects

margins adjusted for the tumour response after NACThence 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? Isa further reduction in surgical radicality for disease within

the breast safe, analogous to the trend towards conservativeaxillary surgery? What is the prognostic impact of such achange in the trend of breast cancer treatment?

Pathological complete response: a good

prognostic factor

Historically, breast cancer was understood to be a localizeddisease that requires radical surgery to achieve a cure.

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 toimprove 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 supe-

rior DFS and OS, especially in the hormone receptor-

negative subgroups (either HER2-positive or -negative)

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914 S. Kmmel, J. Holtschmidt and S. Loibl

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 preoperativeversuspostoperative administration

Trial Preoperative therapy n ypT0/Tis ypN0 (%) BCS (%)

GeparDo11* dd A Doc4 126 95 69

dd A Doc4+Tam 122 57 69

GeparDuo12* dd A Doc+Tam 453 102 66

A C 4 then Doc+Tam 454 192 75

GeparTrio pilot13* TAC6 252 190 n.a.

TAC2 then 4N X 33 6 n.a.

GeparTrio14,15* TAC6 1085 187 68

TAC8 686 290 69 responders

57 non-responders

TAC2 then N X 4 301 69 60

GeparQuattro10,16*

HER2-negative E C4 then Doc4 343 187 68*

E C 4 then Doc+X4 345 165 67

E C 4 then Doc4 then X4 362 191 64

HER2-positive CHT+H for HER2-positive 445 413

AGO-117* E Pac4 335 66 58

dd E3 then dd Pac4 333 132

PREPARE18* E C 4 then Pac4 370 146 67

dd E3 then dd Pac3 then CMF3 363 204 65

SWOG 001219 A C 5 every 3 weeks then Pac12 179 207 n.a.

A15 weekly+C daily then Pac12 177 243

MDACC20 FAC4 100 90 n.a

dd FAC4 99 13

CALGB 4060321 Pac12 then dd A C4 108 390 n.a.

+Bev 9 every 2 weeks 110 430

+Cb 6 every 3 weeks 113 490

+Cb +Bev 112 600

Older trials comparing preop.

and postop. administration

NSABP B-183 A C 4 747 67

Primary surgery 759 60

ABCSG-0722 CMF3 203 59 bpCR 66

Primary surgery 195 60EORTC 1090223 FEC4 350 40 35

Primary surgery 348 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 categoryafter chemotherapy; BCS, breast-conserving surgery; dd, dose dense; A, doxorubicin; Doc, docetaxel; Tam, tamoxifen; C, cyclophosphamide; TAC,docetaxeldoxorubicincyclophosphamide; n.a., not available; N, vinorelbine; X, capecitabine; E, epirubicin; HER, human epidermal growth factorreceptor; CHT, chemotherapy; H, trastuzumab; AGO, Arbeitsgemeinschaft fr Gynkologische Onkologie; Pac, paclitaxel; PREPARE, PreoperativeEpirubicin Paclitaxel Aranesp Study; CMF, cyclophosphamidemethotrexate5-uorouracil; SWOG, Southwest Oncology Group; MDACC, MD

Anderson Cancer Center; FAC, 5-uorouracil 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, breastpathological complete response; EORTC, European Organization for Research and Treatment of Cancer; FEC, 5-uorouracilepirubicincyclophosphamide.

as the correlation with survival is best in these groups. Ithas therefore been used as the primary endpoint for manytrials of neoadjuvant therapy37 41.

The introduction of targeted therapies such astrastuzumab has had further impact on pCR rates andoutcome27. For patients with HER2-overexpressingtumours a further improvement in the efcacy of NACTis conceivable based on the results of the NeoSphere8

and TRYPHAENA4,5 trials. A signicant increase inpCR, dened as the absence of invasive neoplastic cells inthe breast (pathological status after neoadjuvant therapy

(yp) T0/Tis), was observed in the NeoSphere trial8 by

addition of neoadjuvant pertuzumab to trastuzumab anddocetaxel. 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 Adminis-

tration (FDA) approval of pertuzumab for the neoadjuvant

treatment of breast cancer42. In the past, new chemothera-

peutic 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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breast-conserving surgery rates: targeted therapy trials


Buzdaret al.24 Pac4 then FEC4 19 26 53

Pac4 then FEC4+H24 weekly 23 65 57

(164 planned)NSABP B-4125 A C 4 then Pac12

+H weekly 177 494 n.a.

+L 171 474 n.a.

+H weekly+L 171 602 n.a.

CHER-LOB26 Pac12 then FEC4

+H weekly 36 25 67

+L 39 26 58

+H+L 46 47 69

NOAH27,28 A+Pac3 then Pac4 then CMF3

HER2-negative 99 16 n.a.

HER2-positive 118 190 13

HER2-positive+H11 every 3 weeks 117 380 23

Neo ALTTO6 6 weeks L then 12Pac+L 154 247 43

6 weeks H then 12Pac+H 149 295 39

6 weeks L+H then 12P+H+L 152 513 41

TRYPHAENA4 FEC+H+P3 then Doc+H+P3 73 56 n.a.

FEC3 then Doc+H+P3 75 55 n.a.

Doc+Cb+H+P6 77 64 n.a.

NeoSphere8 Doc4+H every 3 weeks 107 215 n.a.

Doc4+H+P every 3 weeks 107 393 n.a.

H+P every 3 weeks 107 112 n.a.

Doc+P every 3 weeks 96 18 n.a.

TECHNO9* E C 4 then Pac+H4 217 390 64

GeparQuinto5,29*

HER2-positive E C4 then Doc4+H 309 446 64

E C 4 then Doc 4+L 311 302 59

HER2-negative E C4 then Doc 4+Bev 956 217 62

E C 4 then Doc 4 969 183 62

NSABP B-407 Doc4 then A C4 392 258 46

Doc4+X then A C 4 393 232 43

Doc4+Gem then AC4 390 269 50

Bev6 for half of all patients 230 with Bev n.a.

276 no Bev

*Numbers are based on original data used for meta-analysis; data in study publication may be different . ypT or N, pathological tumour or node categoryafter chemotherapy; BCS, breast-conserving surgery; Pac, paclitaxel; FEC, 5-uorouracilepirubicincyclophosphamide; 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, cyclophosphamidemethotrexate 5-uorouracil; HER, human epidermal growth factor receptor; Neo ALTTO, Neoadjuvant Lapatinib and/or Trastuzumab TreatmentOptimization; P, pertuzumab; Doc, docetaxel; Cb, carboplatin; TECHNO, Taxol Epirubicin Cyclophosphamide Herceptin Neoadjuvant; E, epirubicin;Bev, bevacizumab; X, capecitabine; Gem, gemcitabine.

Pertuzumab was the rst 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 theregulation for use of pCR as an endpoint in study design to

predict and conrm clinical benet, and the establishment

of a homogeneous denition of pCR. Thus, the avail-

ability of new therapies for patients with high-risk early

breast cancer can be accelerated, while the conrmation 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 carbo-platin with or without bevacizumab was added to conven-tional taxane and anthracycline-containing NACT. The

addition of carboplatin led to a signicant increase in pCR(ypT0/is, N0), but the increase observed with addition ofbevacizumab did not reach signicance.

Pathological complete response

and breast-conserving surgery rates

Despite increasing pCR rates, the rate of BCS has remainedstable, irrespective of the tumour subtype (Tables 13). Too


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breast-conserving surgery rates: trials investigating taxane regimens


NSABP B-272,30 A C 4 1606 115 62

A C 4 then Doc4 805 218 64

Aberdeen31 CVAP4 then CVAP4 52 15 bpCR 67

CVAP4 then Doc 4 52 31 bpCR 48

CVAP4 (no clinical response) then Doc 4 55 2 bpCR n.a.

Diras et al.32 A Pac 4 133 160 58

A C 4 67 10 45

ACCOG33 A C 6 180 160 20

A Do c6 183 120 20

ypT or N, pathological tumour or node category after chemotherapy; BCS, breast-conserving surgery; NSABP, National Surgical Adjuvant Breast andBowel Project; A, doxorubicin; C, cyclophosphamide; Doc, docetaxel; CVAP, cyclophosphamidevincristinedoxorubicinprednisone; bpCR, breastpathological 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 lesslikely, but long-term outcome is superior to that in patients

with ductal carcinoma44. The described high rate of elec-

tive mastectomy might be due to the poorer response to

NACT. Smaller retrospective studies45,46 have addressed

the question of whether rates of negative resection mar-

gins achieved by BCS following NACT are comparable to

those after upfront BCS. Positive margin rates were not

inuenced by NACT, and the rate of detection of residual

tumour in re-excision specimens was not signicantly dif-

ferent. An overall association between lobular subtype and

margin involvement was described; yet, the administration

of NACT itself before surgery for lobular carcinoma didnot have an impact on the probability of residual tumour

in resection margins45.

A study47 concerning the inuence 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 mar-

gin width. For patients with triple-negative tumours and

an increased risk of LRR, no signicant inuence of mar-

gin width on local recurrence, LRR or distant recurrence

was observed. The local recurrence rate was 47 per cent if

resection margins were 2 mm or less compared with 37 per

cent for margins greater than 2 mm after a follow-up of 60months. All patients received adjuvant whole-breast irra-

diation (WBI) and 80 per cent were allocated to adjuvant

chemotherapy, which might have contributed to local con-

trol. No data are available from prospective trials regarding

margin width and oncological safety following NACT. A

subgroup analysis of the neoadjuvant Arbeitsgemeinschaft

fr Gynkologische 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 mas-tectomy after NACT. The St Gallen International Expert

Consensus on the Primary Therapy of Early Breast Can-cer 201349 conrmed the minimal acceptable margin as notumour on the inked area of the specimen and stated that,if BCS is desired, the only absolute contraindications areinability to achieve clear margins after multiple resectionsand inability to deliver adjuvant breast radiotherapy (RT).Bearing in mind the trend towards increasing pCR ratesand the reduction in local therapy, the reasons for the con-tinuing high mastectomy rates after NACT are unclear.

Thorough preoperative clinical assessment is needed inthe planning of breast surgery. The extension of resec-tion should be adapted to the clinical tumour response, and

obstacles that hinder BCS should be identied.For instance, the tumour site should be marked ade-quately. With rising pCR rates, clip placement at the begin-ning of NACT is of paramount importance. Patients withlocally advanced breast cancer, who are scheduled primarilyfor mastectomy after NACT, should be spared a mutilatingprocedure when BCS with the new post-NACT marginsseams 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 guidelinesof the German gynaeco-oncological association50.

One problem seems to be the accurate descriptionof lesion size after NACT. The amount of residualnon-invasive tumour tissue is comparatively greater inpatients with HER2-positive disease than in those withHER-2-negative tumours51. MRI can be used to assessactual tumour size following NACT. In a meta-analysis52

of preoperative MRI after NACT, only a slight overesti-mation of tumour size was found, but levels of agreementbetween measured tumour size and pathological tumoursize were still wide. Moreover, preoperative ultrasoundassessment performed comparably, but was not compared


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directly with MRI12. To the authors knowledge, there arestill no available data showing a positive inuence of preop-erative use of MRI on BCS rates. The accurate predictionof tumour response, especially the reliable detection ofresidual tumour, could be used to guide surgery and avoid

unnecessary mastectomy and reoperations for positivemargins, especially in patients with lobular carcinoma53.

Further studies aiming to determine the best clinicalassessment of pathological tumour response to NACT arerequired. This would allow the improvements in NACTthat have resulted in higher pCR rates to be translated intoa 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 sur-gical complications. The inuence of new agents suchas biologicals and dose-dense therapies on postoperative

wound healing, wound infection, haematoma formationand the need for reoperation has still scarcely been stud-ied. In a recent retrospective analysis54, data were collectedfrom 44 533 patients after breast surgery. A multivariableregression analysis was performed to identify predictorsof postoperative wound complications; 2006 patients hadreceived NACT before surgery. Wound complication rates

were generally low and comparable in the neoadjuvanttreatment and primary surgery groups (34 versus31 per

cent). It was concluded that NACT does not inuencepostoperative wound healing, although there was a trendtowards a higher rate of wound complications (40 percent) among patients who had mastectomy and immedi-ate reconstruction after NACT. However, these rates maybe an underestimate as postoperative complications requir-ing reoperation were excluded. It is understandable thatmastectomies with immediate or delayed reconstructionhave higher postoperative complication rates than BCS55.In smaller series56 58 of immediate breast reconstructionfollowing NACT, complication rates after mastectomy andimmediate autologous or expander/implant reconstruction

with or without preceding NACT were compared, andreported to be similar. Bearing in mind the small samplesizes, NACT did not, however, seem to affect postoperativecomplication rates.

Some reports have raised doubt about whether the useof preoperative bevacizumab is safe59. Bevacizumab inaddition to chemotherapy increases the pCR rate5,7. TheGeparQuinto study60 reported a non-signicant increasein overall surgical complications after preoperative addi-tion of bevacizumab (11versus153 per cent;P= 012), but

revealed an increased risk for patients who required twoor more operations to achieve clear margins for BCS61.Bear and colleagues40 documented a signicant increase innon-infectious wound healing complications when beva-cizumab was administered before and after surgery accord-

ing to the NSABP B-40 protocol (overall non-infectiouswound complication rate 106 and 43 per cent withand without bevacizumab). Complication rates doubled inpatients who had mastectomy and reconstruction. In bothstudies surgery was allowed no earlier than 4 weeks after thelast administration of bevacizumab. The additional adju-

vant administration of ten cycles of bevacizumab in theNSABP B-40 protocol might be a plausible explantion forthe reported increase in wound healing problems.

Golshan and colleagues62 reported an increasedcomplication rate when performing immediate breastreconstruction using expanders. In a single-arm study,

with only 51 patients enrolled, that evaluated neoadjuvantcisplatinum plus bevacizumab, no signicant increasesin wound healing complications following BCS wereobserved compared with the results of a previous studyin which cisplatinum was given without bevacizumab.Nevertheless, loss of the reconstruction (implant orexpander) was reported in four of eight patients. A furtherstudy63 reported no difference in overall surgical com-plication rate among patients treated with neoadjuvantdoxorubicincyclophosphamidepaclitaxel with or with-out bevacizumab. Patients in the two cohorts undergoingmastectomy with or without reconstruction (autologoustissue or implant/expander) were compared. Again, therate of complications was higher when implants/expanders

were used for immediate reconstruction following admin-istration of bevacizumab in a cohort of 119 patients.

Locoregional recurrence after neoadjuvant

chemotherapy

In a meta-analysis64 of nine randomized clinical trials, theclinical outcome of 3861 patients receiving the same sys-temic therapy either before or after surgery was compared.No signicant difference in cancer-related death, diseaseprogression or distant disease recurrence was reported. Asignicant increase in LRR rate was observed in the neoad-

juvant treatment arm (relative risk 122;P= 0015). Four ofthe nine studies included in this meta-analysis allowed RTalone, without any breast surgery, when a complete clinicalresponse was achieved. The NACT regimens administeredin those studies are not comparable with those of the cur-rent standard of care, and clinical response was assessedby palpation and X-ray mammography. Imaging systemshave since been rened (breast MRI). In addition, complete


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response was not proven histologically by biopsy before the

decision to omit surgery was taken. Thus an increase inLRR in the neoadjuvant arm is understandable.

Long-term follow-up results of the NSABP B-18 andB-27 trials have been published recently30. These two stud-

ies included a total of 3088 patients undergoing NACTor adjuvant chemotherapy. All underwent surgery in thecourse of treatment. RT was limited to WBI following

BCS. Chest wall RT following mastectomy or RT ofregional lymph nodes was not allowed in the trial protocols,so an inuence of unstandardized RT on locoregional con-trol was avoided. The 10-year cumulative LRR rate afterNACT was 123 per cent for patients who had a mastec-tomy and 103 per cent for those treated with BCS andconsecutive WBI. Clinical tumour size greater than 5 cm in

patients who had a mastectomy and age below 50 years inthe BCS group had a signicant impact on the risk of LRR

by 10 years. Clinically node-positive (cN+) disease beforeNACT and pathological nodal involvement after NACT

were independent predictors of LRR, irrespective of typeof surgical therapy. Patients who failed to achieve down-

staging of the axilla (cN+ to ypN0) and breast pCR wereat higher risk of LRR. Unfortunately, data concerning hor-mone receptor and HER2 status were not available, andit not could not therefore be determined whether certainsubgroups may benet more, or may be at increased riskof LRR after NACT. Moreover, the direct comparison ofLRR 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 identi-ed, this knowledge could be included when deciding onsurgical treatment. In a recent meta-analysis65 of 12592patients with breast cancer treated with initial surgery (BCSor mastectomy) it was stated that the risk of LRR may vary

between tumour subtypes. Patients with triple-negativebreast cancer or a HER2-positive phenotype have a higherrisk of LRR than patients with luminal tumours. Loweryand co-workers65 reported a LRR rate of 71 per cent forBCSand90 per cent for mastectomy at a median follow-upof 57 months for patients with HER2-positive breast can-

cer, these patients showing the highest risk of LRR. Keep-ing in mind that these data were collected before the era oftrastuzumab and that all NACT was excluded, these ratesmay not apply to modern NACT regimens. All patients

who had BCS underwent adjuvant RT, and 44 per cent ofthose having a mastectomy received chest wall RT. Adju-

vant 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 womenwho did not achieve a pCR, the LRR rate among thoseaged 35 years or less was signicantly higher than thatamong women aged 3650 years (P= 0024). 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? Itcould be speculated that such resistant residual tumourcould increase the overall risk of LRR. The main target ofNACT is shifting from merely downstaging to monitoringtumour response, and tailoring therapy and predictingclinical outcome. At the San Antonio Breast Cancer Sym-posium 2011, the German Breast Group presented datafrom a meta-analysis34 of seven prospective neoadjuvanttrials with a total of 6377 patients. LRR rates were anal-

ysed according to initial tumour stage, intrinsic tumour

subtype, type of surgery, pCR rate and nodal status. Ata median follow-up of 462 months, 485 patients had

experienced LRR. LRR rates for BCS were signicantlylower than those for mastectomy. Not surprisingly, thepercentage of women undergoing BCS declined withincreasing initial clincial tumour (cT) category (rangingfrom 777 per cent for cT1 to 191 per cent for cT4d),and LRR rate rose with increasing tumour size afterNACT (from 47 per cent for ypT0 to 312 per centfor ypT4d). The LRR rate was higher among patients

with non-invasive residual disease (99 versus 37 percent). Comparing tumour subtypes, despite achieving a

pCR, luminal B/HER2-positive tumours had a higherLRR rate (81 per cent) than all other subtypes. Amongpatients who did not achieve a pCR, triple-negativeand non-luminal-like HER2-positive tumours bothdisplayed an extraordinary LRR rate of about 18 per cent.

Weksberg and colleagues67 investigated the prognosticoutcome of salvage therapy in patients with local recur-rence after NACT and BCS. Data were analysed retro-spectively for 1589 patients, of whom 448 had undergonesurgery after NACT. Among these, 26 per cent of patientsinitially treated with BCS, and 58 per cent treated withNACT and subsequent BCS, experienced LRR at a medianfollow-up of 91 months. Higher nuclear grade, higher

tumour stage and larger number of involved lymph nodesin the NACT group may account for the difference inLRR rate itself. No signicant differences in DFS, OS andlocoregional control were detected in the two groups fol-lowing salvage treatment for isolated LRR.

Therefore, resection within new margins after NACTis safe and should be offered to more patients, enablingtranslation of the increasing pCR rates into higher BCSrates 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-benecial 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 withaffected sentinel lymph nodes (SLNs) without alteringLRR signicantly. 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

eld WBI and adjuvant systemic therapy was mandatory

in that setting. At median follow-up of 63 years, possible

undetected remaining axillary disease in these patients

did not translate into a signicant difference in local

recurrence or OS rate.

These conclusions apply to breast cancer in an adju-

vant treatment plan, but are they exportable to the neoad-

juvant 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 treat-

ment? This would allow patients whose axillary lymph

nodes were cleared of tumour cells to be identied and

avoid ALND. Two recent prospective multicentre trialshave addressed some of these questions.

The ACOSOG Z1071 trial71 enrolled 701 patients with

non-metastatic breast cancer of any T category and con-

rmed axillary involvement. Patients underwent SLNBfollowed 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 927 per cent,

and a FNR of 126 per cent was reported (39 patients with

a negative SLN among 310 with residual axillary disease).

This was slightly above the predened 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,

the FNR increased to 31 per cent (17 patients with a neg-

ative SLN among 54 with residual axillary disease). Eventhough dual-agent mapping (blue dye and radiotracer) wasused in most patients, in only 809 per cent were two ormore SLNs detected. If the system requires three or more

sentinel nodes to be collected to achieve a FNR of less than10 per cent, two questions arise. Is a secondary ALNDnecessary in 439 per cent of patients, if in only 571 per

cent more than three SLNs are detected and the additionalharvesting of some neighbouring lymph nodes is not vali-dated? Is the initial idea of SLNB compromised if ve ormore SLNs are removed in over 20 per cent of patients?

A possible inuence could be related to the fact that allpatients 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 tumourburden in the desired lymph nodes. Therefore, the feasi-

bility of SLNB following NACT remains uncertain basedon these results.

A second prospective multicentre study that evaluated thereliability of SLNB after NACT is the SENTINA study72.

A total of 2234 patients scheduled to receive NACT wereenrolled in the trial and data from 1737 were used inthe nal analysis. Clinically node-negative patients (palpa-tion and ultrasonography) were staged by SLNB beforeNACT (arm A+B) and clinically node-positive patients

went straight to NACT (arm C+D). Patients who werenode-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 608 per cent) and proved to befalse-negative in over 50 per cent. Patients who convertedto clinically node-negative disease after NACT receivedSLNB plus immediate ALND (arm C), whereas those with

persistent clinical axillary disease received ALND (arm D).The SLN detection rate was 801 per cent in arm C withan overall FNR of 142 per cent (243 per cent if 1 SLNremoved, 185 per cent if 2 SLNs removed and less than 10per cent if more than 2 SLNs removed). Interestingly, theFNR was only 86 per cent if combined mapping (blue dye

and radiotracer) was used, although this was not signicantcompared with the rate when radiotracer alone was used.

According to Kuehn and colleagues72, a re-SLNB biopsyshould not be done after NACT (arm B), because the detec-tion rate and FNR are unfavourable after the initial lym-phatic drainage of the tumour bed has been discontinuedat primary surgery. In arm C, the lymph node detection

rate after NACT was signicantly lower than that in armA+B (801 versus99 per cent), possibly owing to the tis-sue reaction to NACT. Unfortunately, an additional arm


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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 inthe 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 centof patients having SLNB after NACT. An overall FNRabove 10 per cent is to be expected, and a much higherFNR when only one SLN is harvested. However, whetherthese patients with undetected residual axillary disease areat increased risk of recurrence remains unclear. In the adju-

vant setting, the results of the ACOSOG Z0011 trial sug-

gest that possible undetected remaining axillary disease in27 per cent of patients does not lead to a signicant increase

in local recurrence rate after 63 years of follow-up. This

rate of undetected residual axillary tumour roughly equalsthe 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 contrastto the patients who had SLNB after NACT, 58 per centof patients in the ACOSOG Z0011 study received adju-

vant chemotherapy and all were scheduled for adjuvantWBI. In the event of BCS, subgroups undergoing SLNalone and those having SLNB followed by ALND wouldboth have WBI, which would presumably further reduce

the tumour burden in the axilla. Patients undergoing mas-

tectomy with a good tumour response but a false-negativeSLNB after NACT might be at increased risk, becausethey would receive neither further chemotherapy noradjuvant RT.

Long-term data from these studies are needed to deter-mine how many of the patients with a false-negative SLNB

would develop LRR as rst tumour recurrence and howthis would affect OS. New studies addressing these issuesare 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. TheACOSOG Z1071 trial71 has reported that such a switchfrom cN+ to ypN0 can be obtained in 41 per cent. Cur-rently the NSABP B-51 trial (NCT01872975) is recruitingpatients with T13, biopsy-proven node-positive breastcancer undergoing NACT, who have negative axillarynodes at the time of surgery (ypN0 veried by ALND

or SLNB) (http://www.nsabp.pitt.edu/B-51.asp). Patientsundergoing 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 SLNBwithout ALND after NACT. In this study protocol, forpatients with histologically proven axillary involvementbefore NACT, a broad spectrum of further multimodal

therapy is envisaged.

Conclusion

An increasing number of patients are being treated in theneoadjuvant setting. Knowledge on early response-guidedtherapy and the prognostic impact of pCR on survivalhas increased in recent years. With NACT regimensbecoming more and more effective, the need for surgicaltherapies is beginning to be questioned. For example, the

question of whether irradiation alone, without any surgicalresection of the primary tumour, is an option following apCR has been raised73. No breast surgery at all for patientsachieving a pCR is provocative, but might become anoption in the future. Still, the crucial question remains:by what means can these patients be identied reliably

among those with minimal residual tumour? Previousstudies74,75 that have analysed this option retrospectivelyused palpation to assess for complete clinical response.

The ndings concerning DFS and OS after RT aloneare interesting. Owing to small sample sizes, the prog-nostic impact did not reach statistical signicance, and

a substantial number of patients had to undergo salvagemastectomy. Before prospective trials investigating this

matter can be undertaken, a reliable method for pre-dicting pCR has to be evaluated. Promising additionalpost-neoadjuvant therapies for patients who fail to achievea pCR are currently being investigated. For example,the KATHERINE study (NCT01772472) is recruiting

patients with HER2-positive residual tumour after NACTwho will be randomized to treatment with adjuvantstandard trastuzumab versusadjuvant trastuzumab emtan-sine (http://clinicaltrials.gov/ct2/show/record/NCT01772472)76. Based on available data, surgery within newmargins seems to be safe, although not tested in a

prospective randomized clinical trial, and should result

in a higher BCS rate. However, many questions stillremain and need to be addressed in future clinicaltrials.

Acknowledgements

The authors thank B. Lederer, German Breast Groupheadquarters, for editorial support.Disclosure:The authors declare no conict of interest.


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www.abstracts2view.com/sabcs13/view.php?nu=SABCS13L

_627&terms [accessed 24 January 2014].

BJSSpecial Issue on Surgical Innovations: Call for Papers

This special issue of BJSfor 2015 will focus on surgical innovation in its broadest meaning. It will

include a number of invited reviews on topics ranging from cutting edge gene and nanotechnology,

all the way to new surgical techniques. Authors are encouraged to submit articles on this theme and

the closing date for submissions is 30 thJune 2014. The issue will be digital-only and we invite

simultaneous submission of videos and other digital material to maximize the use of this media. BJS

referee standards and process will remain, and all successful authors will be required to produce a

podcast to enhance their publication.

Please refer to Instructions to Authors on the BJSwebsite (www.bjs.co.uk). Your article should be

submitted via our online system ScholarOne Manuscripts (http://mc.manuscriptcentral.com/bjs).


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