Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients

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EJSO 38 (2012) 44e51

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Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients M. Meier-Meitinger a,1, C. Rauh b,1, B. Adamietz a, P.A. Fasching b,c,*, S.A. Schwab a, L. Haeberle b, A. Hein b, C.M. Bayer b, M.R. Bani b, M.P. Lux b, A. Hartmann d, D.L. Wachter d, M. Uder a, R. Schulz-Wendtland a, M.W. Beckmann b, K. Heusinger b a

University Breast Centre Franconia, Institute of Diagnostic Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Maximiliansplatz 1, 91054 Erlangen, Germany b University Breast Centre Franconia, Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University ErlangenNuremberg, Universitaetsstrasse 21-23, 91054 Erlangen, Germany c University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA d University Breast Centre Franconia, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstrasse 21, 91054 Erlangen, Germany Accepted 10 October 2011 Available online 26 October 2011

Abstract Background: Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. Methods: The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. Results: In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. Conclusion: Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned. Ó 2011 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; Tumour size; Re-excision; Mastectomy; Ultrasound

Introduction

* Corresponding author. University Breast Centre Franconia, Department of Gynaecology and Obstetrics, University Hospital Erlangen, FriedrichAlexander University Erlangen-Nuremberg, Universitaetsstrasse 21-23, 91054 Erlangen, Germany. Tel.: þ49 9131 91 88 0611; fax: þ49 9131 91 88 0119. E-mail address: [email protected] (P.A. Fasching). 1 These authors contributed equally to this work. 0748-7983/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2011.10.008

Improvements in cancer therapy try to balance quality of life against aggressiveness of therapy. One example is the introduction of breast conserving surgery (BCS) and subsequent radiation for breast cancer patients, improving cosmetic results of the surgery without compromising oncological safety.1,2 Another example for the improvement of surgical treatment is the introduction of sentinel node biopsy. Removing only the first axillary lymph nodes

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reduced subsequent lymphedema prevalence drastically, without leading to more recurrences.3 Furthermore, during the last decade the systematic implementation of quality assured patient care and certification of breast centres has been a successful effort in Germany and all across Europe.4 The German Cancer society (DKG), the German Society for Senology (DGS) and the European Society for Mastology (EUSOMA) have discussed several markers for quality standards. The proportion of patients treated with sentinel node biopsy, the proportion of patients with BCS, and the proportion of patients with one breast surgery instead of many are some of these markers. This article concerns with the two latter quality markers, which challenge the interdisciplinary communication between radiologists, surgeons, oncologists and pathologists.5 Pretherapeutic tumour size assessment has a direct influence on the decisions of surgeons and oncologists. A large tumour is considered to be eligible for neoadjuvant therapy, either to monitor the therapy or to increase the rate of BCS. Eligibility for BCS is assessed by the breast surgeon on the basis of tumour size, the ratio of tumour size to breast size and the location of the tumour. In our analysis we explored the association between the accuracy of tumour size assessment and the risk for repeated surgeries in patients for whom a primary BCS was planned. Previously, we could show, that mammographic density, multifocality, the presence of an in situ component and tumour size was independently associated with a higher rate of reexcisions.6 Suboptimal or inaccurate clinical staging may therefore lead to incorrect decision-making regarding subsequent surgical procedures. It has been shown that several diagnostic methods have different accuracies concerning the tumour size assessment.7 In some subgroups of patients the over- and underestimation can be even greater than 1 cm.8,9 The focus of this new study is to explore whether the accuracy of the preoperative tumour size assessment has an influence on the rate of re-excisions and mastectomies. Patients and methods Patients Patients were selected from a consecutive cohort of 3054 patients with invasive breast cancer, who have been treated from January 2003 to December 2009 at the University Breast Centre Franconia. The cohort comprised self referred women, women who were referred by their primary-care physician due to a suspicious finding, and women who took part in the population-based mammography screening program. Patient and tumour characteristics, treatment data and follow-up have been documented as part of quality assured patient care. The documented data is broadly consistent with the documentation guidelines established by the European Society of Mastology (EUSOMA) and the German Society of Mastology and the German Cancer Society.4 Patients were eligible, if they

45

were at least 18 years old and if the invasive breast cancer was diagnosed by core needle biopsy. Mammogram (MG) had to be performed at the breast centre. Additionally, at least one of the diagnostic methods clinical examination (CE) or ultrasound (US) had to be available as well. Exclusion of patients was done in the following hierarchical order: MG was not performed at the breast centre (n ¼ 154), previous neoadjuvant chemotherapy (n ¼ 681), primary mastectomy (n ¼ 488). Patients have been excluded as well, if the first surgery resulted in a mastectomy due to intraoperative findings (n ¼ 72). The rate of repeated surgeries and mastectomies in women with a tumour size under 0.5 cm and over 5 cm was so low and high respectively, that it seemed unreasonable to include these patients into the analysis (exclusion of 68 patients). Patients gave informed consent for storage of their data, use for scientific analysis and the assurance of quality control of breast cancer treatment. Additionally the Ethics Committee of the medical faculty of the University Hospital approved the study. A total of 1591 women were included in our analysis.

Diagnostics and surgical procedure The breast lesions were assessed using MG, US and CE. The two largest diameters were documented. For standard mediolateral-oblique and craniocaudal mammograms one of the following mammography systems was used: Mammomat Novation, Mammomat 3000, Mammomat 3 (all Siemens AG, Erlangen, Germany), or Fischer SenoScan (Fischer Imaging Corporation, Denver, USA). Bilateral breast B-mode US was performed with one of the following ultrasound devices: Acuson-Antares, Sonoline-Adara or Sonoline-G60S (Siemens AG, Erlangen, Germany) with 10.0 MHz linear transducers. The maximum dimension of the hypoechoic core of the tumour without involvement of hyperechoic halo was measured to the nearest millimetre. Concerning the surgical procedure, mammographic bracket wire localization was the standard procedure. All patients underwent wide local tumour excision, with ventral excision extending to the skin and dorsal excision extending to the pectoral fascia. Aim during the surgical procedure was to achieve tumour free margins of more than 1 cm. The tumour specimen was marked threedimensionally and assessed radiographically. When necessary, the radiologist recommended a re-excision during primary surgery in order to confirm the radiographic completeness of the resection. Additionally, the pathologist assessed the tumour margins macroscopically and recommended a re-excision, if the specimen margins were not clear of tumour. In the other cases re-excision was performed as a second operation if one or more positive margins were found at final histological examination of the surgical specimen. Margins were defined as pathologically

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positive when invasive or in situ disease was found directly in the ink marked cut edge of the specimen. Histopathological features like tumour staging (pT), grading (G), hormone receptor (HR) status and HER2/neu (HER2) status were performed by standard histopathological procedures in one institution.

For 1316 (83%) a single surgery was sufficient to remove the tumour with free margins. At least one additional surgery was performed on 275 (17%) patients due to positive margin status after the first breast operation. In 138 patients (9%) a mastectomy was ultimately necessary. Univariate associations with re-excision status

Statistical considerations Patients were grouped according to their re-excision and mastectomy status (outcomes). Patient characteristics were summarized as median and range or frequency and percentage. For the assessment of differences between the groups, appropriate unpaired tests were used. Continuous characteristics were compared with t-tests and c2-tests or Fisher’s exact tests were used for categorical characteristics. Multiple logistic regression models were developed to identify patient characteristics that where associated with the outcomes. For each outcome two settings were analysed: One with all patient characteristics and simple differences between the pathological tumour size and the measurement methods as predictors, and another one with all patient characteristics and percent adjusted differences as predictors. In order to get stable variable selection results, the selection procedure was carried out repetitively on 500 bootstrap samples.10 On each bootstrap sample a stepwise backward model selection starting with all predictors were performed to obtain the best model according to the Akaike information criterion. The retained predictors of each bootstrap sample were recorded and a final variable selection was done according to Sauerbrei and Schumacher.11 Adjusted Odds ratios (ORs) of finally selected predictors are shown. The predictive ability of the final model was measured by the area under the curve (AUC) of the receiver operation characteristic. Considering overfitting, the AUCs were evaluated with 10-fold cross validation with 20 repetitions and with the .632þ bootstrapping method with 500 bootstrap samples.12,13 All of the tests were two-sided, and a P value < 0.05 was regarded as statistically significant. Calculations were carried out using the R system for statistical computing (version 2.11.1; R Development Core Team, Vienna, Austria, 2010). Results Patient characteristics The study included 1591 patients with primary invasive breast cancer. Patient and tumour characteristics are presented in Table 1a and 1b Patients were in median 59 years old (range 25e89). Tumours had a median size of 15 mm (range 5e50). Clinical examination, mammogram and ultrasound underestimated the tumours in average by median of 1 mm (range 25 to 42 mm) respectively.

Comparing the groups of patients with one surgery with patients, who had at least two surgeries, showed some differences in the univariate analysis (Table 1a). Patients with larger tumours, multifocal tumours or tumours with in situ components were more likely to require multiple surgeries. Interestingly patients with a positive HER2 status were more likely to have to undergo a second surgery as well. Age, nodal status, grading, ER and PRstatus and mammographic density had no significant influence on the re-excision rate. As expected the median of the difference between the pathological tumour size and the clinical examination d(clin) was higher in the group of patients, who needed a re-excision (0 mm vs. 2 mm). Similar effects were seen for the difference concerning the mammographic size assessment d(MG) (1 mm vs. 2 mm) and the ultrasound assessment d(US) (0 mm vs. 2 mm). In order to adjust for initial tumour size, percent differences with reference to the pathological tumour size dp(clin), dp(MG) and dp(US) were compared between the groups as well. Tumours in the group of patients who needed a re-excision had an underestimation of tumour size with a median of 12%, whereas estimation of tumour size in the group of patients with one surgery was quite accurate (medians 0e5%). Differences between the groups remained significant for the percent adjusted differences except for the clinical examination. Similar effects were seen, when comparing the patients, who ultimately needed a mastectomy with those, who did not (Table 1b), however the percent adjusted deviations (dp) showed no significant differences between the two groups, nor did HER2 status. Multivariate analysis for the prediction of re-excision status To adjust for possible confounders, logistic regression models were built for re-excision and mastectomy as outcome variables. For each outcome variable, models were built either with the simple difference between pathological tumour size and measurement method [d(clin), d(MG) and d(US)] (Table 2a), or with the tumour size adjusted percent deviation [dp(clin), dp(MG) and dp(US)] (Table 2b). For the outcome variable “re-excision” the variable ultrasound measurement error remained in both final regression models (i.e. the simple deviation and the percent deviation) and so did HER2 status, incidence of an in situ component, multifocality and nodal status (Table 2a). Per

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Table 1a Patient and tumour characteristics and their association with re-excision. (d(clin): difference between pathological tumour size and assessment by clinical examination; d(MG): difference between pathological tumour size and assessment by mammogram; d(US): difference between pathological tumour size and assessment by ultrasound; dp(clin), dp(MG) and dp(US) are the respective percent differences with reference to the pathological tumour size; ER: Estrogen receptor status; PR: Progesterone receptor status; HER2: HER2/neu status; MD: ACR-BIRADS mammographic density; SD: standards deviation). Characteristic

Pathological tumour size in mm Age d(clin) d(MG) d(US) dp(clin) dp(MG) dp(US) HER2 Multifocality In situ Component Histology

Tumour size Staging Nodal status Grading

ER PR MD

Neg Pos No Yes No Yes Ductal Lobular Other pT1 pT2 Neg Pos 1 2 3 Neg Pos Neg Pos 1 2 3 4

All (N ¼ 1591)

No Re-excision (N ¼ 1316)

At Least One Re-excision (N ¼ 275)

Median (range) or count (percentage)

Mean (range) or count (percentage)

Mean (range) or count (percentage)

15 (5e50)

15 (5e46)

17 (5e50)

<0.00001

59 (25, 89) 1 (28, 40) 1 (25, 42) 1 (25, 42) 5 (500, 100) 6 (200, 100) 6 (340, 100) 1236 (100) 188 (100) 1301 (100) 268 (100) 654 (100) 921 (100) 1243 (100) 236 (100) 108 (100) 1169 (100) 420 (100) 1157 (100) 420 (100) 271 (100) 903 (100) 376 (100) 261 (100) 1201 (100) 414 (100) 1047 (100) 154 (100) 439 (100) 344 (100) 91 (100)

59 (25, 89) 0 (28, 28) 1 (25, 29) 0 (25, 31) 0 (500, 100) 5 (200, 100) 0 (340, 100) 1039 (84) 136 (72) 1139 (88) 159 (59) 594 (91) 712 (77) 1044 (84) 179 (76) 90 (83) 1006 (86) 309 (74) 981 (85) 329 (78) 233 (86) 738 (82) 315 (84) 216 (83) 994 (83) 340 (82) 869 (83) 137 (89) 361 (82) 285 (83) 75 (82)

57 (32, 88) 2 (27, 40) 2 (18, 42) 2 (17, 42) 12 (233, 100) 12 (150, 100) 12 (233, 100) 197 (16) 52 (28) 162 (12) 109 (41) 60 (9) 209 (23) 199 (16) 57 (24) 18 (17) 163 (14) 111 (26) 176 (15) 91 (22) 38 (14) 165 (18) 61 (16) 45 (17) 207 (17) 74 (18) 178 (17) 17 (11) 78 (18) 59 (17) 16 (18)

<0.01 <0.001 <0.01 <0.00001 0.09 0.02 0.02 <0.0001

10 mm, that the tumour was underestimated, the risk for a re-excision was increased with an OR of 1.9 (95% CI: 1.4e2.6). Per 100 percent underestimation the risk was increased with an OR of 3.3 (95% CI: 1.6e6.9). Interestingly HER2 status remained in both final regression models. Patients with a positive HER2 status seemed to have an increased risk for a re-excision with an OR of 2.0 (95% CI: 1.05e3.8). Concerning the outcome variable “mastectomy” (Table 2b), multifocality and sonographical tumour size deviation were independently associated with a higher mastectomy rate. However, building a model with the percentage of the deviation, multifocality and pathological tumour size were found to be the only independent predictors and the sonographical tumour size assessment was not part of this model any more. The AUC, which measures the model’s predictive strength, was between 0.75 and 0.77 for the prediction of

P-Value

<0.00001 <0.00001 <0.01 <0.00001 <0.01 0.24

1.00 0.69 0.26

a re-excision and between 0.80 and 0.82 for the prediction of a mastectomy (Tables 2a and 2b). Analysis for unifocal tumors In the above described logistic regression models, multifocality was the predominant factor with ORs between 5.8 and 11.5. However the majority of tumours were not multifocal (n ¼ 1301; 82%). Additionally it seems trivial that a multifocal tumour, which was not described as multifocal before surgery, could lead to multiple surgeries. Therefore we repeated the construction of our regression models just for the subgroup of patients with unifocal tumours. Data concerning re-excision is shown in Table 3. Sonographical deviations remained in the same final models. However the effect sizes seemed to be a little bit greater, pointing at a more important role of sonographical tumour size assessment in the group of unifocal tumours. Per

48

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Table 1b Patient and tumour characteristics and their association with mastectomy. (d(clin): difference between pathological tumour size and assessment by clinical examination; d(MG): difference between pathological tumour size and assessment by mammogram; d(US): difference between pathological tumour size and assessment by ultrasound; dp(clin), dp(MG) and dp(US) are the respective percent differences with reference to the pathological tumour size; ER: Estrogen receptor status; PR: Progesterone receptor status; HER2: HER2/neu status; MD: ACR-BIRADS mammographic density; SD: standards deviation). Characteristic

Pathological Tumour Size in mm Age d(clin) d(MD) d(US) dp(clin) dp(MG) dp(US) HER2 Multifocality In situ Component Histology

Tumour size Staging Nodal status Grading

ER PR MD

Neg Pos No Yes No Yes Ductal Lobular Other pT1 pT2 Neg Pos 1 2 3 Neg Pos Neg Pos 1 2 3 4

All (N ¼ 1591)

Breast Conserving (N ¼ 1453)

Mastectomy (N ¼ 138)

Median (Range) or Count (Percentage)

Mean (Range) or Count (Percentage)

Mean (Range) or Count (Percentage)

15 (5, 50)

15 (5, 50)

19 (6, 50)

<0.00001

59 (25, 89) 1 (28, 40) 1 (25, 42) 1 (25, 42) 5 (500, 100) 6 (200, 100) 6 (340, 100) 1236 (100) 188 (100) 1301 (100) 268 (100) 654 (100) 921 (100) 1243 (100) 236 (100) 108 (100) 1169 (100) 420 (100) 1157 (100) 420 (100) 271 (100) 903 (100) 376 (100) 261 (100) 1201 (100) 414 (100) 1047 (100) 154 (100) 439 (100) 344 (100) 91 (100)

59 (25, 89) 1 (28, 28) 1 (25, 29) 1 (25, 39) 5 (500, 100) 5 (200, 100) 5 (340, 100) 1141 (92) 170 (90) 1235 (95) 198 (74) 626 (96) 815 (88) 1150 (92.5) 200 (85) 100 (93) 1095 (94) 357 (85) 1080 (93) 364 (87) 254 (94) 817 (90.5) 348 (93) 236 (90) 1106 (92) 379 (91.5) 962 (92) 145 (94) 400 (91) 305 (89) 85 (93)

57 (32, 88) 2 (27, 40) 2 (12, 42) 2 (17, 42) 13 (212, 100) 13 (150, 100) 15 (212, 100) 95 (8) 18 (10) 66 (5) 70 (26) 28 (4) 106 (12) 93 (7.5) 36 (15) 8 (7) 74 (6) 63 (15) 77 (7) 56 (13) 17 (6) 86 (9.5) 28 (7) 25 (10) 95 (8) 35 (8.5) 85 (8) 9 (6) 39 (9) 39 (11) 6 (7)

0.02 0.02 <0.01 <0.001 0.78 0.30 0.16 0.37

10 mm deviation OR was 2.6 (95%CI: 1.7e4.0) with regard to the re-excision rate. Again HER2 status seemed to have an influence on the re-excision rate as well. With regard to the outcome parameter mastectomy, ultrasound deviation remained in the regression model including the absolute deviation but not in the model concerning the respective percent adjusted variable. Per 10 mm deviation the OR was 3.4 (95%CI: 1.9e6.3). Discussion In this retrospective study we showed that some tumour and diagnostic characteristics e especially multifocality, the incidence of an in situ component, a positive HER2 status and the preoperative sonographical tumour size underestimation e are independent predictors for the need of a second surgery and a mastectomy in patients for whom a primary BCS was planned. The issue is clinically

P-Value

<0.00001 <0.00001 <0.001 <0.00001 <0.0001 0.17

0.37 0.83 0.19

important because it has been shown in some studies, that the number of re-excisions which are required to obtain negative margins, are associated with an increased risk of local recurrence.14,15

Comparison with other studies The rate of re-excision in our study (17.3%) lies within the range of repeated surgeries in other studies (10%e 57%).6,16e21 Our study could confirm risk factors such as age, tumour size and tumour stage, multifocality and the presence of an in situ component.6,18,19,22 Other factors such as mammographic density could not be confirmed as being significantly associated with the number of surgeries ( p ¼ 0.26), although the direction of the previously reported effect was the same.9 Women with a higher density

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Table 2a Multiple logistic regression with stepwise backwards variable selection for the prediction of the need of a re-excision (final model). Only datasets with all available variables were used (n ¼ 607). Predictive strength of the models are provided as area under the curve (AUC) of receiver operating characteristic, invalidated), bootstrap validated)) and cross-validated))). (HER2: HER2/neu status. d(US): absolute difference between ultrasound assessment and pathological tumour size; dp(US): percentage with of d(US) with regard to pathological tumour size). Characteristic

N

OR (95% CI)

Prediction of reexicision including tumour size assessment deviation as absolute differences (AUC ¼ 0.77)/0.76))/0.76)))) HER2 Neg 530 1 (reference) Pos 77 2.0 (1.1, 3.8) Multifocality No 500 1 Yes 107 5.8 (3.5, 9.7) In situ Component No 259 1 Yes 348 1.9 (1.1, 3.3) d(US) per cm 607 1.9 (1.4, 2.6) Nodal Status Negative 259 1 Positive 348 1.7 (1.04, 2.9) Prediction of re-excision including tumour size assessment deviation as percent deviation (AUC ¼ 0.76)/0.75))/0.75)))) HER2 Negative 530 1 (reference) Positive 77 2.0 (1.04, 3.7) Multifocality No 500 1 (reference) Yes 107 6.05 (3.6, 10.1) In situ Component No 259 1 (reference) Yes 348 1.8 (1.1, 3.2) dp(US) Per 100% 607 3.3 (1.6, 6.9) Nodal Status Negative 259 1 (reference) Positive 348 1.8 (1.1, 3.0)

P-Value e 0.03 e < 0.00001 e 0.02 <0.001 e 0.03 e 0.03 e < 0.00001 e 0.02 < 0.01 e 0.02

Table 2b Multiple logistic regression with stepwise backwards variable selection for the prediction of the need of a mastectomy (final model). Only datasets with all available variables were used (n ¼ 607). Predictive strength of the models are provided as area under the curve (AUC) of receiver operating characteristic, invalidated), bootstrap validated)) and cross-validated))). (d(US): absolute difference between ultrasound assessment and pathological tumour size). Characteristic

N

OR (95% CI)

P-Value

Prediction of mastectomy including tumour size assessment deviation as absolute differences (AUC ¼ 0.82)/0.81))/0.81)))) Multifocality No 500 Yes 107 11.5 (6.2, 22.1) d(US) Per cm 607 1.8 (1.3, 2.7)

e <0.00001 <0.01

Prediction of mastectomy including tumour size assessment deviation as percent deviation (AUC ¼ 0.82)/0.80))/0.80)))) Pathological tumour size Per cm 607 1.7 (1.3e2.4) Multifocality No 500 1 (Reference) Yes 107 10.9 (5.8, 21.0)

<0.001 e <0.00001

Table 3 Multiple logistic regression with stepwise backwards variable selection for the prediction of the need of a re-excision in the subgroup of unifocal and unicentric tumours (final model). Only datasets with all available variables were used (n ¼ 500). Predictive strength of the models are provided as area under the curve (AUC) of receiver operating characteristic, invalidated), bootstrap validated)) and cross-validated))). (HER2: HER2/neu status. d(US): absolute difference between ultrasound assessment and pathological tumour size; dp(US): percentage with of d(US) with regard to pathological tumour size). Characteristic

N

OR (95% CI)

Prediction of reexicision including tumour size assessment deviation as absolute differences (AUC ¼ 0.70)/0.68))/0.68)))) HER2 Neg 437 1 Pos 63 2.8 (1.3, 5.9) In situ Component No 225 1 Yes 275 1.8 (0.9, 3.6) d(US) Per cm 500 2.6 (1.7, 4.0) Grading Per increasing category 500 0.7 (0.4, 1.2) Prediction of re-excision including tumour size assessment deviation as percent deviation (AUC ¼ 0.71)/0.66))/0.66)))) Pathological Tumour size Per cm 500 1.9 (1.3, 2.9) HER2 Negative 437 Positive 63 2.5 (1.1, 5.4) In situ Component No 225 Yes 275 1.8 (0.9, 3.6) dp(US) Per 100% 500 2.11 (0.7, 7.2) Grading Per increasing category 500 0.62 (0.4, 1.08)

P-Value e <0.01 e 0.09 <0.00001 0.17 <0.01 0.02 0.08 0.22 0.08

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seemed to have a non-significant higher rate of reexcisions. Aim of our study was to investigate the preoperative tumour size assessment and the underestimation seemed to be the main problem concerning ultrasound measurements with regard to re-excision rates. In accordance to other studies ultrasonography underestimated the size of breast lesions.7,8,23,24 The hyperechoic halo was not included in our tumour size assessment. This could be one of the reasons for underestimation. There is data that inclusion of the hyperechoic halo could minimize tumour underestimation in some tumours.25 There are no standards, whether to include this tumour imaging feature into tumour size assessment or not. It is known, that not all tumours have a hyperechoic halo. The histological and molecular nature of this halo is not well understood either.26 Role of molecular subtypes Different from other studies our study has found HER2 status as being predictive for the need of a re-excision. If this is a true finding, it would give interesting implications, how molecular features interact with histological and macroanatomical features and ultimately result in an altered presentation in imaging methods. There is some evidence, that tumours have different imaging appearances according to their molecular subtype. In a recent study HER2 overexpressing tumours seemed to be ill-defined in the ultrasound exam.26 Other subtypes like the basal like tumours were reported to have less likely a halogenic echo in this study and luminal-like tumours seemed to have distally attenuating tumours. We do not have additional data on the appearance of the tumours but the fact, that tumours with a positive HER2 status were associated with a higher percentage of re-excisions would be in concordance of a difficult delineation of the tumours in the ultrasound. HER2 status could therefore serve as an indicator for possible additional imaging methods for better assessment of these tumours. Clinical implications Knowing that tumour size assessment has an impact on the re-excision rate, it would be logical to improve the assessment at least for tumours that have a high risk for reexcision. Factors that are available preoperatively are age, tumour type and HER2 status. Having these indicators, patients with a high risk for re-excisions could be examined with further imaging methods or the surgeon could prepare for additional intraoperative measures. Preoperatively, tumour size assessment by magnet resonance imaging could be helpful in those patients. Moreover it was shown that a more accurate tumour size assessment could be achieved by the use of elastography.25 Intraoperative radiograms have been used as a standard in all of our patients, and this procedure should be the standard of care. The strength of this approach is, that the

margins can be assessed not only for the visible tumour mass, but also in relation to ductal carcinoma in situ. The method is capable of identifying positive margins intraoperatively and can reduce the need for a second operation, as it allows immediate re-excision.27e29 Nevertheless multifocality and the incidence of an in situ component did have an influence on the re-excision rate, implying that not all in situ components at the specimen margin can be detected with this method. Another way, that has been discussed to reduce the need for further surgeries, is the intraoperative assessment of frozen-section analysis of tumour margins. We did not use this procedure in our present study. But it could be taken into consideration, to reduce the need for a second operation in patients that are at high risk. In comparison with the final histopathological findings, this method has been reported to provide a false-positive rate of between 0% and 1.1% and false-negative rates of 0.1% and 4.4%.30 The costs of this procedure and its accuracy, particularly in smaller tumours, need to be taken into consideration as well. Conclusion We could show that accuracy of preoperative tumour size assessment has an influence on the number of re-excisions and even on the number of mastectomies. The accurate tumour size assessment and the interdisciplinary use of this data seem to be necessary to protect patients from second surgeries. Our data provide promising results implying that it might be possible to identify women, who are at high risk for a second surgery. It has to be investigated in further studies, which measures like elastography, MRI or automated whole breast ultrasound have to be taken to provide the interdisciplinary team within a breast centre with the necessary information to reduce the rate of second surgeries. Conflict of interest None of the authors has any financial and personal relationships with other people or organizations to disclose that could inappropriately influence their work. This includes employment relationships, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding, except KH, who is funded by the ELAN grant program of the University Hospital Erlangen.

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