Preoperative chemotherapy for T2 breast cancer is associated with improved surgical outcome

Available online at www.sciencedirect.com

ScienceDirect EJSO 41 (2015) 1226e1233

www.ejso.com

Preoperative chemotherapy for T2 breast cancer is associated with improved surgical outcome H. Karanlik a,*, I. Ozgur b, N. Cabioglu c, F. Sen d, K. Erturk d, B. Kilic a, S. Onder e, M. Deniz a, E. Yavuz e, A. Aydiner d a

Surgical Oncology Unit, Institute of Oncology, Istanbul University, Istanbul, Turkey b Department of Surgery, Acibadem International Hospital, Istanbul, Turkey c Department of Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey d Medical Oncology Unit, Institute of Oncology, Istanbul University, Istanbul, Turkey e Department of Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Accepted 3 June 2015 Available online 21 June 2015

Abstract Background: The aim of this study is to compare the clinical outcome in T2 breast cancer patients who underwent preoperative chemotherapy (PC) and who did not. The study also tried to define a subgroup of patients, who are more beneficial after PC in terms of lower re-excision rates, better cosmetic results and local recurrence free survival. Materials and methods: 251 consecutive patients treated for nonmetastatic T2 invasive breast cancer were analyzed retrospectively. Of those; 141 underwent primary surgery (PS) followed by chemotherapy, whereas 110 were treated with combination of PC and surgery. Results: The patients who were treated with PC had a significantly higher incidence of negative margins and lower rate of re-excision (5% vs. 16%, p ¼ 0.02). Of all patients attempted breast conserving surgery (BCS), patients in the PC group were more likely to undergo BCS as their definitive operation compared to patients with PS group (BCS rates; PC group: 99% vs. PS group: 92%, p ¼ 0.05). Multifocal disease (OR: 7, 95% Cl, 2.7e18.4, p ¼ 0.0001) and PC (OR ¼ 0.2; 95% CI, 0.06e0.72, p ¼ 0.01) were factors associated with margin positivity in patients treated with BCS. There was no statistically significant difference in 5 year local-recurrence free survival rates between 2 groups. Conclusions: Our study shows that PC significantly decreases the re-excision in patients undergoing BCS with primary T2 breast tumors. This data suggests that any patient with a tumor greater than 2 cm might be considered for PC to increase BCS success with final negative margins. Ó 2015 Published by Elsevier Ltd.

Keywords: Preoperative chemotherapy; Breast cancer; T2 breast tumor

Introduction According to the prospective, randomized trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP B18 and B27), patients undergoing preoperative chemotherapy (PC) do not exhibit significant benefit with respect to survival outcome when compared to patients undergoing adjuvant chemotherapy (AC).1e4 However, PC treatment regimen confers multiple other advantages to the * Corresponding author. Istanbul University, Institute of Oncology, Surgical Oncology Unit, Capa 34193, Istanbul, Turkey. Tel.: þ90 532 402 5354; fax: þ90 212 534 8078. E-mail address: [email protected] (H. Karanlik). http://dx.doi.org/10.1016/j.ejso.2015.06.003 0748-7983/Ó 2015 Published by Elsevier Ltd.

patients. Firstly, PC provides important independent prognostic information by monitoring in vivo tumor response. Previous studies demonstrated improved overall survival was associated with pathological complete response as determined by disappearance of invasive cancer in the excised breast and lymph nodes.2,3 Furthermore, in nonreponders to initial PC regimen, a new chemotherapy regimen could be considered that could afford better results.4 However, it is not possible to measure the tumor response in patients undergoing AC because the primary tumor and lymph nodes have been removed. Breast conserving surgery is the preferred modality for early stage breast cancer, even though there is no significant difference in survival outcome compared to mastectomy.5,6

H. Karanlik et al. / EJSO 41 (2015) 1226e1233

Although achievement of negative surgical margins is the most important factor to minimize the local recurrence in breast-conserving surgery,7 cosmetic outcome should also be considered. However, excision of a greater tissue volume to obtain negative margins might compromise cosmetic outcome.8,9 Improved local control after breast conservation was associated with increased use of systemic therapies including chemotherapy and hormonal therapies, and age >50, but not margin width.10,11 Therefore, breastconserving operations should aim for excision of the smallest volume of tissue while attaining negative margins. These findings have motivated increased study and utilization of preoperative chemotherapy. For patients with smaller breast cancers, however, uncertainty remains regarding indications for, and benefits of, preoperative systemic therapy. Because these patients were initially before PC thought to be candidates for breast-conserving therapy, the advantage associated with preoperative therapy is unclear. Furthermore, the tumor might disappear followed by PC, and there might be difficulties to localize the lesion if the tumor was not marked with a clip before starting with chemotherapy. By reducing the size of the primary tumor, preoperative chemotherapy may contribute to a decrease in the rate of re-excision after partial mastectomy; however, little data is available in the literature to support this hypothesis. It is also not clear if there is an advantage of PC in these patients with T2 breast cancer according to their tumor features. The aim of this study is to determine the effect of preoperative chemotherapy on the rate of reexcision, local recurrence and cosmetic outcomes after BCS in patients with primary T2 tumors. Material and methods A retrospective analysis of the medical records identified 262 consecutive patients who underwent mastectomy or breast conserving surgery for nonmetastatic T2 invasive breast cancer between December 2008 and September 2011. Of those, 11 patients were excluded from the study. The exclusion criteria were incomplete data (n ¼ 10) and male gender (n ¼ 1) (Fig. 1). Of the remaining 251 patients, 110 received preoperative chemotherapy (PC) followed by surgery, whereas breast conserving surgery was initially attempted according to the clinical and biological features of the tumor, axillary status, and patient or physician preferences. Patients were histopathologically diagnosed by core biopsy and were eligible if the tumor was clinically measured between 2 and 5 cm. Exclusion criteria were male gender, diagnosis with excisional biopsy or no definitive surgery. Study variables included age, histology, clinical stage, pathologic tumor size and lymph node status, menopausal status, tumor grade, estrogen receptor (ER), progesterone receptor (PgR) and HER-2 status, lymphovascular invasion (LVI), necrosis, type of chemotherapy, pathological response in the breast and axillary lymph nodes, surgical details, microscopic evaluation of surgical

1227

Figure 1. Diagram of the study.

margins, re-excision rates, and information regarding recurrence-free survival. This study was approved by the Institutional Review Board of the Institute of Oncology, University of Istanbul. Evaluation and treatment modalities Our multidisciplinary team coordinated patient care and reviews clinical presentation, imaging studies, and histopathologic data before determining the appropriate course of treatment. Patient age, tumor features, clinical stage, and patient or physician preference were used to individualize treatment. Tumors were evaluated by appearance on clinical examination, mammography, ultrasound and magnetic resonance imaging (MRI). Ultrasonography was used to evaluate tumor size for all patients. Patients in primary chemotherapy group were evaluated with MRI both before and after chemotherapy. All radiological evaluation was performed by the same radiologist at our institute. Preoperative chemotherapy was considered for patients with invasive tumors according to the clinical and biological features of the tumor, axillary status, and patient or physician preferences. Patients who received preoperative chemotherapy underwent metallic marker placement at the center of the primary tumor, as we have previously described.12

1228

H. Karanlik et al. / EJSO 41 (2015) 1226e1233

All patients in PC group received an anthracycline-based chemotherapy regimen, which included:

Trastuzumab was administered in all HER-2 positive patients for 1 year.

(1) 4AC þ 4T (105 patients): 60 mg/m2 doxorubicin and 600 mg/m2 cyclophosphamide on day 1, respectively, every 21 days for 4 cycles, followed by 100 mg/m2 docetaxel on day 1, every 21 days for 4 cycles. (2) TAC (5 patients): 75 mg/m2 docetaxel on day 1, 60 mg/ m2 doxorubicin on day 1, 600 mg/m2 cyclophosphamide on day 1, every 21 days for 6 cycles. (3) Trastuzumab: after an 8 mg/kg loading dose, 6 mg/kg trastuzumab were given on day 1, every 21 days for 1 year.

Data analysis

Patients were scheduled to undergo surgery 3e4 weeks after PC, either breast conserving surgery or mastectomy based both on surgeon and patient discretion, and level I and II axillary dissection if the pre-chemotherapy lymph node involvement was present in fine needle aspiration biopsy (FNAB). Patients in the primary surgery (PS) group underwent breast conserving surgery or mastectomy. Sentinel lymph node biopsy (SLNB) was performed in patients with clinically negative axilla. Axillary dissection was performed in patients having positive SLNB and patients who were preoperatively diagnosed as having pathologically positive lymph node via FNAB. Pathologic specimens were oriented by the surgeon intraoperatively and color coded by the pathologists. Specimens were serially sectioned at 2e3 mm intervals, and the distance from the tumor to the closest margin was measured. Macroscopic evaluation after inking the specimen along with frozen section analysis in selective cases was utilized for intraoperative margin assessment. If the tumor was closer than 5 mm on frozen section macroscopically, the margin was accepted as close. Cavity shaving was performed for all patients with close or positive margins in both groups. Patients having positive margins on final pathology were considered for re-excision or mastectomy as a second procedure. Pathological complete response (pCR) was evaluated based on the resected specimen after PC. Pathological specimens with no residual invasive carcinoma cells in the original tumor or lymph nodes were classified as pCR. Tumors with residual carcinoma in situ were included in the pCR group. Patients with mastectomy were given 50 Gy to the chest wall and 46e50 Gy to adjacent lymphatic regions in all PC group and in PS group with axillary lymph node metastasis. Patients with breast conservation received 46e50 Gy radiation to the whole breast as tangential fields and a boost to the tumor bed of 10e14 Gy in both groups. Regional lymph node irradiation was added to radiation field in PS group when patient had lymph node metastasis and in all PC group patients after breast conserving surgery. Tamoxifen (20 mg/day), anastrozole (1 mg/day) or letrozole (2.5 mg/ day) was given to ER- and/or PgR-positive patients for 5 years according to the standard practice at that time.

Demographic, clinical, and pathological data were gathered. Intraoperative data including resection volume and the rate of intraoperative re-excision was recorded. To assess the associations between the documented variables and margin status or the need for re-excision or mastectomy, each parameter was tested by using the Fisher’s exact test or Chi-square test in two-tailed univariate analyses. In addition, a stepwise reverse logistic regression model was used to assess the significant associations in a multivariate model. The dependent variable was re-excision or mastectomy as a 2nd procedure due to margin positivity. Independent variables included the various clinicopathologic variables. Age was dichotomized as 45 years versus >45 years whereas clinical tumor size was divided into 3 groups (21e30 mm, 31e40 mm, and 41e50 mm). Results were reported as odds ratio (OR) with 95% confidence intervals (CIs). Recurrence-free survival was defined as the time from the date of surgery until the first determined local recurrence or last follow-up. The duration of local recurrence free survival was analyzed by the KaplaneMeier method, and their differences were assessed using the log-rank test. The Statistical Package for the Social Sciences (SPSS) program, version 22.0 (SPSS Inc., Chicago, IL, USA) was used in statistical analyses. A p value equal or less than 0.05 was considered as statistically significant. For cosmetic evaluation, patient and patients’ pictures were evaluated by 2 independent nurses (at median 12 months, minemax: 6e36 months) and classified using 4 category scales: excellent, good, fair, and poor (Harvard scale).13e15 Results Patient demographic and tumor characteristics 262 patients were included in the study based on inclusion criteria specifying clinical and radiological findings. Eleven cases were excluded from the analysis. Therefore, 251 patients were analyzed; 110 underwent preoperative chemotherapy and 141 underwent primary surgery. Patients in the PC group were younger and more likely to be premenopausal than patients in the surgery first group, but the differences were not found to be statistically significant. The patient and tumor characteristics are shown in Table 1. The clinical presentation of patients in the PC group was more advanced than that of patients in the PS group although all patients had T2 tumor size. Patients in the PC group presented with a larger mean tumor size (PCgroup, 38.4 mm; versus 30.7 mm, p < 0.0001) and more lymph node positivity ( p ¼ 0.04) with clinical and radiological examination at the presentation. The histopathological factors were similar with respect to predominant

H. Karanlik et al. / EJSO 41 (2015) 1226e1233 Table 1 Clinical and tumor characteristics of patients. Primary surgery (n ¼ 141) Mean age, years 52.5  14 Menopausal status Pre-/perimenopausal 61 (43%) Postmenopausal 80 (57%) BMI, mean, SD 25.1  4.6 Education level Primary school or less 92 (65%) High school or more 49 (35%) Tumor localization quadrant Outer upper 57 (40.4%) Outer lower 30 (21.3%) Inner upper 20 (14.2%) Inner lower 19 (13.5%) Central/overlapping 15 (10.6%) Histology Invasive ductal 116 (82.3%) Invasive lobular 6 (4.2%) Mixed type 19 (13.5%) Mean tumor size, mma 30.7  9 Mean tumor size, mmb 31.2  11 CN Negative 64 (45%) Positive 77 (55%) Multifocality Yes 28 (20%) No 113 (80%) Lymphovascular invasion Yes 58 (41%) No 83 (59%) Extensive intraductal component (EIC) Yes 83 (59%) No 58 (41%) Estrogen receptor Positive 119 (84%) Negative 22 (16%) Progesterone receptor Positive 107 (76%) Negative 34 (24%) HER-2/neu status Positive 29 (21%) Negative 112 (79%)

Preoperative chemotherapy (n ¼ 110)

p value

49.9  11.9

0.08

53 (48%) 57 (52%) 26.3  4.2

0.6 0.63

67 (61%) 43 (39%)

0.6

45 28 15 12 10

(40.9%) (25.5%) (13.6%) (10.9%) (9.1%)

0.75

98 (89.1%) 3 (2.7%) 9 (8.2%) 38.4  8.9 17.3  12.1

0.18 <0.0001 <0.0001

34 (31%) 76 (69%)

0.04

28 (25%) 82 (75%)

0.38

48 (44%) 62 (56%)

0.7

71 (64%) 39 (36%)

0.15

76 (69%) 34 (31%)

0.004

63 (57%) 47 (43%)

0.003

26 (24%) 84 (76%)

1229

response rate correlated significantly with prechemotherapy tumor size; it was 81% (25/31) for tumors where the maximum diameter rounded off to 3 cm, 50% (12/24) for 4 cm tumors, and 7% (4/55) for 5 cm tumors ( p < 0.01), respectively. 54 (49.1%) patients were node positive and 56 (50.9%) were node negative after PC. Preoperative chemotherapy resulted in 24 node negative patients out of 76 clinically node positive patients. Two patients who were initially diagnosed clinically node negative turned to be node positive in pathology specimens. Surgical outcomes A slightly higher percentage of patients in the PS underwent BCS as their initial surgery, but this was not statistically significant ( p ¼ 0.09). The final surgical therapy was not different between groups ( p > 0.05). The surgical outcomes of 196 patients who underwent initial BCS are shown in Table 2. The patients in the PC group were more likely to have negative margins and less likely to undergo re-excision for a positive/close margin (PC, 5% vs. PS, 16%, p ¼ 0.02) compared to patients in the PS group. Furthermore, of 18 patients in the PS group who underwent re-excision, 9 required mastectomy, whereas of 4 patients in the preoperative chemotherapy group that required reexcision, only one had a mastectomy. Therefore, of all patients undergoing initial BCS, a much greater percentage in the preoperative chemotherapy group ended up with BCS as their definitive operation (99% vs. 92%, p ¼ 0.05). The re-excision rates for the all BCS patients differed by tumor size and treatment group as follows: 11% for 21e30 mm tumors, 19% for 31e40 mm tumors, and 14% for 41e50 mm tumors in the PS group. In the PC group, however, re-excision was needed only in 7% of tumors with a size between 41 and 50 mm tumors. Therefore, PC decreased the rate of re-excision in all tumor diameter Table 2 Surgical outcomes of patients.

0.65

a

Before surgery or chemotherapy according to the clinical and radiological findings. b Tumor size measured from pathologic specimens.

histology, histological grade, and HER-2/neu status. There was a high rate of poorly differentiated tumors in both groups. Patients in the PS group were more likely to have estrogen and progesterone receptor positivity than patients in the PC group ( p < 0.01). PC resulted in a clinical response in all 98% (108 of 110) of patients. Of these, 54% (59 of 110) had a clinical complete response and 44% (49 of 110) had a clinical partial response. The remaining 2% (2 of 110) had either stable disease or disease progression and were classified as nonresponders. Overall 37% (41 of 110) of patients had a pathologic complete response. The pathologic complete

Primary surgery (n ¼ 141) Initial operation Breast conserving 116 (82%) surgery Mastectomy 25 (18%) 158.1  58.2 Volume of initial excised specimen, cm3 Cavity shaving Yes 36 (31%) No 80 (69%) Re-excision/mastectomy as a 2nd procedure Yes 18 (16%) No 98 (84%) Final operation Breast conserving 107 (76%) surgery Mastectomy 34 (24%)

Preoperative chemotherapy (n ¼ 110)

p value

80 (73%) 30 (27%) 132.2  50.4

0.09 0.04

25 (31%) 55 (69%)

0.1

4 (5%) 76 (95%)

0.02

79 (72%) 31 (28%)

0.9

1230

H. Karanlik et al. / EJSO 41 (2015) 1226e1233

groups. The initial excised volumes were also lower in PC group ( p ¼ 0.04, Table 2). PC increased breast conserving surgery ratio from 81% to 95.8% in 31e40 mm tumors and from 59.1% to 63.6% in 41e50 mm tumors according to tumor size. Cosmetic outcome as good/excellent was found to be better in the PC (92%) group compared to PS group (80%) ( p ¼ 0.03). Median duration of follow up was 55.9 months (minemax, 20e74 months). The 5-year local recurrence free survival rates were not different between 2 groups (97.9% in PS group vs 97.3% in PC group, p ¼ 0.8) (Fig. 2). Factors effecting re-excision rates were further investigated in patients treated with BCS. Age, preoperative chemotherapy, presence of multifocality and histologic type was found to be statistically significant in univariate analysis (Table 3). Multivariate analysis showed that patients with multifocality (vs unifocality; OR ¼ 7; 95% CI, 2.7e18.4, p ¼ 0.0001) were more likely, and patients receiving preoperative chemotherapy (vs primary surgery; OR ¼ 0.2; 95% CI, 0.06e0.72, p ¼ 0.01) were less likely to have margin positivity and re-excision/mastectomy compared to others (Table 4). Discussion Patients who underwent breast conserving surgery after PC had a lower rate of positive margins, smaller lumpectomies, and re-excisions despite an initial clinical presentation at a more advanced clinical stage. Several prospective, randomized clinical trials have shown that there is no difference in overall survival between patients treated with PC and treated with PS.1,2,4 Breast cancer treatment cannot be evaluated simply as overall survival. It effects every aspect of patients’ quality of life.5,10 Higher rates of breast conservation after PC was demonstrated in the NSABP B18 study for stage T2 (71% for PC versus

Table 3 Factors affecting margin positivity in BCS patient. Margin positive Preoperative chemotherapy Yes 4 (5%) No 18 (15.5%) Age 45 14 (20%) >45 8 (6.3%) Clinical tumor size 21e30 mm 11 (10.2%) 31e40 mm 4 (10%) 41e50 mm 7 (14.6%) cN N() 10 (11.2%) N(þ) 12 (11.2%) Histology Invasive ductal 17 (9.7%) Invasive lobular 2 (50%) Mixed 3 (17.6%) Multifocality Yes 12 (32.4%) No 10 (6.3%) Lymphovascular invasion Yes 7 (7.6%) No 15 (14.4%) Extensive intraductal component Yes 14 (12%) No 8 (10%) Estrogen receptor Positive 19 (12.3%) Negative 3 (7.3%) Progesterone receptor Positive 17 (12.6%) Negative 5 (8.2%) HER2-neu Positive 5 (11.1%) Negative 17 (11.3%)

Margin negative

p value

76 (95%) 98 (84.5%)

0.02

56 (80%) 118 (93.7%)

0.004

97 (89.9%) 36 (90%) 41 (85.4%)

0.7

79 (88.8%) 95 (88.8%)

0.99

158 (90.3%) 2 (50%) 14 (82.4%)

0.03

25 (67.6%) 149 (93.7%)

0.0001

85 (92.4%) 89 (85.6%)

0.1

102 (88%) 72 (90%)

0.9

136 (87.7%) 38 (92.7%)

0.4

118 (87.4%) 56 (91.8%)

0.4

40 (88.9%) 134 (88.7%)

0.98

63% for PS) tumors despite a larger clinical tumor size at initial presentation.1 Bonadonna et al.2 reported 89% breast conservation for stage T2 breast tumors. Boughey et al.16 also reported higher BCS rate (44% versus 33%) in stage T2 breast tumors between 2 group of patients either receiving PC or PS. Christy et al.17 found a statistically significant higher breast-conserving operation rate (64% versus 45%; p ¼ 0.05) in patients receiving PC versus surgery group with stage T2 2e4 cm breast tumors. Our study demonstrated increased BCS rate in PC group compared to surgery alone. Although there are too many factors

Table 4 Logistic regression analysis for factors associated with margin positivity in patients with breast conserving surgery.

Figure 2. 5-year local recurrence free survival rates.

Age (45 vs > 45) Preoperative chemotherapy (yes vs no) Multifocality (yes vs no) Histology (IDC vs ILC)

Odds ratio

95% CI

p value

0.4 0.2

0.14e1.12 0.06e0.72

0.08 0.01

7 2.6

2.7e18.4 0.7e9.8

<0.0001 0.16

H. Karanlik et al. / EJSO 41 (2015) 1226e1233

effecting BCS rate, such different rates in these studies may be explained due to patients’ or physicians’ desire to save the breast. More randomized trials should be conducted to figure out variables. Several studies examined adverse effects of excessive tissue resection and cosmetic outcomes. Poor cosmesis after breast conservation is determined to be the result of larger excision volumes and need for re-excisions of the tumor bed.8,9,18 Also rate of re-excision is reported to be between 24 and 57%,19e21 and additional surgery is required in nearly half of the patients to achieve negative margins.22e24 Every additional surgery interferes with cosmetic outcome worse and brings extra anxiety, annoyance and cost. Our study demonstrated lower excision volume which ended up as better cosmetic outcome at the PC group. PC is shown to reduce the re-excision rate after BCS. Sadetzki et al. reported 10% of re-excision rate following PC in stage II and III breast tumors.25 Similarly reexcision rate was 12.4% in German GEPARDUO trial.26 The need for re-excision rate in our study was smaller in the PC group compared to PS group (16% vs. 5%). Retrospective nature of our study brings some limitations. Both groups are not completely comparable. Since PC group have larger and more aggressive tumors the rates of positive margins and re-excisions are to be expected to be higher. However, re-excision rates were surprisingly found to be lower in the PC group than PS group that makes our data more remarkable and valuable. The will and motivation for BCS was different between two groups. It was affected by both objective and subjective criteria and the will was towards mastectomy even though BCS was technically feasible. Of the 30 patients in the chemotherapy group who underwent initial mastectomy, only 2 were due to lack of response to chemotherapy. The others were due to multifocal disease, or patient’s choice. The breast size to tumor ratio also influenced both the surgeon’s and patient’s decision between mastectomy and breast conservation. Initial tumor size was found to be related to rate of breast conservation. This rate is similar in patients who received PC and patients with primary surgery. When we categorize our patients according to the tumor size, breast conservation rate decreases with increasing tumor size in the PS group, however, in PC group, primary tumor size was not effective. Newman et al. reported initial tumor size was not to be predictive for BCS which differs from our study.27 Sadetzki et al. described postchemotherapy tumor size as predictor of successful local control.25 The meta-analysis done by Mauri et al. reported higher local recurrence rates in patients receiving PC before surgery compared to post-surgery chemotherapy patients.28 The higher local recurrence in PC group can be explained due to inadequate resection of tumor involved margins which appear normal during surgery but containing tumor deposits within fibrotic breast tissue. The advantage of PC prior to surgery is the chance to achieve negative margins while resecting less tissue due to tumor shrinkage. Lannin et al.29

1231

reported the required tissue resection volume to be to 4 times greater than the tumor itself for 3e5 cm tumor. So PC gives the chance to achieve negative margins while resecting smaller volumes even you resect the entire involved breast tissue. Breast cancer tumor size assessment is important both as a prognostic factor and as a therapeutic identifier. Some studies show high correlation between tumor specimen size and tumor size on MRI,30e32 but it is accepted to combine all radiologic imaging methods and clinical examination to assess the tumor size.33,34 It was our chance to have a specialized radiologist working at our unit. All patients were evaluated by the same specialized breast radiologist in our unit prior to operation to lessen the bias in terms of radiologic evaluation. At centers that do not possess that occasion it is difficult to obtain the standardization due to variety in radiologic methods and being evaluated by different radiologists. Despite that effort tumor size assessment may bring some limitations to the study. As margin involvement is associated with local recurrence control, it is preferred to re-excise involved margins.35 Our study demonstrated worse prognostic factors for PC group. Both groups have similar tumor size, but PC group has lower receptor positivity rate and higher axillary positivity. Therefore, local recurrence could be expected to be higher in PC group. Despite those poor prognostic factors in the PC group, no difference was found in local recurrence rates between both groups. Risk factors associated with positive margins were investigated in several studies. Age, family history, large tumor size, nodal involvement, presence of LVI, extensive intraductal component, and ductal or lobular extension were reported to be associated with positive margins.7 Two studies reported increased margin involvement with increase in tumor size.22,36 Several studies have also shown an association between lobular carcinoma and positive margins.23,37,38 We investigated the clinical and pathological factors associated with margin positivity. Age, not having received preoperative chemotherapy, multifocality and lobular histologic type were significantly found to be associated with increased margin positivity in univariate analyses. Furthermore, multifocality and not having received PC remained as significant factors associated with margin positivity in multivariate analyses. Breast conservation surgery and mastectomy offer patients equal survival whereas BCS gives a better quality of life. Our data shows that PC significantly decreases the rate of re-excision in patients undergoing BCS with primary T2 tumors. Our findings suggest any patient with T2 breast tumor could be oncologically safely considered for PC even if BCS is feasible. Conflict of interest The authors of this piece identify that there is no conflict of interest to claim.

1232

H. Karanlik et al. / EJSO 41 (2015) 1226e1233

Funding source No particular funding source was obtained for the development and conducting of this study. Ethical approval This study meets the standards of ethical approval of the University of Istanbul. References 1. Fisher B, Brown A, Mamounas E, et al. 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. J Clin Oncol 1997;15:2483–93. 2. Bonadonna G, Valagussa P, Brambilla C, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998;16:93–100. 3. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B18. J Natl Cancer Inst Monogr 2001;30:96–102. 4. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003;21:4165–74. 5. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002 Oct 17;347(16):1233–41. 6. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002 Oct 17; 347(16):1227–32. 7. Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002; 184:383–93. 8. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992;10:356–63. 9. Cochrane RA, Valasiadou P, Wilson AR, Al-Ghazal SK, Macmillan RD. Cosmesis and satisfaction after breast-conserving surgery correlates with the percentage of breast volume excised. Br J Surg 2003;90:1505–9. 10. Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with earlystage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014 Mar;21(3):717–30. http:// dx.doi.org/10.1245/s10434-014-3480-5 Epub 2014 Jan 29. 11. Cabioglu N, Hunt KK, Buchholz TA, et al. Improving local control with breast-conserving therapy: a 27-year single-institution experience. Cancer 2005 Jul 1;104(1):20–9. 12. Asoglu O, Muslumanoglu M, Igci A, et al. Breast conserving surgery after primary chemotherapy in locally advanced breast cancer. Acta Chir Belg 2005;105:62–8. 13. Cardoso MJ, Cardoso JS, Vrieling C, et al. Recommendations for the aesthetic evaluation of breast cancer conservative treatment. Breast Cancer Res Treat 2012 Oct;135(3):629–37. http://dx.doi.org/ 10.1007/s10549-012-1978-8 Epub 2012 Feb 4. 14. Oliveira HP, Cardoso JS, Magalh~aes A, Cardoso. Methods for the aesthetic evaluation of breast Cancer conservation treatment: a technological review. Curr Med Imaging Rev 2013;9:32–46.

15. Cardoso MJ1, Oliveira H, Cardoso J. Assessing cosmetic results after breast conserving surgery. J Surg Oncol 2014 Jul;110(1):37–44. http:// dx.doi.org/10.1002/jso.23596 Epub 2014 Mar 13. 16. Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg 2006;244:464–70. 17. Christy CJ, Thorsteinsson D, Grube BJ, et al. Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter. Ann Surg Oncol 2009 Mar;16(3):697–702. http://dx.doi.org/10.1245/s10434-008-0268-5 Epub 2009 Jan 9. 18. 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. 19. Anscher MS, Jones P, Prosnitz LR, et al. Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy. Ann Surg 1993;218(1):22–8. 20. Mullenix PS, Cuadrado DG, Steele SR, et al. Secondary operations are frequently required to complete the surgical phase of therapy in the era of breast conservation and sentinel lymph node biopsy. Am J Surg 2004;187(5):643–6. 21. Swanson GP, Rynearson K, Symmonds R. Significance of margins of excision on breast cancer recurrence. Am J Clin Oncol 2002;25(5): 438–41. 22. Tartter PI, Bleiweiss IJ, Levchenko S. Factors associated with clear biopsy margins and clear reexcision margins in breast cancer specimens from candidates for breast conservation. J Am Coll Surg 1997;185(3): 268–73. 23. Smitt MC, Nowels KW, Zdeblick MJ, et al. The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995;76(2):259–67. 24. Mirza NQ, Vlastos G, Meric F, et al. Predictors of locoregional recurrence among patients with early-stage breast cancer treated with breast-conserving therapy. Ann Surg Oncol 2002;9(3):256–65. 25. Sadetzki S, Oberman B, Zipple D, et al. Breast conservation after neoadjuvant chemotherapy. Ann Surg Oncol 2005;12(6):480–7. 26. Loibl S, von Minckwitz G, Raab G, et al. Surgical procedures after neoadjuvant chemotherapy in operable breast cancer: results of the GEPARDUO trial. Ann Surg Oncol 2006;13(11):1434–42. 27. Newman LA, Buzdar AU, Singletary SE, et al. A prospective trial of preoperative chemotherapy in resectable breast cancer: predictors of breast-conservation therapy feasibility. Ann Surg Oncol 2002;9(3): 228–34. 28. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97(3):188–94. 29. Lannin DR, Grube B, Black DS, Ponn T. Breast tattoos for planning surgery following neoadjuvant chemotherapy. Am J Surg 2007 Oct; 194(4):518–20. 30. Hata T, Takahashi H, Wataanabe K, et al. Magnetic resonance imaging for preoperative evaluation of breast cancer: a comparative study with mammography and ultrasonography. J Am Coll Surg 2004;198: 190–7. 31. Onesti JK, Mangus BE, Helmer SD, Osland JS. Breast cancer tumor size: correlation between magnetic resonance imaging and pathology measurements. Am J Surg 2008;196:844–50. 32. Schouten van der Velden AP, Boetes C, Bult P, Wobbes T. The value of magnetic resonance imaging in diagnosis and size assessment of in situ and small invasive breast cancer. Am J Surg 2006; 192:172–8. 33. Berg WA, Gutierrez L, NessAiver MS, et al. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004 Dec;233(3): 830–49. Epub 2004 Oct 14. 34. Shoma A, Moutamed A, Ameen M, Abdelwahab A. Ultrasound for accurate measurement of invasive breast cancer tumor size. Breast J 2006 May-Jun;12(3):252–6.

H. Karanlik et al. / EJSO 41 (2015) 1226e1233 35. Macmillan RD, Purushotham AD, George WD. Local recurrence after breast-conserving surgery for breast cancer. Br J Surg 1996;83(2): 149–55. 36. Luu HH, Otis CN, Reed Jr WP, Garb JL, Frank JL. The unsatisfactory margin in breast cancer surgery. Am J Surg 1999;178(5):362–6. 37. Chagpar AB, Martin 2nd RC, Hagendoorn LJ, Chao C, McMasters KM. Lumpectomy margins are affected by tumor size

1233

and histologic subtype but not by biopsy technique. Am J Surg 2004;188(4):399–402. 38. Moore MM, Borossa G, Imbrie JZ, et al. Association of infiltrating lobular carcinoma with positive surgical margins after breastconservation therapy. Ann Surg 2000;231(6):877–82.