Association of surgical margins with local recurrence in patients undergoing breast-conserving surgery after neoadjuvant chemotherapy

Association of surgical margins with local recurrence in patients undergoing breast-conserving surgery after neoadjuvant chemotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Association of surgical margins with local recurrence in patients undergoing breast-conserving surgery after neoadjuvant chemotherapy Joseph Lin, Sam Li-Sheng Chen, Dar-Ren Chen, Kuo-Juei Lin, Yu-Fen Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-17122/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 May, 2020 Read the published version in BMC Cancer → Version 1 posted 13 You are reading this latest preprint version Abstract Background The aim of the current study was to report a single-institution experience using breast-conserving surgery after neoadjuvant chemotherapy (NACT), focusing on the association between microscopic resection margin status and locoregional recurrence (LRR). Methods Our institutional prospectively maintained database was reviewed to identify patients who were treated with NACT between January 2008 and April 2018. Results Among the main partial mastectomy specimens available for analysis (n = 161), 28 had margins 2 mm. LRR occurred in 16 patients (9.9%) and distant metastases were detected in 27 (16.8%) patients. There was no significant difference in the LRR between the > 2 mm margin group with a 60-month cumulative survival of 85.2% compared with 76.2% for the ≤ 2 mm group ( P = 0.335) in the Kaplan-Meier analysis. When we stratified patients by margin widths of ≥ 1 mm or < 1 mm, there was no LRR-free survival benefit observed for the ≥ 1 mm pathologic excision margin group in the univariate analysis (hazard ratio = 0.443; 95% confidence interval = 0.142–1.383; P = 0.161) with a 60-month cumulative LRR-free survival of 84.9% compared with 69.5% for the < 1 mm margin cohort ( P = 0.150). Conclusions In the absence of multiple scattered microscopic tumour foci, a negative margin of no ink on tumour maybe sufficient for stage I–III invasive breast cancer treated with NACT and breast-conserving surgery. Cancer Biology Oncology Neoadjuvant Breast-conserving surgery Surgical margin Recurrence Figures Figure 1 Figure 2 Figure 3 Background Despite the lack of overall survival benefits, the use of neoadjuvant chemotherapy (NACT) in early-stage breast cancer nonetheless manifests other advantages; as such, it converts patients into applicants for breast-conserving surgery (BCS) after lowering tumour volumes and reduces the use of axillary lymph node dissection [ 1 , 2 ]. Moreover, it allows the assessment of therapeutic response to a distinct chemotherapy regimen. The ultimate goals of BCS are complete removal of the breast tumour with adequate margins and simultaneous preservation of the natural shape of the breast [ 3 ]. Studies have demonstrated that a “no ink on tumour” lumpectomy margin is adequate for invasive breast cancer treated with BCS followed by whole-breast radiation [ 4 , 5 ], but those patients display higher locoregional recurrence (LRR) rates than mastectomy patients [ 6 ]. Despite the increasing evidence demonstrating the feasibility of BCS after NACT [ 7 ], the combined use of NACT and BCS has certainly drawn concerns of high LRR in patients with locally advanced breast cancer as reported by several studies [ 8 – 10 ]. Furthermore, increased pathological complete response (pCR) rates with the use of newer therapeutic agents which was not translated into a higher rate of BCS may have attributed to the distraction in relation to the adequate margin on BCS after NACT [ 11 ]. The risk of LRR after BCS could be influenced by factors related to therapeutic strategies, tumour subtypes and surgical margin status. Negative margins reduce the risk of local recurrence, but to date, there is no consensus on what constitutes an adequate negative margin in BCS after NACT. The aim of the current study was to report a single-institution experience using BCS after NACT, focusing on the association between microscopic resection margin status and LRR, as this information can be crucial in improving surgical options after NACT considering the risks and potential benefits in this setting. Methods This study obtained approval from the Changhua Christian Hospital. In this study, patients with breast cancer receiving NACT from January 2008 to April 2018 were enrolled. Initial diagnosis of breast cancer was made through core needle biopsy with ultrasound guidance, through which information on receptor status was obtained using immunohistochemical staining. Disease stage was classified based on the 2010 staging system of the American Joint Committee of Cancer (AJCC) TNM criteria. Information on Ki-67 expression in pre-therapeutic core needle biopsies was not available until 2018 at our hospital, and histology grade was used as an alternative measurement to determine proliferation activity. Intrinsic subtypes were therefore determined as follows: luminal (ER + and/or progesterone receptor (PR) +, HER2–, all grades), luminal HER2 (ER + and/or PR+, HER2+, all grades), HER2-type (ER–, PR– and HER2+) and triple negative (ER–, PR– and HER2–) [ 12 , 13 ]. Imaging examinations to assess breast and lymph nodes included ultrasonography, mammography and magnetic resonance imaging (MRI); the largest dimension recorded from these examinations was defined as the tumour size. Indications for BCS remained homogenous during the study period: absence of multicentric disease or extensive microcalcification, lack of chest wall or skin involvement and predictable sufficiency of breast volume after BCS. Partial mastectomy specimens were sent to surgical pathologists for microscopic assessment. All patients underwent whole-breast radiation therapy for a total dose of 5000 cGY given in 25–28 fractions with or without a boost to the primary tumour site. Both pre-NACT and post-NACT tumour size were determined by imaging (either MRI or ultrasonography). Our institutional definition of pCR was eradication of invasive cancer and in-situ cancer in the breast and axillary (ypT0 ypN0), which was consistent with the meta-analysis of Cortazar et al. [ 14 ] Histological variants of breast carcinoma were classified into the following subtypes: (1) infiltrating ductal carcinoma (IDC), (2) infiltrating lobular carcinoma (ILC), (3) IDC + ductal carcinoma in situ (DCIS) (DCIS component > 10%), (4) ILC + lobular carcinoma in situ (LCIS) (LCIS component > 10%), (5) IDC + ILC or (6) others (mucinous, medullary, etc.). Primary tumour response to NACT was monitored by ultrasonography after each cycle of chemotherapy, and for tumours that have progressively decreased in size, an ultrasound-guided metallic marker insertion was done for future localisation. All specimens were oriented with sutures, dye-inked followed by sectioning at 3- to 5-mm intervals, and the smallest distance between the tumour edge and an inked normal tissue margin was measured using an ocular micrometre (to the nearest 1 mm if > 2 mm distance or to the nearest 0.1 mm if 2 mm, 1–2 mm and < 1 mm) of the resection margin. The primary outcome of interest was any LRR that was defined as recurrence tumour in the ipsilateral breast parenchyma or metastatic disease in the internal mammary, ipsilateral axillary, infraclavicular or supraclavicular nodes [ 15 ]. Secondary outcomes included event-free survival (free of LRR, distant metastasis and death). Time to event was defined as the interval from the definite surgery and the date of the first recurrence. Clinicopathological characteristics were compared by Mann–Whitney U test for medians and chi-square test for proportions. Kaplan–Meier (KM) survival curves were generated to compare the survival outcomes according to the margin status and the use of MRI [ 16 ], and two-sided log rank test was used to test the significant difference between survival experiences [ 17 ]. Statistical analysis was performed using MedCalc statistical software version 18.5 (MedCalc Software bvba, Ostend, Belgium), and a significance level of 5% was used in all analyses. Results A total of 555 cases were identified, but 127 were excluded because of the following reasons: stage IV breast cancer (n = 65), bilateral breast cancer (n = 12), lost to follow-up (n = 13), expired without surgery (n = 10) and on-going NACT (n = 27). Of the remaining 428 patients, 172 patients (40.2%) had undergone BCS with radiotherapy and 256 (59.8%) underwent mastectomy (Fig. 1 ). Of the 172 BCS patients, 11 had involved margin based on pathological examination, and this left us with 161 patients for analysis. The median age of the studied population was 47.4 years (range 25.4–87.3); 65 (40.4%) patients aged ≥ 50 years and 96 (50.6%) patients aged < 50 years. NACT comprised of 4–6 courses of anthracycline-based (n = 33, 20.5%), taxane-based (n = 14, 8.7%), combined anthracycline-taxane-based (n = 65, 40.4%) and HER2-targeted agents added regimens (n = 46, 28.6%). IDC represented 145 (90.1%) of all patients, which was considered the most common histopathological type in this study. Statistical associations between the three margin groups and tumour characteristics are summarised in Table 1 . Table 1 Patient characteristics (n = 161) Surgical margin Characteristics All (n = 161) (%) < 1 mm (n = 28) (%) ≥ 1 mm, < 2 mm (n = 21) (%) ≥ 2 mm (n = 112) (%) P Age, year Median (range) 47.4 (25.4–87.3) 51.7 (27.6–87.3) 46.4 (25.4–68.5) 46.9 (27.6–74.7) Mean ± SD 48.1 ± 11.0 51.7 ± 13.5 46.3 ± 10.1 47.5 ± 10.4 2 cm, ≤ 5 cm) 132 (82.0) 24 (85.7) 18 (85.7) 90 (80.4) T3 (> 5 cm) 11 (6.8) 1 (3.6) 2 (9.5) 8 (7.1) Lymph node status Negative 34 (21.1) 6 (21.4) 5 (23.8) 23 (20.5) 0.944 Positive 127 (78.9) 22 (78.6) 16 (76.2) 89 (79.5) Histological type IDC 145 (90.1) 22 (78.6) 19 (90.5) 104 (92.9) 0.152 IDC + DCIS 12 (7.5) 4(14.3) 1 (4.8) 7 (6.2) Others 4 (2.5) 2 (7.1) 1 (4.8) 1 (0.9) Histological grade in situ 2 (1.3) 1 (3.6) 1 (5.0) 0 (0) 0.173 I 17 (11.3) 4 (14.3) 1 (5.0) 12 (11.8) II 77 (51.3) 16 (57.1) 13 (65.0) 48 (47.1) III 54 (36.0) 7 (25.0) 5 (25.0) 42 (41.2) Missing 11 0 1 10 Intrinsic subtype Luminal 53 (32.9) 9 (32.1) 11 (52.4) 33 (29.5) 0.379 Luminal HER2 41 (25.5) 8 (28.6) 3 (14.3) 30 (26.8) HER2 21 (13.0) 5 (17.9) 3 (14.3) 13 (11.6) TNBC 46 (28.6) 6 (21.4) 4 (19.0) 36 (32.1) Chemotherapy Anthracycline-based 33 (20.5) 5 (17.9) 7 (33.3) 21 (18.8) 0.427 Taxane-based 14 (8.7) 2 (7.1) 2 (9.5) 10 (8.9) Combined anthracycline and taxane 65 40.4) 10 (35.7) 7 (33.3) 48 (42.9) HER2 targeting agent contained 46 (28.6) 9 (32.1) 5 (23.8) 32 (28.6) Others 3 (1.9) 2 (7.1) 0 (0) 1 (0.9) Follow-up, month Median (range) 34.7 (5.3–118.9) 23.5 (5.3–105.5) 39.3 (7.7–105.6) 35.8 (6.9–118.9) Mean ± SD 44.9 ± 31.8 36.1 ± 29.5 49.3 ± 34.2 46.2 ± 31.9 Regarding histological grading, 17 cases (11.3%) were grade I, 77 cases (51.3%) were grade II, 54 cases (36%) were grade III and 11 cases did not have grade status. Luminal subtype represented 53 (32.9%) of all patients, triple negative, luminal HER2 and HER2 subtypes represented 46 (28.6%), 41 (25.5%) and 21 (13%) of all BCS patients, respectively. The median follow-up time was 47 months (range 25–87). Thirty-eight patients (22.1%) achieved a pCR; overall pCR was 8.9% (5/56) in luminal subtype patients, 18.2% (8/44) in luminal HER2 subtype patients, 50% (12/24) in HER2 subtype patients and 27.1% (13/48) in triple negative breast cancer (TNBC) patients. Their pCR rates according to molecular subtypes are shown in Fig. 2 . Among the main partial mastectomy specimens available for analysis (n = 161), 28 had margins 2 mm. Involved margins were reported in seven patients, and all of them underwent re-excision to obtain negative margins. Overall, LRR occurred in 16 patients (9.9%) and distant metastases were detected in 27 (16.8%) patients. Of these patients with LRR, an in-breast recurrence developed in 10 patients, five patients had nodal failure and one patient exhibited two sites of LRR simultaneously. There were 4 (4/28, 14.3%) LRR events in the 2 mm group. There was no significant difference in the LRR between the > 2 mm margin group with a 60-month cumulative survival of 85.2% compared with 76.2% for the ≤ 2 mm group ( P = 0.335; Fig. 3 .a) in the KM analysis. When we stratified patients by margin widths of ≥ 1 mm or < 1 mm, there was no LRR-free survival benefit observed for the ≥ 1 mm pathologic excision margin group in the univariate analysis (hazard ratio = 0.443; 95% confidence interval = 0.142–1.383; P = 0.161) (Table 2 ) with a 60-month cumulative LRR-free survival of 84.9% compared with 69.5% for the 2 mm versus ≤ 2 mm and no difference for ≥ 1 mm versus < 1 mm (Fig. 3 .c-d). Table 2 Univariate logistic regression analysis of LRR-free survival and event-free survival LRR-free survival Event-free survival Variables Hazard ratio 95% confidence interval P Hazard ratio 95% confidence interval P Age, years (≥ 50 vs. 2 vs. ≤ 2) 1.270 0.167–9.637 0.817 0.815 0.247–2.686 0.737 Lymph node (positive vs. negative) 2.682 0.609–11.811 0.192 1.972 0.757–5.135 0.164 Histological grade (3 vs. 0–2) 0.851 0.295–2.453 0.766 1.098 0.520–2.316 0.807 ER (positive vs. negative) 0.927 0.334–2.574 0.884 0.884 0.435–1.797 0.734 PR (positive vs. negative) 0.977 0.362–2.633 0.963 0.926 0.456–1.881 0.832 HER2 (positive vs. negative) 1.555 0.583–4.146 0.378 1.174 0.583–2.361 0.654 Ki-67 labelling index, % (≥ 14 vs. < 14) 3.253 0.688–15.388 0.137 1.950 0.756–5.034 0.167 Surgical margin, mm (≥ 1 vs. < 1) 0.443 0.142–1.383 0.161 0.554 0.239–1.284 0.169 The logistic regression analysis analyses included age, lymph node status (positive vs. negative), histological grade, receptor status, Ki-67 index, pCR status and surgical margin distance. On the univariate analyses, these variables are independent of LRR-free survival and event-free survival (Table 2 ). Only lymph node status was found to be a significant predictor of event-free survival (hazard ratio = 3.374; 95% confidence interval = 1.020–11.155; P = 0.046) on multivariate analysis. Discussion The introduction of target therapy and advancement of chemotherapeutic treatments have brought an increase in pCR rates, but BCS rates following NACT stay relatively unaffected [ 11 ], partly because an increase number of patients may opt for mastectomy treatments due to a lack of consensus on adequate margin in BCS after NACT. These findings may reflect discrepancies in practice among clinicians and guidelines with the consequence of re-excision to gain wider margins. In the present study, 428 women with untreated operable breast cancer received NACT from January 2008 to April 2018; 40.2% (n = 172) of them underwent BCS and the remaining 59.8% (n = 256) had mastectomy. In the present study, the overall BCS rate of 40.2% for patients was lower than that of 49.4% in the surgery first cohort from our previous study [ 18 ] despite comparable pCR rates of 22.1% with other studies [ 19 , 20 ]. This may have resulted from the higher LRR after BCS in patients who were treated with NACT [ 8 – 10 ], as one of our senior surgeons who performed more than half of the analysed BCS cases in this study had a BCS rate of 56%. This variation between surgeons in clinical practices further lends credence to the consensus on a safe margin width in this patient population. In our institution, diagnostic ultrasonography was performed by the operating surgeons after each cycle of NACT to evaluate tumour size and therapeutic response. Further, a metallic marker was only inserted in tumours that had progressively decreased in size for future localisation. Therefore, we have a lower rate of wire localisation due to an extensive usage of breast ultrasonography, and this low rate does not reflect the simplicity in choosing the optimal resected volume for complete tumour excision while preserving the cosmetic integrity of the breast. Moreover, most patients in this cohort underwent MRI before and after NACT, and this may give additional information in estimation of disease burden during the surgery as other studies suggested [ 21 – 23 ]. Volder et al. [ 24 ] reported an involved margin rate of 24.3% in patients who received NACT and BCS, with additional 17.7% of patients with close (≤ 1 mm) margin width identified in a nationwide pathologic study. Differences in therapeutic approaches among hospitals may have contributed to the high-observed margin rate (24.3%) in this population-based study. Others reported a lower rate of re-excision in primary chemotherapy. Christy et al. [ 25 ] demonstrated that preoperative chemotherapy resulted in a significantly higher incidence of negative margins (90% vs. 55%; P < 0.01) and a lower re-excision rate (6% vs. 37%; P < 0.01) compared with primary surgery. Karanlik et al. [ 26 ] reported that NACT was more likely to have negative margins (95% vs. 84%; P = 0.02) and less likely receive re-excision (4% vs. 8%; P = 0.02) as well. Our study also reported a low re-excision rate, re-excision surgery was given in 4.1% (7/172) of patients, and these seven patients all had an involved margin at the first place. Additional 14.5% (25/172) of patients with margin < 1 mm would have added to this re-excision rate (4.1 + 14.5 = 18.6%) if < 1 mm margin width was considered positive. The lower re-excision rate did not however bring a higher recurrence rate. Moreover, 16 patients (9.9%, 16/161) experienced LRR and 10 of them had breast-only local recurrence (6.2%, 10/161) during the follow-up. Our results were comparable to Mittendorf et al. [ 27 ] who reported 5- and 10-years LRR of 7% and 10%, respectively. Our low re-excision rate did not correlate with a higher recurrence rate, and it was further supported by our multivariate analysis that failed to show the association between LRR and margin distance. A few studies assessed the margin distance and outcomes in patients treated with BCS following NACT, and the results have been inconsistent. Chen et al. [ 19 ] reported on 340 cases treated at MD Anderson Cancer Centre between 1987 and 2000 and discovered no association between 5-year LRR-free survival and margin distances (> 2 mm vs. ≤ 2 mm). LRR and ipsilateral breast tumour recurrence were correlated with advanced nodal involvement, residual tumour > 2 cm, multifocal residual disease and lymphovascular space invasion. In contrast, the Institute Curie reported that an increased ipsilateral breast tumour recurrence was associated with margins ≤ 2 mm in addition to clinical tumour > 2 cm, age 4% [ 10 ]. The latest study by Choi et al. [ 20 ] on 382 patients showed no association between margin width and local recurrence but rather related to intrinsic subtypes, lack of pCR and positive nodal status. Factors such as age, tumour size, lymph node status, surgical margin, histological grade, Ki-67 index and receptor status were not found to be significant predictors of LRR on univariate analysis in our study. This might have been attributed to our population size due to its insufficient power to detect a difference. However, the low LRR in the present study suggests that even though a statistically significant difference may be achieved by increasing the sample size, this difference may not be translated into a clinically meaningful consequence in the real world. The rates of pCR were highest in HER2 subtype patients (ER–, PR– and HER2+) with 50% followed by TNBC group with 27.1% in our study. While further analysis on pCR and prognosis stratified by subtypes would be statistically underpowered because of small sample size in our analysis, von Minckwitz in his meta-analysis of 6377 patients treated with NACT and BCS showed different prognosis among pCR patients stratified by subtypes [ 13 ]. They reported that pCR was associated with improved disease-free survival in luminal B/HER2 negative, HER2 and TNBC subtypes but not in luminal A or luminal HER2 breast cancer. This may suggest the importance of biologic characteristics of a tumour in achieving local control of breast cancer and the complete resection of the primary tumour may not be essential. SSO-ASTRO introduced guidelines that suggested “no ink on tumour” as adequate margins for women with invasive breast cancer undergoing BCS, but this analysis did not include patients treated with NACT [ 4 ]. The purpose of the current study was to compare margin widths of > 2 mm, 1–2 mm and < 1 mm in NACT patients after BCS and their association with recurrence rate. Our results did not support the idea that ≥ 1 mm margins would decrease LRR, and it is important because it may reduce additional costs and psychological effect by minimising the need for re-excision [ 28 ]. This study had a few limitations. First, this was a retrospective, single-institution study with a comparatively small sample size. Second, the enrolled patients were given different chemotherapy regimens based on the tumour subtype. Additionally, patients with HER2 subtype were underrepresented and it might limit the generalisability of the results. However, this study benefits from its real-world clinical data and a relative standardised strategy to surgical approach and to margin assessment procedure. Further studies with greater sample sizes are necessary to determine the safe surgical margin with NACT and BCS. Conclusion This study has shown no increase in LRR for surgical margins < 1 mm compared with margins ≥ 1 mm. In the absence of multiple scattered microscopic tumour foci, a negative margin of no ink on tumour maybe sufficient for stage I–III invasive breast cancer treated with NACT and BCS, and it is not necessary for re-excision if surgical width is < 1 mm. List of Abbreviations NACT, neoadjuvant chemotherapy; BCS, breast-conserving surgery; LRR, locoregional recurrence; pCR, pathological complete response; AJCC, American Joint Committee of Cancer; PR, progesterone receptor; MRI, magnetic resonance imaging; IDC, infiltrating ductal carcinoma; DCIS, ductal carcinoma in situ; ILC, infiltrating lobular carcinoma; LCIS, lobular carcinoma in situ; TNBC, triple negative breast cancer Declarations Ethics approval and consent to participate Prior to collecting clinical data from the patient’s medical record, a written informed consent was obtained from her. The study protocol was approved by the Institutional Review Board of Changhua Christian Hospital, Taiwan. All methods were carried out in accordance with the Declaration of Helsinki. Consent for publication Not applicable. Availability of data and materials All datasets used or analysed for this study are available from the corresponding author upon reasonable request. Competing interests The authors declare that there are no conflicts of interest relevant to the content of this manuscript. Funding The authors have received no funding for this study. Authors’ contributions The study was designed by DRC. Clinical data acquisition and analysis were performed by JL, DRC, KJL, YFW and LHH. Statistical analyses were performed by JL, SLSC and YFW. The manuscript was written by JL, DRC and YFW. All authors read and approved the manuscript. Acknowledgements We would like to thank Ms. Hung-Ting Lin, Ms. Yun-Cen Chen and Mr. Yung-Liang Yeh for their administrative and technical assistance. References Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB, Jr., Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. 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Eur J Surg Oncol. 2016; 42(7):986-93. Christy CJ, Thorsteinsson D, Grube BJ, Black D, Abu-Khalaf M, Chung GG, DiGiovanna MP, Miller K, Higgins SA, Weidhaas J, Harris L, Tavassoli FA, Lannin DR. Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter. Ann Surg Oncol. 2009; 16(3):697-702. Karanlik H, Ozgur I, Cabioglu N, Sen F, Erturk K, Kilic B, Onder S, Deniz M, Yavuz E, Aydiner A. Preoperative chemotherapy for T2 breast cancer is associated with improved surgical outcome. Eur J Surg Oncol. 2015; 41(9):1226-33. Mittendorf EA, Buchholz TA, Tucker SL, Meric-Bernstam F, Kuerer HM, Gonzalez-Angulo AM, Bedrosian I, Babiera GV, Hoffman K, Yi M, Ross MI, Hortobagyi GN, Hunt KK. Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy. Ann Surg. 2013; 257(2):173-9. Al-Ghazal SK, Blamey RW, Stewart J, Morgan AA. The cosmetic outcome in early breast cancer treated with breast conservation. Eur J Surg Oncol. 1999; 25(6):566-70. Cite Share Download PDF Status: Published Journal Publication published 20 May, 2020 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Major revision 06 Apr, 2020 Review # 4 received at journal 05 Apr, 2020 Review # 2 received at journal 05 Apr, 2020 Reviewer # 4 agreed at journal 04 Apr, 2020 Reviewer # 2 agreed at journal 30 Mar, 2020 Reviewer # 3 agreed at journal 30 Mar, 2020 Review # 1 received at journal 20 Mar, 2020 Reviewers invited by journal 19 Mar, 2020 Reviewer # 1 agreed at journal 19 Mar, 2020 Editor assigned by journal 10 Mar, 2020 Submission checks completed at journal 09 Mar, 2020 Editor invited by journal 09 Mar, 2020 First submitted to journal 06 Mar, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-17122","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":405076,"identity":"d113c9a6-f27f-4d2b-a2d8-9dff319a8254","order_by":1,"name":"Joseph Lin","email":"","orcid":"","institution":"Changhua Christian Medical Foundation Changhua Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Lin","suffix":""},{"id":405077,"identity":"c1617c2f-6564-4812-b0a7-4e2d0f856655","order_by":2,"name":"Sam Li-Sheng Chen","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sam","middleName":"Li-Sheng","lastName":"Chen","suffix":""},{"id":405078,"identity":"53bad731-f408-4916-8a45-a89378c29936","order_by":3,"name":"Dar-Ren Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDCCA1DagIGB8QGCS6QWZgM4F69OJC1sEkRp4Tt+9tmHjzsY5M3Ze49V/Ki5w8AvffwC88c23Fokz6Qbz5x5hsFwZ8+5tJs9x54xSPblFDAcxKPF4EAaMzNvG0OCwY0cs9uMDYcZDM7wJDAc3IZHy/lnzMx/QVruvzErJk7LDaAtjGBbeMyYIVrYD+DVInnjGTNjbxuD4YYzOcaSPccO80j28DAcOPsPtxa+82nMDD/bGOQNjp8x/PCj5rAcPw/7wwcVZ3BrgYL/cBYPEBkcIKgBDbA/IFXHKBgFo2AUDG8AACgAVS2w0BUeAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-0897-4374","institution":"Changhua Christian Medical Foundation Changhua Christian Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Dar-Ren","middleName":"","lastName":"Chen","suffix":""},{"id":405079,"identity":"47f8c113-a3f5-422d-992b-46c710b94391","order_by":4,"name":"Kuo-Juei Lin","email":"","orcid":"","institution":"E-Da Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kuo-Juei","middleName":"","lastName":"Lin","suffix":""},{"id":405080,"identity":"f48bea86-a20d-432b-938b-7ad7096a058c","order_by":5,"name":"Yu-Fen Wang","email":"","orcid":"","institution":"Changhua Christian Medical Foundation Changhua Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu-Fen","middleName":"","lastName":"Wang","suffix":""},{"id":405081,"identity":"13b774ce-eefb-44f9-9106-01012bea205a","order_by":6,"name":"Ling-Hui Huang","email":"","orcid":"","institution":"Changhua Christian Medical Foundation Changhua Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ling-Hui","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2020-03-11 11:30:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-17122/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-17122/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-020-06955-6","type":"published","date":"2020-05-20T21:12:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":643791,"identity":"27647d91-06ba-44c8-a1c0-dc12b4943fab","added_by":"auto","created_at":"2020-03-13 15:11:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46165,"visible":true,"origin":"","legend":"Flow chart of patients treated with NACT followed by surgical treatment.","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-17122/v1/Figure 1.png"},{"id":643792,"identity":"6d205294-9c9b-4112-b0dd-b85efcfe4c71","added_by":"auto","created_at":"2020-03-13 15:11:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44086,"visible":true,"origin":"","legend":"Complete pathologic response of NACT patients with BCS by molecular subtypes.","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-17122/v1/Figure 2.png"},{"id":643793,"identity":"0309bff6-ffd2-4ca2-a40e-f8b8e6a311f7","added_by":"auto","created_at":"2020-03-13 15:11:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":268914,"visible":true,"origin":"","legend":"Kaplan–Meier curves. The results demonstrated the relationship between surgical margins and locoregional recurrence-free survival and event-free survival, respectively. a and c, ≤ 2 mm versus \u003e 2 mm. b and d, \u003c 1 mm versus ≥ 1 mm.","description":"","filename":"FIgure3.png","url":"https://assets-eu.researchsquare.com/files/rs-17122/v1/FIgure 3.png"},{"id":13493608,"identity":"ec0a68ce-6a0d-4d7e-b7c3-891dc50b88e7","added_by":"auto","created_at":"2021-09-16 22:36:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":635141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-17122/v1/72fd6d28-cd0c-433f-9db1-af4fe252b17c.pdf"}],"financialInterests":"","formattedTitle":"Association of surgical margins with local recurrence in patients undergoing breast-conserving surgery after neoadjuvant chemotherapy","fulltext":[{"header":"Background","content":" \u003cp\u003eDespite the lack of overall survival benefits, the use of neoadjuvant chemotherapy (NACT) in early-stage breast cancer nonetheless manifests other advantages; as such, it converts patients into applicants for breast-conserving surgery (BCS) after lowering tumour volumes and reduces the use of axillary lymph node dissection [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Moreover, it allows the assessment of therapeutic response to a distinct chemotherapy regimen. The ultimate goals of BCS are complete removal of the breast tumour with adequate margins and simultaneous preservation of the natural shape of the breast [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Studies have demonstrated that a \u0026ldquo;no ink on tumour\u0026rdquo; lumpectomy margin is adequate for invasive breast cancer treated with BCS followed by whole-breast radiation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], but those patients display higher locoregional recurrence (LRR) rates than mastectomy patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Despite the increasing evidence demonstrating the feasibility of BCS after NACT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], the combined use of NACT and BCS has certainly drawn concerns of high LRR in patients with locally advanced breast cancer as reported by several studies [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, increased pathological complete response (pCR) rates with the use of newer therapeutic agents which was not translated into a higher rate of BCS may have attributed to the distraction in relation to the adequate margin on BCS after NACT [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The risk of LRR after BCS could be influenced by factors related to therapeutic strategies, tumour subtypes and surgical margin status. Negative margins reduce the risk of local recurrence, but to date, there is no consensus on what constitutes an adequate negative margin in BCS after NACT. The aim of the current study was to report a single-institution experience using BCS after NACT, focusing on the association between microscopic resection margin status and LRR, as this information can be crucial in improving surgical options after NACT considering the risks and potential benefits in this setting.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eThis study obtained approval from the Changhua Christian Hospital. In this study, patients with breast cancer receiving NACT from January 2008 to April 2018 were enrolled. Initial diagnosis of breast cancer was made through core needle biopsy with ultrasound guidance, through which information on receptor status was obtained using immunohistochemical staining. Disease stage was classified based on the 2010 staging system of the American Joint Committee of Cancer (AJCC) TNM criteria.\u003c/p\u003e \u003cp\u003eInformation on Ki-67 expression in pre-therapeutic core needle biopsies was not available until 2018\u0026nbsp;at our hospital, and histology grade was used as an alternative measurement to determine proliferation activity. Intrinsic subtypes were therefore determined as follows: luminal (ER\u0026thinsp;+\u0026thinsp;and/or progesterone receptor (PR) +, HER2\u0026ndash;, all grades), luminal HER2 (ER\u0026thinsp;+\u0026thinsp;and/or PR+, HER2+, all grades), HER2-type (ER\u0026ndash;, PR\u0026ndash; and HER2+) and triple negative (ER\u0026ndash;, PR\u0026ndash; and HER2\u0026ndash;) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImaging examinations to assess breast and lymph nodes included ultrasonography, mammography and magnetic resonance imaging (MRI); the largest dimension recorded from these examinations was defined as the tumour size. Indications for BCS remained homogenous during the study period: absence of multicentric disease or extensive microcalcification, lack of chest wall or skin involvement and predictable sufficiency of breast volume after BCS. Partial mastectomy specimens were sent to surgical pathologists for microscopic assessment. All patients underwent whole-breast radiation therapy for a total dose of 5000 cGY given in 25\u0026ndash;28 fractions with or without a boost to the primary tumour site. Both pre-NACT and post-NACT tumour size were determined by imaging (either MRI or ultrasonography). Our institutional definition of pCR was eradication of invasive cancer and in-situ cancer in the breast and axillary (ypT0 ypN0), which was consistent with the meta-analysis of Cortazar et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eHistological variants of breast carcinoma were classified into the following subtypes: (1) infiltrating ductal carcinoma (IDC), (2) infiltrating lobular carcinoma (ILC), (3) IDC\u0026thinsp;+\u0026thinsp;ductal carcinoma in situ (DCIS) (DCIS component\u0026thinsp;\u0026gt;\u0026thinsp;10%), (4) ILC\u0026thinsp;+\u0026thinsp;lobular carcinoma in situ (LCIS) (LCIS component\u0026thinsp;\u0026gt;\u0026thinsp;10%), (5) IDC\u0026thinsp;+\u0026thinsp;ILC or (6) others (mucinous, medullary, etc.). Primary tumour response to NACT was monitored by ultrasonography after each cycle of chemotherapy, and for tumours that have progressively decreased in size, an ultrasound-guided metallic marker insertion was done for future localisation.\u003c/p\u003e \u003cp\u003eAll specimens were oriented with sutures, dye-inked followed by sectioning at 3- to 5-mm intervals, and the smallest distance between the tumour edge and an inked normal tissue margin was measured using an ocular micrometre (to the nearest 1\u0026nbsp;mm if\u0026thinsp;\u0026gt;\u0026thinsp;2\u0026nbsp;mm distance or to the nearest 0.1\u0026nbsp;mm if\u0026thinsp;\u0026lt;\u0026thinsp;2\u0026nbsp;mm). An involved margin was defined as invasive disease at the inked resection margin, whereas uninvolved margins were classified microscopically and reported within a specified distance (\u0026gt;\u0026thinsp;2\u0026nbsp;mm, 1\u0026ndash;2\u0026nbsp;mm and \u0026lt;\u0026thinsp;1\u0026nbsp;mm) of the resection margin.\u003c/p\u003e \u003cp\u003eThe primary outcome of interest was any LRR that was defined as recurrence tumour in the ipsilateral breast parenchyma or metastatic disease in the internal mammary, ipsilateral axillary, infraclavicular or supraclavicular nodes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Secondary outcomes included event-free survival (free of LRR, distant metastasis and death). Time to event was defined as the interval from the definite surgery and the date of the first recurrence.\u003c/p\u003e \u003cp\u003eClinicopathological characteristics were compared by Mann\u0026ndash;Whitney \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eU\u003c/span\u003e test for medians and chi-square test for proportions. Kaplan\u0026ndash;Meier (KM) survival curves were generated to compare the survival outcomes according to the margin status and the use of MRI [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and two-sided log rank test was used to test the significant difference between survival experiences [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Statistical analysis was performed using MedCalc statistical software version 18.5 (MedCalc Software bvba, Ostend, Belgium), and a significance level of 5% was used in all analyses.\u003c/p\u003e "},{"header":"Results","content":" \u003cp\u003eA total of 555 cases were identified, but 127 were excluded because of the following reasons: stage IV breast cancer (n\u0026thinsp;=\u0026thinsp;65), bilateral breast cancer (n\u0026thinsp;=\u0026thinsp;12), lost to follow-up (n\u0026thinsp;=\u0026thinsp;13), expired without surgery (n\u0026thinsp;=\u0026thinsp;10) and on-going NACT (n\u0026thinsp;=\u0026thinsp;27). Of the remaining 428 patients, 172 patients (40.2%) had undergone BCS with radiotherapy and 256 (59.8%) underwent mastectomy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 172 BCS patients, 11 had involved margin based on pathological examination, and this left us with 161 patients for analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe median age of the studied population was 47.4\u0026nbsp;years (range 25.4\u0026ndash;87.3); 65 (40.4%) patients aged\u0026thinsp;\u0026ge;\u0026thinsp;50\u0026nbsp;years and 96 (50.6%) patients aged\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026nbsp;years. NACT comprised of 4\u0026ndash;6 courses of anthracycline-based (n\u0026thinsp;=\u0026thinsp;33, 20.5%), taxane-based (n\u0026thinsp;=\u0026thinsp;14, 8.7%), combined anthracycline-taxane-based (n\u0026thinsp;=\u0026thinsp;65, 40.4%) and HER2-targeted agents added regimens (n\u0026thinsp;=\u0026thinsp;46, 28.6%). IDC represented 145 (90.1%) of all patients, which was considered the most common histopathological type in this study. Statistical associations between the three margin groups and tumour characteristics are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003ePatient characteristics (n\u0026thinsp;=\u0026thinsp;161)\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eSurgical margin\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eCharacteristics\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eAll\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e(n\u0026thinsp;=\u0026thinsp;161) (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e\u0026lt;\u0026thinsp;1\u0026nbsp;mm\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e(n\u0026thinsp;=\u0026thinsp;28) (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e\u0026ge;\u0026thinsp;1\u0026nbsp;mm, \u0026lt; 2\u0026nbsp;mm\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e(n\u0026thinsp;=\u0026thinsp;21) (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e\u0026ge;\u0026thinsp;2\u0026nbsp;mm\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e(n\u0026thinsp;=\u0026thinsp;112) (%)\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eAge, year\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian (range)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e47.4\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(25.4\u0026ndash;87.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e51.7\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(27.6\u0026ndash;87.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.4\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(25.4\u0026ndash;68.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.9\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(27.6\u0026ndash;74.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e51.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e47.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;50\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e96 (59.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (46.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (57.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e71 (63.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.254\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026ge;\u0026thinsp;50\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e65 (40.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (53.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e41 (36.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eTumor size\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eT1 (\u0026le;\u0026thinsp;2\u0026nbsp;cm)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (11.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (10.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e14 (12.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.782\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2 (\u0026gt;\u0026thinsp;2\u0026nbsp;cm, \u0026le; 5\u0026nbsp;cm)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e132 (82.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e24 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e90 (80.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3 (\u0026gt;\u0026thinsp;5\u0026nbsp;cm)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e11 (6.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (3.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (7.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eLymph node status\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eNegative\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e34 (21.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (21.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (23.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e23 (20.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.944\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePositive\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e127 (78.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e22 (78.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (76.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e89 (79.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eHistological type\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIDC\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e145 (90.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e22 (78.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e19 (90.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e104 (92.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.152\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIDC\u0026thinsp;+\u0026thinsp;DCIS\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (7.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e4(14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (6.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eOthers\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (2.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (7.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (0.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eHistological grade\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ein situ\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (1.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (3.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (5.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.173\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eI\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e17 (11.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (5.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (11.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eII\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e77 (51.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (57.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (65.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e48 (47.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIII\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e54 (36.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (25.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (25.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e42 (41.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMissing\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e10\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eIntrinsic subtype\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLuminal\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e53 (32.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (32.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e11 (52.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e33 (29.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.379\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLuminal HER2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e41 (25.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e30 (26.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHER2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (13.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (17.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (11.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTNBC\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e46 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (21.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (19.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e36 (32.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eChemotherapy\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAnthracycline-based\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e33 (20.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (17.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (33.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (18.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.427\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTaxane-based\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e14 (8.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (7.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (8.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCombined anthracycline and taxane\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e65 40.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (35.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (33.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e48 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHER2 targeting agent contained\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e46 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (32.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (23.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e32 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eOthers\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (1.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (7.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (0.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eFollow-up, month\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian (range)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e34.7\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(5.3\u0026ndash;118.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e23.5\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(5.3\u0026ndash;105.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e39.3\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(7.7\u0026ndash;105.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e35.8\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(6.9\u0026ndash;118.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;31.8\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e36.1\u0026thinsp;\u0026plusmn;\u0026thinsp;29.5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;34.2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.2\u0026thinsp;\u0026plusmn;\u0026thinsp;31.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding histological grading, 17 cases (11.3%) were grade I, 77 cases (51.3%) were grade II, 54 cases (36%) were grade III and 11 cases did not have grade status. Luminal subtype represented 53 (32.9%) of all patients, triple negative, luminal HER2 and HER2 subtypes represented 46 (28.6%), 41 (25.5%) and 21 (13%) of all BCS patients, respectively. The median follow-up time was 47 months (range 25\u0026ndash;87). Thirty-eight patients (22.1%) achieved a pCR; overall pCR was 8.9% (5/56) in luminal subtype patients, 18.2% (8/44) in luminal HER2 subtype patients, 50% (12/24) in HER2 subtype patients and 27.1% (13/48) in triple negative breast cancer (TNBC) patients. Their pCR rates according to molecular subtypes are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the main partial mastectomy specimens available for analysis (n\u0026thinsp;=\u0026thinsp;161), 28 had margins\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026nbsp;mm, 21 had margin width of 1\u0026ndash;2\u0026nbsp;mm and the remaining 112 had margins\u0026thinsp;\u0026gt;\u0026thinsp;2\u0026nbsp;mm. Involved margins were reported in seven patients, and all of them underwent re-excision to obtain negative margins. Overall, LRR occurred in 16 patients (9.9%) and distant metastases were detected in 27 (16.8%) patients. Of these patients with LRR, an in-breast recurrence developed in 10 patients, five patients had nodal failure and one patient exhibited two sites of LRR simultaneously.\u003c/p\u003e \u003cp\u003eThere were 4 (4/28, 14.3%) LRR events in the \u0026lt;\u0026thinsp;1\u0026nbsp;mm margin cohort, 2 (2/21, 9.5%) in the 1\u0026ndash;2\u0026nbsp;mm group and 10 (10/112, 8.9%) in the \u0026gt;\u0026thinsp;2\u0026nbsp;mm group. There was no significant difference in the LRR between the \u0026gt;\u0026thinsp;2\u0026nbsp;mm margin group with a 60-month cumulative survival of 85.2% compared with 76.2% for the \u0026le;\u0026thinsp;2\u0026nbsp;mm group (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.335; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.a) in the KM analysis. When we stratified patients by margin widths of \u0026ge;\u0026thinsp;1\u0026nbsp;mm or \u0026lt;\u0026thinsp;1\u0026nbsp;mm, there was no LRR-free survival benefit observed for the \u0026ge;\u0026thinsp;1\u0026nbsp;mm pathologic excision margin group in the univariate analysis (hazard ratio\u0026thinsp;=\u0026thinsp;0.443; 95% confidence interval\u0026thinsp;=\u0026thinsp;0.142\u0026ndash;1.383; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.161) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) with a 60-month cumulative LRR-free survival of 84.9% compared with 69.5% for the \u0026lt;\u0026thinsp;1\u0026nbsp;mm margin cohort (\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.150; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.b). In the survival analysis for event-free survival, there was no significant difference for margins\u0026thinsp;\u0026gt;\u0026thinsp;2\u0026nbsp;mm versus \u0026le;\u0026thinsp;2\u0026nbsp;mm and no difference for \u0026ge;\u0026thinsp;1\u0026nbsp;mm versus \u0026lt;\u0026thinsp;1\u0026nbsp;mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.c-d).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eUnivariate logistic regression analysis of LRR-free survival and event-free survival\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eLRR-free survival\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003eEvent-free survival\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eVariables\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eHazard ratio\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e95%\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003econfidence interval\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eHazard ratio\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003e95%\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003econfidence interval\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAge, years\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u0026ge;\u0026thinsp;50 vs. \u0026lt; 50)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.013\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.368\u0026ndash;2.789\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.980\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.856\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.413\u0026ndash;1.775\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.676\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTumor size, cm\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u0026gt;\u0026thinsp;2 vs. \u0026le; 2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.270\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.167\u0026ndash;9.637\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.817\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.815\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.247\u0026ndash;2.686\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.737\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLymph node\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(positive vs. negative)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.682\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.609\u0026ndash;11.811\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.192\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.972\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.757\u0026ndash;5.135\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.164\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHistological grade\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(3 vs. 0\u0026ndash;2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.851\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.295\u0026ndash;2.453\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.766\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.098\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.520\u0026ndash;2.316\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.807\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eER\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(positive vs. negative)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.927\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.334\u0026ndash;2.574\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.884\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.884\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.435\u0026ndash;1.797\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.734\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePR\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(positive vs. negative)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.977\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.362\u0026ndash;2.633\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.963\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.926\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.456\u0026ndash;1.881\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.832\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHER2\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(positive vs. negative)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.555\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.583\u0026ndash;4.146\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.378\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.174\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.583\u0026ndash;2.361\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.654\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eKi-67 labelling index, %\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u0026ge;\u0026thinsp;14 vs. \u0026lt; 14)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e3.253\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.688\u0026ndash;15.388\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.137\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.950\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.756\u0026ndash;5.034\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.167\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSurgical margin, mm\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u0026ge;\u0026thinsp;1 vs. \u0026lt; 1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.443\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.142\u0026ndash;1.383\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.161\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.554\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.239\u0026ndash;1.284\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.169\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe logistic regression analysis analyses included age, lymph node status (positive vs. negative), histological grade, receptor status, Ki-67 index, pCR status and surgical margin distance. On the univariate analyses, these variables are independent of LRR-free survival and event-free survival (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Only lymph node status was found to be a significant predictor of event-free survival (hazard ratio\u0026thinsp;=\u0026thinsp;3.374; 95% confidence interval\u0026thinsp;=\u0026thinsp;1.020\u0026ndash;11.155; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.046) on multivariate analysis.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe introduction of target therapy and advancement of chemotherapeutic treatments have brought an increase in pCR rates, but BCS rates following NACT stay relatively unaffected [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], partly because an increase number of patients may opt for mastectomy treatments due to a lack of consensus on adequate margin in BCS after NACT. These findings may reflect discrepancies in practice among clinicians and guidelines with the consequence of re-excision to gain wider margins. In the present study, 428 women with untreated operable breast cancer received NACT from January 2008 to April 2018; 40.2% (n\u0026thinsp;=\u0026thinsp;172) of them underwent BCS and the remaining 59.8% (n\u0026thinsp;=\u0026thinsp;256) had mastectomy. In the present study, the overall BCS rate of 40.2% for patients was lower than that of 49.4% in the surgery first cohort from our previous study [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] despite comparable pCR rates of 22.1% with other studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This may have resulted from the higher LRR after BCS in patients who were treated with NACT [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], as one of our senior surgeons who performed more than half of the analysed BCS cases in this study had a BCS rate of 56%. This variation between surgeons in clinical practices further lends credence to the consensus on a safe margin width in this patient population.\u003c/p\u003e \u003cp\u003eIn our institution, diagnostic ultrasonography was performed by the operating surgeons after each cycle of NACT to evaluate tumour size and therapeutic response. Further, a metallic marker was only inserted in tumours that had progressively decreased in size for future localisation. Therefore, we have a lower rate of wire localisation due to an extensive usage of breast ultrasonography, and this low rate does not reflect the simplicity in choosing the optimal resected volume for complete tumour excision while preserving the cosmetic integrity of the breast. Moreover, most patients in this cohort underwent MRI before and after NACT, and this may give additional information in estimation of disease burden during the surgery as other studies suggested [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVolder et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] reported an involved margin rate of 24.3% in patients who received NACT and BCS, with additional 17.7% of patients with close (\u0026le;\u0026thinsp;1\u0026nbsp;mm) margin width identified in a nationwide pathologic study. Differences in therapeutic approaches among hospitals may have contributed to the high-observed margin rate (24.3%) in this population-based study. Others reported a lower rate of re-excision in primary chemotherapy. Christy et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] demonstrated that preoperative chemotherapy resulted in a significantly higher incidence of negative margins (90% vs. 55%; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and a lower re-excision rate (6% vs. 37%; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u003c/span\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared with primary surgery. Karanlik et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported that NACT was more likely to have negative margins (95% vs. 84%; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.02) and less likely receive re-excision (4% vs. 8%; \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eP\u0026thinsp;=\u003c/span\u003e\u0026thinsp;0.02) as well.\u003c/p\u003e \u003cp\u003eOur study also reported a low re-excision rate, re-excision surgery was given in 4.1% (7/172) of patients, and these seven patients all had an involved margin at the first place. Additional 14.5% (25/172) of patients with margin\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026nbsp;mm would have added to this re-excision rate (4.1\u0026thinsp;+\u0026thinsp;14.5\u0026thinsp;=\u0026thinsp;18.6%) if\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026nbsp;mm margin width was considered positive. The lower re-excision rate did not however bring a higher recurrence rate. Moreover, 16 patients (9.9%, 16/161) experienced LRR and 10 of them had breast-only local recurrence (6.2%, 10/161) during the follow-up. Our results were comparable to Mittendorf et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] who reported 5- and 10-years LRR of 7% and 10%, respectively. Our low re-excision rate did not correlate with a higher recurrence rate, and it was further supported by our multivariate analysis that failed to show the association between LRR and margin distance.\u003c/p\u003e \u003cp\u003eA few studies assessed the margin distance and outcomes in patients treated with BCS following NACT, and the results have been inconsistent. Chen et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported on 340 cases treated at MD Anderson Cancer Centre between 1987 and 2000 and discovered no association between 5-year LRR-free survival and margin distances (\u0026gt;\u0026thinsp;2\u0026nbsp;mm vs. \u0026le; 2\u0026nbsp;mm). LRR and ipsilateral breast tumour recurrence were correlated with advanced nodal involvement, residual tumour\u0026thinsp;\u0026gt;\u0026thinsp;2\u0026nbsp;cm, multifocal residual disease and lymphovascular space invasion. In contrast, the Institute Curie reported that an increased ipsilateral breast tumour recurrence was associated with margins\u0026thinsp;\u0026le;\u0026thinsp;2\u0026nbsp;mm in addition to clinical tumour\u0026thinsp;\u0026gt;\u0026thinsp;2\u0026nbsp;cm, age\u0026thinsp;\u0026lt;\u0026thinsp;40 and S-phase fraction\u0026thinsp;\u0026gt;\u0026thinsp;4% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The latest study by Choi et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] on 382 patients showed no association between margin width and local recurrence but rather related to intrinsic subtypes, lack of pCR and positive nodal status. Factors such as age, tumour size, lymph node status, surgical margin, histological grade, Ki-67 index and receptor status were not found to be significant predictors of LRR on univariate analysis in our study. This might have been attributed to our population size due to its insufficient power to detect a difference. However, the low LRR in the present study suggests that even though a statistically significant difference may be achieved by increasing the sample size, this difference may not be translated into a clinically meaningful consequence in the real world.\u003c/p\u003e \u003cp\u003eThe rates of pCR were highest in HER2 subtype patients (ER\u0026ndash;, PR\u0026ndash; and HER2+) with 50% followed by TNBC group with 27.1% in our study. While further analysis on pCR and prognosis stratified by subtypes would be statistically underpowered because of small sample size in our analysis, von Minckwitz in his meta-analysis of 6377 patients treated with NACT and BCS showed different prognosis among pCR patients stratified by subtypes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. They reported that pCR was associated with improved disease-free survival in luminal B/HER2 negative, HER2 and TNBC subtypes but not in luminal A or luminal HER2 breast cancer. This may suggest the importance of biologic characteristics of a tumour in achieving local control of breast cancer and the complete resection of the primary tumour may not be essential.\u003c/p\u003e \u003cp\u003eSSO-ASTRO introduced guidelines that suggested \u0026ldquo;no ink on tumour\u0026rdquo; as adequate margins for women with invasive breast cancer undergoing BCS, but this analysis did not include patients treated with NACT [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The purpose of the current study was to compare margin widths of \u0026gt;\u0026thinsp;2\u0026nbsp;mm, 1\u0026ndash;2\u0026nbsp;mm and \u0026lt;\u0026thinsp;1\u0026nbsp;mm in NACT patients after BCS and their association with recurrence rate. Our results did not support the idea that \u0026ge;\u0026thinsp;1\u0026nbsp;mm margins would decrease LRR, and it is important because it may reduce additional costs and psychological effect by minimising the need for re-excision [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study had a few limitations. First, this was a retrospective, single-institution study with a comparatively small sample size. Second, the enrolled patients were given different chemotherapy regimens based on the tumour subtype. Additionally, patients with HER2 subtype were underrepresented and it might limit the generalisability of the results. However, this study benefits from its real-world clinical data and a relative standardised strategy to surgical approach and to margin assessment procedure. Further studies with greater sample sizes are necessary to determine the safe surgical margin with NACT and BCS.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eThis study has shown no increase in LRR for surgical margins \u0026lt; 1 mm compared with margins \u0026ge; 1 mm. In the absence of multiple scattered microscopic tumour foci, a negative margin of no ink on tumour maybe sufficient for stage I\u0026ndash;III invasive breast cancer treated with NACT and BCS, and it is not necessary for re-excision if surgical width is \u0026lt; 1 mm.\u003c/p\u003e"},{"header":"List of Abbreviations","content":"\u003cp\u003eNACT, neoadjuvant chemotherapy; BCS, breast-conserving surgery; LRR, locoregional recurrence; pCR, pathological complete response; AJCC, American Joint Committee of Cancer; PR, progesterone receptor; MRI, magnetic resonance imaging; IDC, infiltrating ductal carcinoma; DCIS, ductal carcinoma in situ; ILC, infiltrating lobular carcinoma; LCIS, lobular carcinoma in situ; TNBC, triple negative breast cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval \u003c/strong\u003e\u003cstrong\u003eand consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrior to collecting clinical data from the patient\u0026rsquo;s medical record, a written informed consent was obtained from her. The study protocol was approved by the Institutional Review Board of Changhua Christian Hospital, Taiwan. All methods were carried out in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll datasets used or analysed for this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting \u003c/strong\u003e\u003cstrong\u003einterests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest relevant to the content of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have received no funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; \u003c/strong\u003e\u003cstrong\u003econtributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was designed by DRC. Clinical data acquisition and analysis were performed by JL, DRC, KJL, YFW and LHH. Statistical analyses were performed by JL, SLSC and YFW. The manuscript was written by JL, DRC and YFW. All authors read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Ms. Hung-Ting Lin, Ms. Yun-Cen Chen and Mr. Yung-Liang Yeh for their administrative and technical assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB, Jr., Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. 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Ann Oncol. 2011; 22(8):1736-47.\u003c/li\u003e\n\u003cli\u003evon Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012; 30(15):1796-804.\u003c/li\u003e\n\u003cli\u003eCortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE, Jr., Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014; 384(9938):164-72.\u003c/li\u003e\n\u003cli\u003eWapnir IL, Anderson SJ, Mamounas EP, Geyer CE, Jr., Jeong JH, Tan-Chiu E, Fisher B, Wolmark N. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol. 2006; 24(13):2028-37.\u003c/li\u003e\n\u003cli\u003eKaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc. 1958; 53(282):457-81.\u003c/li\u003e\n\u003cli\u003ePeto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977; 35(1):1-39.\u003c/li\u003e\n\u003cli\u003eLai HW, Chen CJ, Lin YJ, Chen SL, Wu HK, Wu YT, Kuo SJ, Chen ST, Chen DR. Does Breast Magnetic Resonance Imaging Combined With Conventional Imaging Modalities Decrease the Rates of Surgical Margin Involvement and Reoperation?: A Case-Control Comparative Analysis. Medicine (Baltimore). 2016; 95(22):e3810.\u003c/li\u003e\n\u003cli\u003eChen AM, Meric-Bernstam F, Hunt KK, Thames HD, Oswald MJ, Outlaw ED, Strom EA, McNeese MD, Kuerer HM, Ross MI, Singletary SE, Ames FC, Feig BW, Sahin AA, Perkins GH, Schechter NR, Hortobagyi GN, Buchholz TA. Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin Oncol. 2004; 22(12):2303-12.\u003c/li\u003e\n\u003cli\u003eChoi J, Laws A, Hu J, Barry W, Golshan M, King T. Margins in Breast-Conserving Surgery After Neoadjuvant Therapy. Ann Surg Oncol. 2018; 25(12):3541-7.\u003c/li\u003e\n\u003cli\u003eFischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the therapeutic approach. Radiology. 1999; 213(3):881-8.\u003c/li\u003e\n\u003cli\u003eJochelson MS, Lampen-Sachar K, Gibbons G, Dang C, Lake D, Morris EA, Morrow M. Do MRI and mammography reliably identify candidates for breast conservation after neoadjuvant chemotherapy? Ann Surg Oncol. 2015; 22(5):1490-5.\u003c/li\u003e\n\u003cli\u003eSung JS, Li J, Da Costa G, Patil S, Van Zee KJ, Dershaw DD, Morris EA. Preoperative breast MRI for early-stage breast cancer: effect on surgical and long-term outcomes. Am J Roentgenol. 2014; 202(6):1376-82.\u003c/li\u003e\n\u003cli\u003eVolders JH, Haloua MH, Krekel NM, Negenborn VL, Barbe E, Sietses C, Jozwiak K, Meijer S, van den Tol MP, the nationwide n, registry of h, cytopathology in the N. Neoadjuvant chemotherapy in breast-conserving surgery - Consequences on margin status and excision volumes: A nationwide pathology study. Eur J Surg Oncol. 2016; 42(7):986-93.\u003c/li\u003e\n\u003cli\u003eChristy CJ, Thorsteinsson D, Grube BJ, Black D, Abu-Khalaf M, Chung GG, DiGiovanna MP, Miller K, Higgins SA, Weidhaas J, Harris L, Tavassoli FA, Lannin DR. Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter. Ann Surg Oncol. 2009; 16(3):697-702.\u003c/li\u003e\n\u003cli\u003eKaranlik H, Ozgur I, Cabioglu N, Sen F, Erturk K, Kilic B, Onder S, Deniz M, Yavuz E, Aydiner A. Preoperative chemotherapy for T2 breast cancer is associated with improved surgical outcome. Eur J Surg Oncol. 2015; 41(9):1226-33.\u003c/li\u003e\n\u003cli\u003eMittendorf EA, Buchholz TA, Tucker SL, Meric-Bernstam F, Kuerer HM, Gonzalez-Angulo AM, Bedrosian I, Babiera GV, Hoffman K, Yi M, Ross MI, Hortobagyi GN, Hunt KK. Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy. Ann Surg. 2013; 257(2):173-9.\u003c/li\u003e\n\u003cli\u003eAl-Ghazal SK, Blamey RW, Stewart J, Morgan AA. The cosmetic outcome in early breast cancer treated with breast conservation. Eur J Surg Oncol. 1999; 25(6):566-70.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neoadjuvant, Breast-conserving surgery, Surgical margin, Recurrence","lastPublishedDoi":"10.21203/rs.3.rs-17122/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-17122/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground The aim of the current study was to report a single-institution experience using breast-conserving surgery after neoadjuvant chemotherapy (NACT), focusing on the association between microscopic resection margin status and locoregional recurrence (LRR). Methods Our institutional prospectively maintained database was reviewed to identify patients who were treated with NACT between January 2008 and April 2018. Results Among the main partial mastectomy specimens available for analysis (n = 161), 28 had margins \u0026lt; 1 mm, 21 had margin width of 1–2 mm and the remaining 112 had margins \u0026gt; 2 mm. LRR occurred in 16 patients (9.9%) and distant metastases were detected in 27 (16.8%) patients. There was no significant difference in the LRR between the \u0026gt; 2 mm margin group with a 60-month cumulative survival of 85.2% compared with 76.2% for the ≤ 2 mm group ( P = 0.335) in the Kaplan-Meier analysis. When we stratified patients by margin widths of ≥ 1 mm or \u0026lt; 1 mm, there was no LRR-free survival benefit observed for the ≥ 1 mm pathologic excision margin group in the univariate analysis (hazard ratio = 0.443; 95% confidence interval = 0.142–1.383; P = 0.161) with a 60-month cumulative LRR-free survival of 84.9% compared with 69.5% for the \u0026lt; 1 mm margin cohort ( P = 0.150). Conclusions In the absence of multiple scattered microscopic tumour foci, a negative margin of no ink on tumour maybe sufficient for stage I–III invasive breast cancer treated with NACT and breast-conserving surgery.\u003c/p\u003e","manuscriptTitle":"Association of surgical margins with local recurrence in patients undergoing breast-conserving surgery after neoadjuvant chemotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-03-13 15:11:54","doi":"10.21203/rs.3.rs-17122/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-04-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-04-05T12:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-04-05T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nThe authors hit an important issue of recurrence rates after neoadjuvant chemotherapy in correlation with the margins of the resected tumor specimen. We found a number of issues in this paper which we consider as critical for the decision of publishing it:\n\nIn the introduction, the definition of TNBC is missing ( ER, PR \u003c 1 % ? or 10 %, Her2 2+, FISH available?). A comparable low caseload over 10 years (16 patients per year only as an average number of patients eligible for this study) was recruited. Cutting down this caseload to different subtypes, the actual number of cases is too low to draw conclusions from. During this 10 years treatment modalities will have changed worldwide. Moreover, core biopsy - a standard before neoadjuvant chemotherapy - was only available from 2018 on, as Ki 67 was not in use routinely - both is a routine requirement. The tumor size has to measured at least in 2 diameters, not in 1 dimension only, as indicated in den manuscript. Interestingly, the rate of breast conserving therapy is very low with 40 %, whereas in our countries the rate is approximately 80 % (according to EUSOMA analyses, in which we took part). What is also striking, is the low rate of pCR of 22,1 %. Even in high proliferative tumors like TNBC, the rate of pCR is unacceptably low. On the other hand, the margin rates are comparably high at 24,3 %. There is no description on whether there has been a concentric or digital response of the tumours and whether multiple foci have been detected. Furthermore, each breast tumor should receive a marker, because of the risk of missing the tumor in case of a pathological near-response.\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **No**\n* Are the conclusions drawn adequately supported by the data shown?: **No**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I am able to assess the statistics**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"reviewerAgreed","content":"","date":"2020-04-04T12:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-03-30T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-03-30T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-03-20T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nThis paper addresses an important issue in contemporary surgical management of tumours following neoadjuvant chemotherapy (NACT). In the context of primary breast conserving surgery (BCS), margin status is considered a major predictor of ipsilateral breast tumour recurrence (IBTR) but no consensus on what constitutes an 'adequate' width of surgical margin existed until dual publication of an international consensus statement in 2014 (Moran M, et al. Ann Surg Oncol 2014l 3: 704 - 716 + JCO paper). BCS represents a balance between oncological mandates and cosmetic outcomes with surgeons aiming to excise tumour with 'negative' margins and acceptable cosmesis; the closer ink is to tumour, then the narrower are margins and a positive margin is associated with ink on cancer cells. Eva Singletary published one of the first major reviews of surgical margins almost 20 years ago and concluded that it was unacceptable to have tumour at the margin as positive margins were associated with a doubling of rates of IBTR compared with non-positive margins. However, there was no correlation between the width of surgical margin and rates of IBTR [SINGLETARY E, 2002]. This consensus on margins was based on a large meta-analysis involving 28,162 patients with invasive breast cancer and defined a relative category of 'close' with cancer cells between a defined distance (negative margin) and the surgical resection margins (no tumour at ink) [HOUSSAMI N, et al. Ann Surg Oncol 2014; 21: 717 - 730]. The odds ratio for IBTR was 1.98 [p\u003c0.001] for positive or close margins compared with negative margins and 2.44 [p\u003c0.0001] for positive versus negative margins. There was no statistical evidence that increase in margin width from 'no tumour at ink' to 1mm, 2mm or 5mm influenced odds of local recurrence with adjustment for follow up time. On the basis of this meta-analysis, no tumour at ink has been adopted around the world as the standard definition of a negative margin (although here in the United Kingdom the Association of Breast Surgery have chosen 1mm as the minimum distance due to the nuances of pathological examination).\n\nThis meta-analysis only applied to BCS in a primary context and not after NACT; it was emphasized previously that this consensus did not apply to neoadjuvant patients and until recently a 2mm margin was generally considered safer for declaration of a negative margin when BCS followed NACT. The St Gallen consensus conference (2017) endorsed no tumour at ink rather than 2mm, but this was not based on robust data. The authors of this paper have conducted a single centre study involving analysis of 161 patients undergoing BCS after NACT using several different chemotherapy schedules. This retrospective study covered the period from 2008 to 2018 during which time there has been great improvement in targeted therapies and rates of complete pathological response (pCR). It would appear there was no standard margin policy during this period for NACT patients and a range of margin distances were available and permitted this analysis (presumably based on a radial method for margin assessment as apposed to the shave method). Nonetheless, two-thirds of patients (112/161) had a margin width of \u003e2mm which is perhaps reassuring. Kaplan-Meier analysis has been used to compare rates of loco-regional recurrence (LRR) (9.9% overall) for margins of \u003e2mm versus ≤2mm. There was no significant difference in rates of LRR between these two margin categories with cumulative survival (60 months) of 85.2% and 76.2% respectively (p=0.335). Furthermore, there was no significant difference in rates of LRR for a margin width of ≥1mm versus \u003c1mm, although the number of events in each of these margin width categories was relatively small (4/28 recurrences for \u003c1mm group and 2.121 for the 1 - 2mm group. However, the analysis does support the conclusion of no significant differences in event-free survival analysis when comparing \u003e2mm with ≤2mm and ≥1mm with \u003c1mm. Rates of pCR (breast and axilla) were 22.1% overall but highest for HER2 positive (50%) and triple negative breast cancers (27.1%) and numbers were too small to permit any subgroup analysis to determine whether margin mandate should be based on tumour subtype (there is no evidence for this in the published literature to date).\n\nAll patients had a marker clip inserted in the tumour before commencement of NACT and localisation for impalpable tumours (on completion of chemotherapy) was undertaken with either a guide-wire or ultrasound with a 'senior' surgeon undertaking more than half of the cases of BCS in this study.\n\nThis study helps to provide clarification on the optimum margin width for BCS following NACT. The study is smaller than several other similar one involving about twice the number of cases (300 - 400), but the methodology and statistical analysis are robust.\n\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **Unable to assess**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I am able to assess the statistics**\n* Quality of written English: **Needs some language corrections before being published**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"reviewersInvited","content":"","date":"2020-03-19T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-03-19T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-03-10T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-03-09T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-03-09T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-03-06T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"93e3bedb-0eac-4d10-9e7f-a82451648c24","owner":[],"postedDate":"March 13th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":69736,"name":"Cancer Biology"},{"id":69737,"name":"Oncology"}],"tags":[],"updatedAt":"2021-07-22T21:12:42+00:00","versionOfRecord":{"articleIdentity":"rs-17122","link":"https://doi.org/10.1186/s12885-020-06955-6","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2020-05-20 21:12:42","publishedOnDateReadable":"May 20th, 2020"},"versionCreatedAt":"2020-03-13 15:11:54","video":"","vorDoi":"10.1186/s12885-020-06955-6","vorDoiUrl":"https://doi.org/10.1186/s12885-020-06955-6","workflowStages":[]},"version":"v1","identity":"rs-17122","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-17122","identity":"rs-17122","version":["v1"]},"buildId":"wLkW0s4AflPzk-lpfg-fK","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}