Stage-to-stage Comparison of Neoadjuvant Chemotherapy Versus Adjuvant Chemotherapy in Pathological Lymph Node Positive Breast Cancer Patients

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1 Original Articles Jpn J Clin Oncol 2012;42(11) doi: /jjco/hys130 Advance Access Publication 21 August 2012 Stage-to-stage Comparison of Neoadjuvant Chemotherapy Versus Adjuvant Chemotherapy in Pathological Lymph Node Positive Breast Cancer Patients Nam Kwon Lee 1, Kyung Hwan Shin 1,2,*, In Hae Park 2, Keun Seok Lee 2, Jungsil Ro 2, So-Youn Jung 2, Seeyoun Lee 2, Seok Won Kim 2, Tae Hyun Kim 1, Joo-Young Kim 1, Han-Sung Kang 2 and Kwan Ho Cho 1 1 Proton Therapy Center, Research Institute and Hospital, National Cancer Center and 2 Center for Breast Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea *For reprints and all correspondence: Kyung Hwan Shin, Proton Therapy Center and Center for Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do , Republic of Korea. radiat@ncc.re.kr Received June 18, 2012; accepted July 24, 2012 Objective: The purpose of this study was to investigate the prognostic implications of postneoadjuvant chemotherapy on the survival outcomes of breast cancer patients with persistent positive axillary lymph nodes by performing a stage-to-stage comparison between neoadjuvant chemotherapy and initial surgery. Methods: Retrospective analysis was performed on 813 breast cancer patients with positive axillary lymph node after surgery, who were treated between 2001 and Of these, 269 patients received neoadjuvant chemotherapy, and 544 patients were treated with surgery followed by adjuvant chemotherapy. The median follow-up time was 5.9 years. Results: The 5-year disease-free survival rates for patients in the neoadjuvant chemotherapy and adjuvant chemotherapy groups were 73 and 88%, respectively (P, 0.001). The 5- and 9-year disease-free survival rates for ypstage II (82 and 76%) were significantly worse than those for pstage II (93 and 80%, P ¼ 0.002), and the rates for ypstage III (64 and 50%) were worse than those for pstage III (74 and 66%, P ¼ 0.04). The disease-free survival of ypstage II was similar to that of pstage III (P ¼ 0.16). Similar results were seen when comparing distant metastasis-free survival rates. Using multivariate analyses, grade, age, hormonal receptor status, final pathological stage and neoadjuvant chemotherapy itself were found to be independent negative prognostic factors for disease-free survival. Conclusions: Stage-to-stage comparison of pathologically node-positive patients revealed that the survival outcome at each ypstage after neoadjuvant chemotherapy was worse than that for the comparable pstage. These data may help to formulate more accurate prognoses for patients with residual positive nodes after neoadjuvant chemotherapy. Key words: breast neoplasm neoadjuvant treatment disease-free survival INTRODUCTION Several clinical trials have demonstrated the comparable outcomes of neoadjuvant chemotherapy (NCT) and adjuvant chemotherapy (ACT) (1 4). Pathological complete response (pcr)ornegativeaxillarylymphnode(aln)afternctis associated with a favourable long-term outcome, whereas non-pcr patients are reported to have poorer outcomes (3,5 8). Published rates of pathological responses after NCT # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 996 Stage-to-stage comparison in breast cancer are variable, ranging from 4 to 29%, indicating that the majority of NCT patients are non-complete responders (4). For ACT, the post-operative pathological lymph-node classification ( pn) is the single most important prognostic factor and is used for the indication of adjuvant therapy. In contrast, for NCT, the original stage, the response to NCT and the post-nct pathological lymph-node classification (ypn) are all considered as prognostic factors, and all inform the decision whether to perform additional adjuvant therapy. The poor prognosis associated with persistent nodal involvement after NCT has been reported in several studies, but outcomes stratified by ypn have not been compared with those stratified by pn in breast cancer patients. Since 2001, we have conducted two prospective clinical trials of NCT for clinically node-positive breast cancer patients at the National Cancer Center (NCC) in Goyang, Korea (9,10). The goal of these trials was to characterize the response to NCT. The study population consisted of patients with locally advanced breast cancer (LABC) and clinical regional node involvement. During the same time period, patients who were not enrolled in the NCT trials but who had a positive pn status were given ACT. Here, we present the results of our investigation into the prognostic implications of NCT on the survival outcomes of breast cancer patients with persistent positive ALN based on stage-to-stage comparison of the NCT and ACT patient groups. PATIENTS AND METHODS PATIENTS Our patient database was used to select breast cancer patients referred to the NCC between 2001 and 2006, who were treated either with NCT followed by surgery or with surgery followed by ACT. In total, we identified 407 NCT patients and 1775 ACT patients. Of the NCT patients, 44 (11%) achieved pcr and 94 (23%) showed ypn0 after NCT and so were excluded from this study. The number of ACT patients who were classified as pn0 was 1231 (69%), and they were also excluded. The remaining 269 patients with persistent positive ypn and 544 ACT patients with positive pn were included in our analysis, which was performed in accordance with the guidelines of the Institutional Review Board of the NCC. All patients underwent a standard pretreatment workup, including medical history, physical examination, pathology review, mammography, ultrasound (US) and other imaging studies, as necessary. In the NCT group, all patients had palpable ALN. Although identification of positive ALN was not routinely confirmed by pathological analysis, US-guided biopsies confirmed positive ALN in 26 patients (9.7%). Among the remaining 243 NCT patients, one or more imaging studies using fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), CT or magnetic resonance imaging were done to identify ALN involvement. No sentinel lymph node procedures were performed prior to NCT. In the ACT group, all patients underwent standard pre-operative workups using US. US only was used on 222 patients (41%), PET/CT combined with US was performed on 57 (11%) patients and CT combined with US was performed on 265 (49%) patients. All tumours were staged according to the American Joint Committee on Cancer staging Manual, 6th edition. TREATMENT In the NCT group, modified radical mastectomy (MRM) was performed in 108 patients (40%) and breast-conserving surgery (BCS) in 161 patients (60%). In the ACT group, MRM was performed in 152 patients (28%) and BCS in 392 patients (72%). For cases in which the pathological examination indicated the positive resection margins, patients underwent re-excision to produce negative margins or were considered for mastectomy. Re-excision was performed on 34 patients (13%) in the NCT group and 78 patients (14%) in the ACT group. Of note, 10 patients (3.7%) in the NCT group and 5 patients (0.9%) in the ACT group with positive resection margins declined further surgery. No further revisionsurgerywasattemptedin 93 patients (11%) with close resection margins (,2 mm). Standard level I and II ALN dissections were performed in all patients. Radiotherapy (RT) in all patients with persistent positive ypn after NCT was our institutional policy. For ACT patients, RT was delivered to all BCS patients as well as to MRM patients with pt3, pn2-n3 or pn1 with extra-capsular invasion. In total, RT was administered to 257 NCT patients (96%) and 442 ACT patients (81%). Twelve patients (4.5%) in the NCT group refused RT. In the ACT group, 102 patients (19%) did not receive RT; 76 of these were mastectomy patients who were not indicated for RT. RT was performed using tangential fields at a median dose of 50.4 Gy delivered in 28 fractions over 5.5 weeks. After BCS, all patients received an electron boost (median 10 Gy in five fractions). An additional boost dose of 4 10 Gy was given to patients with positive or close resection margins. Regional nodal RT was delivered, including the supraclavicular fossa, to all NCT patients as well as to ACT patients with pn2-n3 status (median 45 Gy). Internal mammary nodal RT (median 55.8 Gy) was administered to 13 patients (4.8%) in the NCT group and 4 patients (0.7%) in the ACT group. In all cases, the initial planned RT was completed. Of the NCT patients, 245 (91%) were treated in one of the two prospective institutional clinical trials. Full details of the treatment have been reported elsewhere (9). Briefly, NCT consisted of four to six courses of non-taxane-containing (n ¼ 131, 49%) or taxane-containing treatments (n ¼ 138, 51%). Of the 245 total patients, additional ACT after surgery was administered to 233 patients (87%). In the ACT group, ACT was administered to 192 (35%) patients using a non-taxane-containing regimen and to 352 patients (65%) using a taxane-containing regimen.

3 Jpn J Clin Oncol 2012;42(11) 997 Adjuvant hormone suppression therapy (HST) was offered to patients with oestrogen receptor (ER)-positive or progesterone receptor (PR)-positive tumours in one or more tests. In all, 202 patients (75%) in the NCT group and 419 patients (77%) in the ACT group received HST with tamoxifen or aromatase inhibitors. Following RT, trastuzumab (Herceptin w ) was administered for 1 year to 30 of 58 patients (52%) in the NCT group and 35 of 107 patients (33%) in the ACT group with c-erbb2-overexpressing tumours. STATISTICAL ANALYSIS Endpoints were loco-regional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). LRR was defined as recurrence in the ipsilateral breast, chest wall or regional lymph nodes. Recurrence at any other site was considered DM. DFS was defined as the time interval from NCT initiation (NCT), or surgery (ACT), until any type of recurrence. If no recurrence was documented, survival rates were calculated as the time interval from the initiation of treatment until the date of the last follow-up, or death. Chi-square, Fisher s exact or t-tests were used for intergroup comparisons. Survival was estimated using the Kaplan Meier method. Differences in survival were compared using the log-rank test. Hazard ratios (HRs) were calculated using a multivariate Cox proportional hazard model. Statistical significance was defined by P-values, Statistical analyses were carried out using SPSS software (release 18; SPSS, Chicago, IL, USA). RESULTS COMPARISON OF PATIENT AND PATHOLOGICAL CHARACTERISTICS Table 1 provides the individual and pathological characteristics of the NCT and ACT groups. The median age at the time of diagnosis was 46 years (range, 24 73) for NCT patients and 47 years (range, 27 77) for ACT patients. Infiltrating ductal carcinoma affected 96% of patients in each group, and the remaining 4% of patients had tumours of other types. All patients in the NCT group exhibited clinically positive nodal status, but only 298 patients (55%) in the ACT group were considered to have positive nodes clinically; the other 246 ACT patients (45%) were considered to have negative nodes clinically (cn0) (P, 0.001). The ypn classification of the NCT group appeared more advanced than did the ACT group of comparable pn classification (P, 0.001). The pathological T classification was not different between the two groups (P ¼ 0.82). In general, the pathological characteristics of the NCT group were more aggressive compared with those of the ACT group with respect to ER status (P ¼ 0.01), PR status (P ¼ 0.05) and lymphovascular invasion (LVI) positivity (84% for NCT versus 77% for ACT, P ¼ 0.002). However, the mean value of Ki-67 expression was higher in the ACT group (P, 0.001). Table 1. Patient and pathological characteristics Characteristic Classification Number of patients (%) P value a NCT (n ¼ 269) ACT (n ¼ 544) Age (years),40 61 (23) 105 (19) (77) 439 (81) Clinical nodal status Negative 0 (0) 246 (45),0.001 ypt or pt classification ypn or pn classification Positive 269 (100) 298 (55) T0 T1 133 (49) 245 (45) 0.82 T2 T4 136 (51) 299 (55) N1 141 (52) 404 (74),0.001 N2 N3 128 (48) 140 (26) yp- or pstage II 128 (48) 398 (73),0.001 III 141 (52) 146 (27) Histological grade 1, (45) 297 (55) (48) 232 (43) Unknown 19 (7) 15 (3) ER Positive 183 (68) 417 (77) 0.01 Negative 86 (32) 127 (23) PR Positive 159 (61) 371 (68) 0.05 Negative 104 (39) 173 (32) HER2 receptor b Positive 58 (22) 107 (20) 0.53 Negative 211 (78) 437 (80) Ki-67 Mean + SD ,0.001 NCT, neoadjuvant chemotherapy; ACT, adjuvant chemotherapy; ER, oestrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; SD, standard deviation. a Chi-square test, Fisher s exact test or t-test. b Immunohistochemistry 3þ or fluorescent in situ hybridization (FISH)-positive. COMPARISON OF FAILURE PATTERNS AND SURVIVAL The median follow-up period of surviving patients was 5.8 years for the NCT group and 5.9 years for the ACT group. In the NCT group, 81 patients (30%) developed treatment failures over the follow-up period; 4 patients (1.5%) had LRR only, 55 (20%) had DM only and 22 (8.2%) had both. In the ACT group, 81 patients (15%) developed treatment failures; 9 patients (1.7%) had LRR only, 53 (10%) had DM only and 19 (2.8%) had both. LRR only rates did not differ between the two groups, but there was a significant difference in total LRR rates between the NCT (9.7%) and ACT (5.1%) groups (P ¼ 0.02). The NCT group also exhibited significantly higher total recurrence and DM rates than the ACT group (P, 0.001). The 5-year DFS rates for patients in the NCT and ACT groups were 73 and 88%, respectively (P, 0.001). The 9-year DFS rates stratified by pstage and ypstage were 80% for pstage II, 76% for ypstage II, 66% for pstage III and 50% for ypstage III (Fig. 1). The DFS

4 998 Stage-to-stage comparison in breast cancer Figure 1. Comparison of disease-free survival (DFS) curves in patients stratified by post-neoadjuvant chemotherapy pathological stage (ypstage) or post-operative pathological stage (pstage). Figure 2. Comparison of distant metastasis-free survival (DMFS) curves of patients stratified by post-neoadjuvant chemotherapy pathological stage (ypstage) or post-operative pathological stage (pstage). rate of ypstage II was significantly worse than that of pstage II (P ¼ 0.002), and similarly, the DFS rate of ypstage III was worse than that of pstage III (P ¼ 0.04). The DFS curve of ypstage II was located between those of pstage II and III, but was closer to pstage III than to pstage II. The DFS of ypstage II was similar to that of pstage III (P ¼ 0.16). With regard to DMFS, results were similar to those in the DFS analysis, with a significant difference between pstage II and Figure 3. Comparison of loco-regional recurrence-free survival (LRRFS) curves of patients stratified by post-neoadjuvant chemotherapy pathological stage (ypstage) or post-operative pathological stage (pstage). ypstage II (P, 0.001) and a non-significant trend between pstage III and ypstage III (P ¼ 0.07; Fig. 2). LRRFS rates were not different between ypstage II and pstage II (P ¼ 0.61), but pstage III exhibited better LRRFS than ypstage III (P ¼ 0.01; Fig. 3). VARIABLES AFFECTING DFS RATES Table 2 displays the results of univariate analysis of clinicopathological variables associated with DFS rates in all patients. Poorer rates of DFS correlated with the variables of age (,40 years), mastectomy, positive resection margin, grade 3, positive LVI, negative ER, negative PR, NCT and yp- or pstage III. The chemotherapy regimen (taxanecontaining or non-taxane-containing) did not significantly correlate with DFS (P ¼ 0.25). In a multivariate analysis of all patients, outcomes of yp- or pstage III and grade 3 were strongly correlated with increased DFS HR of 2.70 and 2.28, respectively (P, 0.001) (Table 3). PR status and age also correlated with DFS. NCT was found to be an independent negative prognostic factor for DFS (HR 1.79; P ¼ 0.001). Multivariate analysis of subgroups of yp- or pstage II (n ¼ 526) and III (n ¼ 287) was also performed. In the yp- or pstage II subgroup, patients with yp- or pt2 T4 classification had lower DFS rates than did those with a yp- or pt0 T1 classification (HR 2.34; P ¼ 0.002). In the yp- or pstage III subgroup, patients with a negative ER had poorer DFS rates than did those with a positive ER (HR 2.43; P, 0.001). NCT, grade 3 and age,40 years were each associated with lower DFS rates for both subgroups, as well as for the total number patients.

5 Jpn J Clin Oncol 2012;42(11) 999 Table 2. Univariate analysis of clinico-pathological variables with disease-free survival for all patients (n ¼ 813) Characteristic Classification n (%) DFS (%) P value a DISCUSSION 5 year 9 year Age (years) (80) , (20) Surgery BCS 553 (68) 87 70,0.001 Mastectomy 260 (32) Resection margin Negative 705 (87) Close 93 (11) Positive 15 (2) Histological grade 1, (52) 89 81, (44) LVI No 144 (18) Yes 648 (80) ER Positive 600 (74) 87 74,0.001 Negative 213 (26) PR Positive 536 (66) 87 76,0.001 Negative 277 (34) HER2 receptor b Negative 648 (80) Positive 165 (20) Ki-67,15% 424 (52) % 362 (45) Chemotherapy ACT 544 (67) 88 77,0.001 NCT 269 (33) yp- or pstage II 526 (65) 90 79,0.001 III 287 (35) BCS, breast-conserving surgery; LVI, lympho-vascular invasion. a Log-rank test. b Immunohistochemistry 3þ or fluorescent in situ hybridization (FISH)-positive. This study shows that breast cancer patients with residual ALN treated with NCT have poor prognostic outcomes. The prognostic value of persistent ALN involvement after NCT for LABC has been evaluated in several studies (11 14). Gajdos et al. (12) reported that both DMFS and overall survival were significantly correlated with the number of involved ALN in patients treated with NCT for LABC. The cumulative 5-year survival rate was 71% for node-negative patients, 54% for patients with one to nine positive nodes and 35% for patients with 10 or more positive nodes after NCT. Data from the MD Anderson Hospital indicated that 10-year survival rates were 65, 44, 32 and 9% when 0, 1 3, 4 9 and 10 or more nodes were involved after NCT, respectively (14). The aforementioned studies have demonstrated that the typical prognosis of a patient with residual disease Table 3. Multivariate analysis of disease-free survival rates Variables Patients with yp- or pstage III (n ¼ 287) Variables Patients with ypor pstage II (n ¼ 526) Variables All patients (n ¼ 813) HR P value a HR P value HR P value yp- or pstage (II versus III) 2.70,0.001 yp- or pt status (T0 1 versus T2 4) ER (þ versus ) 2.43,0.001 Histological grade (1, 2 versus 3) 2.28,0.001 Chemotherapy (ACT versus NCT) Histological grade (1, 2 versus 3) PR (þ versus 2) 1.81,0.001 Histological grade (1, 2 versus 3) Age (40 years versus,40 years) Chemotherapy (ACT versus NCT) Chemotherapy (ACT versus NCT) Age (40 years versus,40 years) Age (40 years versus,40 years) HR, hazard ratio. a Cox proportional hazard model.

6 1000 Stage-to-stage comparison in breast cancer after NCT is poor (11 14). However, no study has compared stage-specific survival outcomes between NCT-treated and initial surgery patients or determined the extent of the poor prognoses of NCT patients. Our calculations of the DFS rates of ypstage II and III patients were comparable with those found in previous studies. However, our extended analysis revealed that these rates were significantly worse than those for pstage II and pstage III patients. Our data also indicated that the prognosis of ypstage II was as poor as pstage III, which may help establish more accurate prognoses for patients with residual positive nodes after NCT. Our study demonstrated that the survival outcomes in the NCT group were worse than those in the ACT group, which may be natural, because the differences in patient and pathological characteristics between the groups are evident (Table 1). Patients in the NCT group had more advanced disease. All patients in the NCT group had palpable ALN at presentation, whereas only 55% of patients in the ACT group had the same. More patients in the NCT group (46%) than in the ACT group (26%) had pn2 N3 classification. A higher mastectomy rate in the NCT group also reflects more advanced disease. But it is notable that NCT was a major independent negative prognostic factor for DFS in multivariate analysis, which indicates that NCT itself contributed to worse survival of node-positive patients after surgery. Other predictors that affected DFS included stage, grade, hormone-receptor status and age, all of which have been previously reported (12,15 17). Several studies have shown that NCT is equivalent to ACT with regard to DM or LRR. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18, as well as the meta-analysis by Mauri et al. demonstrated no differences between NCT and ACT regimens with respect to the outcomes of DFS and DM (3,4). Both of these studies included patients with early-stage disease as well as patients with LABC. In our study, treatment failures, as evidenced by DM, were more frequent in the NCT group than in the ACT group, likely due to the former group s more advanced disease profile. However, as shown in Fig. 2, the pattern of curves for DMFS was similar to that of DFS, implying that poorer prognosis of each ypstage (compared with each pstage) was attributable to higher rates of DM. The presence of nodal involvement after NCT may indicate the existence of persistent systemic micrometastases, which may ultimately be responsible for the patient s demise. There remains much debate about the frequency of LRR in patients with LABC who undergo NCT (18). Mauri et al. (4) found a significant 22% increase in the relative risk for LRR associated with NCT. In a stage-to-stage comparison of LRRFS, we detected no difference between ypstage II and pstage II, despite the fact that 70 of 91 patients with pstage II in the ACT group, who had an MRM, did not receive RT (Fig. 3); only three of 39 ypstage II patients who had an MRM did not receive RT. However, of patients with stage III who received RT, irrespective of the surgery type or the sequence of chemotherapy, pstage III patients exhibited a significantly better LRRFS rate than did ypstage III patients. This implies aggressive behaviour by bulky residual tumours after NCT, which resulted in the poor outcomes of LRR and DM. We included clinically ALN-positive patients in the NCT group who were only diagnosed by one or more imaging studies using US, PET/CT or CT. However, the diagnostic value of PET/CT in regional lymph node classification of breast cancer has not been unequivocally confirmed. Although some studies of axillary staging in breast cancer using PET/CT have shown it to be a highly sensitive approach (offering a detection rate of %), Monzawa et al. reported strong specificity (97%) but poor sensitivity (20%) in the detection of ALN metastases (19,20). The diagnostic accuracy of combining US with PET/CT was reported to be as high as 92%; this can be compared with US (79%) or PET/CT (76%) alone (21). However, because this study performed single-modal imaging on just five NCT-treated patients (2%), the inclusion of so few cn0 patients in this group may have affected the results. In our study, the ACT group included 246 patients (45%) considered cn0 who were later proved to be node-positive after surgery. This may be explained by the fact that the pre-operative workup for 222 patients (41%) was performed using US alone. Additionally, among the 404 ACT patients (74%) with pn1, 75 (14%) were pn1mi. Therefore, pn1mi patients could have been misclassified as cn0. Only nine (3.3%) ypn1mi patients existed in the NCT group, and they were originally classified as gross node-positive before NCT. Thus, the accuracy of diagnosis of ACT patients in our study might not be as high as that for the NCT group. Our data are limited by several factors. This is a retrospective study, and the data set was derived from a heterogeneously treated population, which can introduce inherent biases. We also noticed that tumours in the NCT group seemed to be more extensive than did those in the ACT group, comparing same pathologicla stages. Inequalities in initial clinical node positivity, small-tumour burdens like N1mi, surgery type and pathological characteristics could also affect results. However, when we excluded ypn1mi and pn1mi patients from analysis, DFS rates were similar to those calculated for all patients. Moreover, NCT was found to be an independent negative prognostic factor for DFS in all patients and subgroups of stage II and III after adjusting for the confounding effects of the aforementioned factors. In conclusion, stage-to-stage comparison of pathologically node-positive patients revealed that DFS rates of NCT patients in each ypstage were worse than those of ACT patients in the comparable pstage. In particular, the prognosis of ypstage II patients was similar to that of pstage III patients. Multivariate analysis demonstrated that grade, age, hormone-receptor status, final pathological stage and NCT were all independent prognostic factors for DFS. This study may help to formulate more accurate prognoses for patients with residual positive nodes after NCT. The poor prognosis of patients with persistent ALN involvement after NCT

7 Jpn J Clin Oncol 2012;42(11) 1001 highlights the need to develop alternative treatment modalities, additional treatments and/or more effective strategies and integration of targeted agents such as trastuzumab or bevacizumab with standard NCT, to enhance the response rate after NCT. Funding This research is supported by National Cancer Center grant NCC Conflict of interest statement None declared. References 1.FisherER,WangJ,BryantJ,FisherB,MamounasE,WolmarkN. Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 2002;95: Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24: Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26: Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97: Bonadonna G, Valagussa P, Brambilla C, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998;16: Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16: Kuerer HM, Newman LA, Smith TL, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17: Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008;26: Lee KS, Ro J, Lee ES, et al. Primary systemic therapy with intermittent weekly paclitaxel plus gemcitabine in patients with stage II and III breast cancer: a phase II trial. Invest New Drugs 2010;28: Lee KS, Ro J, Nam BH, et al. A randomized phase-iii trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat 2008;109: Carey LA, Metzger R, Dees EC, et al. American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst 2005;97: Gajdos C, Tartter PI, Estabrook A, Gistrak MA, Jaffer S, Bleiweiss IJ. Relationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer. J Surg Oncol 2002;80: Pierga JY, Mouret E, Dieras V, et al. Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer. Br J Cancer 2000;83: Frye DK, Buzdar AU, Hortobagyi GN. Prognostic significance of axillary involvement after preoperative chemotherapy in stage III breast cancer. Proc Am Soc Clin Oncol 1995;14: Min SY, Lee SJ, Shin KH, et al. Locoregional recurrence of breast cancer in patients treated with breast conservation surgery and radiotherapy following neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2011;81:e Group EBCTC. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365: Honkoop AH, van Diest PJ, de Jong JS, et al. Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. Br J Cancer 1998;77: Buchholz TA. Introduction: locally advanced breast cancer. Semin Radiat Oncol 2009;19: Greco M, Crippa F, Agresti R, et al. Axillary lymph node staging in breast cancer by 2-fluoro-2-deoxy-D-glucose-positron emission tomography: clinical evaluation and alternative management. J Natl Cancer Inst 2001;93: Monzawa S, Adachi S, Suzuki K, et al. Diagnostic performance of fluorodeoxyglucose-positron emission tomography/computed tomography of breast cancer in detecting axillary lymph node metastasis: comparison with ultrasonography and contrast-enhanced CT. Ann Nucl Med 2009;23: Ahn JH, Son EJ, Kim JA, et al. The role of ultrasonography and FDG-PET in axillary lymph node staging of breast cancer. Acta Radiol 2010;51: